Ethnic disparities in cancer mortality in the capital and northeast of the State of São Paulo, Brazil 2001-17.

PURPOSE: There is a paucity of studies investigating cancer disparities in groups defined by ethnicity in transitioning economies. We examined the influence of ethnicity on mortality for the leading cancer types in São Paulo, Brazil, comparing patterns in the capital and the northeast of the state. METHODS: Cancer deaths were obtained from a Brazilian public government database for the Barretos region (2003-2017) and the municipality of São Paulo (2001-2015). Age-standardized rates (ASR) per 100,000 persons-years, by cancer type and sex, for five self-declared racial classifications (white, black, eastern origin (Asian), mixed ethnicity (pardo), and indigenous Brazilians), were calculated using the world standard population. RESULTS: Black Brazilians had higher mortality rates for most common cancer types in Barretos, whereas in São Paulo, white Brazilians had higher rates of mortality from breast, colorectal, and lung cancer. In both regions, lung cancer was the leading cause of cancer death among white, black, and pardo Brazilians, with colorectal cancer deaths leading among Asian Brazilians. Black and pardo Brazilians had higher cervical cancer mortality rates than white Brazilians. CONCLUSION: There are substantial disparities in mortality from different cancers in São Paulo according to ethnicity, pointing to inequities in access to health care services.

Colorectal cancer spatial pattern in the northeast region of São Paulo, Brazil.

Background: This study examined the spatial pattern of the colorectal cancer (CRC) in the 18 municipalities that compose the Regional Health Department of Barretos (RHD-V), which is in the northeast of the state of São Paulo, Brazil. Methods: All incident cases and deaths from CRC between 2002 and 2016 were included. Age-standardized rates (ASR) for incidence and mortality per 100,000 person-years were used to evaluate the spatial distribution for the total and five-year periods. The lethality rates were also assessed. Excess risk maps compared the observed and expected events. Age-standardized net survival was used to evaluate CRC survival. Results: For CRC incidence, the ASR value for the general population over the entire period (2002-2016) was 17.7 (95% CI: 16.7, 18.6), ranging from 16.7 (95% CI: 14.9, 18.4) (2002-2006) to 20.0 (95% CI: 18.3, 21.7) (2012-2016) per 100,000. When males and females were compared, the ASR was 20.1 (95% CI: 18.6, 21.6) and 15.7 (95% CI: 14.5, 17.0) per 100,000, respectively. For CRC mortality (2002-2016), the ASR was 8.2 (95% CI: 7.6, 8.9), ranging from 9.0 (95% CI: 7.8, 10.3) (2002-2006) to 8.2 (95% CI: 7.2, 9.3) (2012-2016) per 100,000. Overall, the excess risk up to 2.0 was more frequent. In terms of survival, municipalities with large port populations had lower survival in comparison with medium port. Conclusions: This study showed a variation in CRC incidence and mortality, with differences considering five-year periods and gender, being the incidence higher in males than females in the entire period, with mortality equivalent to half the incidence. The survival was lower in municipalities with large port populations in comparison with medium port. Knowing spatial patterns of incidence, mortality, lethality, and survival can be necessary to support policymakers to advance or implement effective cancer control programs.

Thyroid Cancer Incidence and Mortality by Socioeconomic Level in the State of São Paulo, Brazil 2001-2017.

OBJECTIVE: Thyroid cancer is rising largely due to greater detection of indolent or slow-growing tumors; we sought to compare the incidence and mortality profiles of thyroid cancer in the State of São Paulo by socioeconomic status (SES). METHODS: Data on thyroid cancer cases diagnosed from 2003 to 2017 in the Barretos Region and from 2001 to 2015 in the municipality of São Paulo were obtained from the respective cancer registries. Corresponding death data were obtained from a Brazilian public government database. Age-standardized rates were calculated and presented as thematic maps. The rates were also calculated by SES and spatial autocorrelation was assessed by global and local indices. RESULTS: There were 419 cases of thyroid cancer and 21 deaths in Barretos, contrasting with the highly populated São Paulo, with 30 489 cases and 673 deaths. The overall incidence rates in São Paulo (15.9) were three times higher than in Barretos (5.7), while incidence rates in women were close to five times higher in Barretos and four times higher in São Paulo than in men. Mortality rates were, in relative terms, very low in both regions. A clear stepwise gradient of increasing thyroid cancer incidence with increasing SES was observed in São Paulo, with rates in very high SES districts four times those of low SES (31.6 vs 8.1). In contrast, the incidence rates in Barretos presented little variation across SES levels. CONCLUSION: Thyroid cancer incidence varied markedly by SES in São Paulo, with incidence rates rising with increasing socioeconomic index. Overdiagnosis is likely to account for a large proportion of the thyroid cancer burden in the capital.

Geographic variations in cancer incidence and mortality in the State of São Paulo, Brazil 2001-17.

BACKGROUND: Cancer is a leading cause of morbidity and mortality in Brazil and the burden is rising. To better inform tailored cancer actions, we compare incidence and mortality profiles according to small areas in the capital and northeast region of the State of São Paulo for the leading cancer types. METHODS: New cancer cases were obtained from cancer registries covering the department of Barretos (2003-2017) and the municipality of São Paulo (2001-2015). Cancer deaths for the same period were obtained from a Brazilian public government database. Age-standardized rates per 100,000 persons-years by cancer and sex are presented as thematic maps, by municipality for Barretos region, and by district for São Paulo. RESULTS: Prostate and breast cancer were the leading forms of cancer incidence in Barretos, with lung cancer leading in terms of cancer mortality in both regions. The highest incidence and mortality rates were seen in municipalities from the northeast of Barretos region in both sexes, while elevated incidence rates were mainly found in São Paulo districts with high and very high socioeconomic status (SES), with mortality rates more dispersed. Breast cancer incidence rates in São Paulo were 30 % higher than Barretos, notably in high and very high SES districts, while corresponding rates of cervical cancer conveyed the opposite profile, with elevated rates in low and medium SES districts. CONCLUSIONS: There is substantial diversity in the cancer profiles in the two regions, by cancer type and sex, with a clear relation between the cancer incidence and mortality patterns observed at the district level and corresponding SES in the capital.

Cancer inequalities in incidence and mortality in the State of São Paulo, Brazil 2001-17.

BACKGROUND: Cancer disparities exist between and within countries; we sought to compare cancer-specific incidence and mortality according to area-level socioeconomic status (SES) in the State of São Paulo, Brazil. METHODS: Cancer cases diagnosed 2003-2017 in the Barretos region and 2001-2015 in the municipality of São Paulo were obtained from the respective cancer registries. Corresponding cancer deaths were obtained from a Brazilian public government database. Age-standardized rates for all cancer combined and the six most common cancers were calculated by SES quartiles. RESULTS: There were 14,628 cancer cases and 7513 cancer deaths in Barretos, and 472,712 corresponding cases and 194,705 deaths in São Paulo. A clear SES-cancer gradient was seen in São Paulo, with rates varying from 188.4 to 333.1 in low to high SES areas, respectively. There was a lesser social gradient for mortality, with rates in low to high SES areas ranging from 86.4 to 98.0 in Barretos, and from 99.2 to 100.1 in São Paulo. The magnitude of the incidence rates rose markedly with increasing SES in São Paulo city for colorectal, lung, female breast, and prostate cancer. Conversely, both cervical cancer incidence and mortality rose with lower levels of SES in both regions. CONCLUSIONS: A clear SES association was seen for cancers of the prostate, female breast, colorectum, and lung for São Paulo. This study offers a better understanding of the cancer incidence and mortality profile according to SES within a highly populated Brazilian state.

The Usefulness of an Online Simplified Screening Questionnaire (SSQ) in Identifying Work-Related Cancers.

To obtain a history of occupational exposure in the workplace, the questionnaire is one of the main sources of information. The aim of this study was to develop an online questionnaire using the REDCap data management platform based on the Work-Related Cancer Surveillance Guidelines, reported by the Brazilian National Cancer Institute. Several issues were taken into consideration for its routine application. It should be simple, easy, capable of being applied in a short time and used in the clinical setting of collecting information on the occupational history of the cancer patient. Consequently, this could enable the compulsory notification of work-related cancer. The questionnaire was developed based on questions about the use of and exposure to carcinogenic factors at work and due to smoking. An entirely electronic version of the cancer patient interview was performed using tablets. The online questionnaire was applied at the Barretos Cancer Hospital, Barretos, to newly diagnosed patients from July 2016 to 2018. A total of 1063 patients were included, and 550 indicated positively when asked "Do you work, or have you worked with this substance and/or in this function?/job?" Of these potentially notified patients, 38 subsequently had compulsorily reported work-related cancer. Another important result of this study was the creation and development of a website. In conclusion, we developed an online tool that could facilitate hospital routines, contributing to generating data for the compulsory notification of work-related cancer and triggering investigations and surveillance actions in Brazil.

The digital expression profile of BMP7, CDKN2C, HIST1H3G, and PKMYT1 genes improves high-grade cervical lesion detection in liquid-based cytology.

BACKGROUND: Some studies reported that differential gene expression could be used as a biomarker for high-grade cervical lesion identification. The aim was to evaluate the gene expression profile of cervical intraepithelial neoplasia (CIN) to identify a gene expression signature of CIN2+ in liquid-based cytology (LBC) samples. METHODS: LBC samples (n = 85) obtained from women who underwent colposcopy were included with benign (n = 13), CIN1 (n = 26), CIN2 (n = 16), and CIN3 (n = 30) diagnoses. After RNA isolation, gene expression profiling was performed using the nCounter PanCancer Pathways, which consists of 730 cancer-related genes. The genes identified were in silico expression evaluated using the UALCAN database. An accurate prediction model to discriminate CIN2+ from

Cancer survival in the northwestern of São Paulo State, Brazil: A population-based study.

BACKGROUND: Population-based cancer registry (PBCR) data provide crucial information for evaluating the effectiveness of cancer services and reflect prospects for cure by estimating population-based cancer survival. This study provides long-term trends in survival among patients diagnosed with cancer in the Barretos region (São Paulo State, Brazil). METHODS: In this population-based study, we estimated the one- and five-year age-standardized net survival rates of 13,246 patients diagnosed with 24 different cancer types in Barretos region between 2000 and 2018. The results were presented by sex, time since diagnosis, disease stage, and period of diagnosis. RESULTS: Marked differences in the one- and five-year age-standardized net survival rates were observed across the cancer sites. Pancreatic cancer had the lowest 5-year net survival (5.5 %, 95 %CI: 2.9-9.4) followed by oesophageal cancer (5.6 %, 95 %CI: 3.0-9.4), while prostate cancer ranked the best (92.1 %, 95 %CI: 87.8-94.9), followed by thyroid cancer (87.4 %, 95 %CI: 69.9-95.1) and female breast cancer (78.3 %, 95 %CI: 74.5-81.6). The survival rates differed substantially according to sex and clinical stage. Comparing the first (2000-2005) and last (2012-2018) periods, cancer survival improved, especially for thyroid, leukemia, and pharyngeal cancers, with differences of 34.4 %, 29.0 %, and 28.7 %, respectively. CONCLUSION: To our knowledge, this is the first study to evaluate long-term cancer survival in the Barretos region, showing an overall improvement over the last two decades. Survival varied by site, indicating the need for multiple cancer control actions in the future with a lower burden of cancer.

Using a Nominal Group Technique to Develop a Science Communication Curriculum for Health Professionals and Clinical Researchers.

Effective science communication is fundamental to closing the gap from research and innovation to clinical implementation. Existing paradigms of science communication are often challenged by a lack of skill and engagement, particularly from those who progress the science. Currently, a standardized curriculum on science communication, with global applicability, does not exist. The purpose of this project is to address the gap in training by health professionals and clinical researchers through the development of a globally relevant curriculum for science communication. The nominal group technique (NGT) was used whereby a convenience sample of eleven science communication experts from across the globe generated, discussed, and arrived at a consensus on topics that should be included in a standardized science communication curriculum. Experts represented diverse backgrounds within the health sciences. Due to the COVID-19 pandemic and geographical constraints, the NGT was conducted virtually. The consensus-building methodology allowed for each expert to equally present ideas and collaborate with one another to create a robust and comprehensive curriculum for effective science communication. Expert panelists reached a consensus on 10 essential components of a standardized global science communication curriculum. Following the refinement of the curriculum topic areas, a virtual meeting with project co-investigators was held to review the topics and discuss relevance, applicability, and appeal to the local contexts. A standardized science communication curriculum is needed for health professionals and clinical researchers. The NGT achieved expert consensus on the core topics. The next steps are to develop the course ensuring optimal participation from learners across the globe.

Deterministic linkage for improving follow-up time in a Brazilian population-based cancer registry.

Population-based cancer registries (PBCR) are the primary source of cancer incidence and survival statistics. The loss to follow-up of these patients is concerning since it reduces the reliability of any statistical analysis. The linkage techniques have been increasingly used to improve data quality in various information systems. The linkage was performed between the databases of the PBCR-Barretos and the mortality database of the state of São Paulo. To evaluate the improvement in the follow-up time of patients, the comparability of the two databases, pre- and post linkage, was made. Three analyses were performed: a comparative analysis of the absolute number of deaths, a comparative analysis of the follow-up time of patients and the survival analysis. After linkage, there was an increase of 813 deaths. The follow-up time of patients was extended and observed in most types of tumours. The comparability of the survival analyses at both time points also showed a decrease in survival probabilities for all tumour types. Deterministic linkage is effective in updating the vital status of registered patients, improving patient follow-up time, and maintaining good quality data from PBCRs, consequently producing more reliable rates, as seen for the survival analyses.

Acessibilidade do termo de consentimento na pesquisa clínica no Brasil / Accessibility of the consent form in Brazilian clinical research / Accesibilidad al formulario de consentimiento en la investigación clínica en Brasil

Resumo O termo de consentimento livre e esclarecido tem a função de informar o participante de pesquisas clínicas sobre a natureza da pesquisa e seus direitos, formalizando sua decisão de participar. Estudos indicam que esse documento é redigido de modo complexo, comprometendo a autonomia do participante. Para este trabalho, foram redigidos dois termos de consentimento da mesma pesquisa hipotética, com estilos de redação diferentes. Ambos os termos foram analisados pela ferramenta Coh-Metrix Port, que avalia métricas linguísticas e acessibilidade textual. A análise indicou que os textos são complexos e exigem alta escolaridade para serem entendidos. Esses achados reforçam a percepção de que, no Brasil, os termos de consentimento podem ter sua real função comprometida e apontam a importância de modificar sua forma de elaboração.

Abstract The informed consent form informs clinical research patients about the nature of the research and their rights, formalizing their decision to participate; however, studies show that this document is written in a complex manner, compromising patient autonomy. Two consent forms from the same hypothetical research were developed with different writing styles and analyzed by the Coh-Metrix Port tool, which evaluates linguistic metrics and textual accessibility. Results showed that both texts were complex and required high schooling level to be understood. These findings reinforce the perception that consent forms may have their real function compromised and point to the importance of changing its elaboration.

Resumen El formulario de consentimiento informado tiene la finalidad de mostrar la naturaleza de la investigación y sus derechos al participante de la investigación clínica para formalizar su decisión de participar en el estudio. Los estudios indican que la redacción de este documento es compleja, lo que compromete la autonomía del participante. Para este estudio se redactaron dos formularios de consentimiento de una misma investigación hipotética, con diferentes estilos de escritura. Para el análisis de ambos formularios se utilizó la herramienta Coh-Metrix Port, que evalúa las métricas lingüísticas y la accesibilidad textual. Los resultados apuntaron a que los textos son complejos, lo que requiere un alto nivel de educación para su comprensión. Estos hallazgos coinciden que, en Brasil, los formularios de consentimiento pueden tener su finalidad comprometida y señalan la necesidad de modificar su forma de elaboración.

Multi-task network for automated analysis of high-resolution endomicroscopy images to detect cervical precancer and cancer.

Cervical cancer is a public health emergency in low- and middle-income countries where resource limitations hamper standard-of-care prevention strategies. The high-resolution endomicroscope (HRME) is a low-cost, point-of-care device with which care providers can image the nuclear morphology of cervical lesions. Here, we propose a deep learning framework to diagnose cervical intraepithelial neoplasia grade 2 or more severe from HRME images. The proposed multi-task convolutional neural network uses nuclear segmentation to learn a diagnostically relevant representation. Nuclear segmentation was trained via proxy labels to circumvent the need for expensive, manually annotated nuclear masks. A dataset of images from over 1600 patients was used to train, validate, and test our algorithm; data from 20% of patients were reserved for testing. An external evaluation set with images from 508 patients was used to further validate our findings. The proposed method consistently outperformed other state-of-the art architectures achieving a test per patient area under the receiver operating characteristic curve (AUC-ROC) of 0.87. Performance was comparable to expert colposcopy with a test sensitivity and specificity of 0.94 (p = 0.3) and 0.58 (p = 1.0), respectively. Patients with recurrent human papillomavirus (HPV) infections are at a higher risk of developing cervical cancer. Thus, we sought to incorporate HPV DNA test results as a feature to inform prediction. We found that incorporating patient HPV status improved test specificity to 0.71 at a sensitivity of 0.94.

Cancer Statistics over Time in Northwestern São Paulo State, Brazil: Incidence and Mortality.

BACKGROUND: Population studies can serve as an essential source of information on cancer's etiology, and assessments of cancer trends over time can detect changes. This study aimed to provide statistics over time on cancer incidence and mortality in the Barretos Region, Brazil. METHODS: Cancer incidence data were obtained from the population-based cancer registry of the Barretos Region, and mortality data were obtained from the Official Federal Database from 2002 to 2016. Age-standardized rates for incidence and mortality were calculated. Joinpoint Regression software was used to estimate the average annual percentage changes (AAPC). RESULTS: Age-standardized rates of incidence increased significantly for colon cancer (AAPC: 2.2), rectum and rectosigmoid (AAPC: 2.4), liver (AAPC: 4.7), female breast (AAPC: 2.2), and thyroid cancer (AAPC: 3.8) but decreased for esophageal (AAPC: -3.2), stomach (AAPC: -4.2), lung (AAPC: -2.0), and ovarian cancer (AAPC: -5.6). The mortality increased for liver cancer (AAPC: 2.3) and decreased for pharyngeal cancer (AAPC: -5.8), stomach cancer (AAPC: -6.6), cervical uterine cancer (AAPC: -5.9), prostate cancer (AAPC: -2.4), and ovarian cancer (AAPC: -3.3). CONCLUSIONS: We observed decreases in some cancers related to tobacco smoking and cervical and stomach cancers related to infectious agents, showing strong regional and national prevention programs' successes. But, we also observed rises in many cancer sites linked to lifestyle factors, such as breast or colorectal cancer, without a sign of declining mortality. IMPACT: These results can impact and support cancer control program implementation and improvement at the community level and extrapolate to the state level and/or the whole country.

Hotspot analysis by confocal microscopy can help to differentiate challenging melanocytic skin lesions.

Some melanocytic lesions do not present enough clinical and dermoscopic features to allow ruling out a possible melanoma diagnosis. These "doubtful melanocytic lesions" pose a very common and challenging scenario in clinical practice and were selected at this study for reflectance confocal microscopy evaluation and subsequent surgical excision for histopathological diagnosis. The study included 110 lesions and three confocal features were statistically able to distinguish benign melanocytic lesions from melanomas: "peripheral hotspot at dermo-epidermal junction", "nucleated roundish cells at the dermo-epidermal junction" and "sheet of cells". The finding of a peripheral hotspot (atypical cells in 1mm2) at the DEJ is highlighted because has not been previously reported in the literature as a confocal feature related to melanomas.

ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer.

OBJECTIVE: The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer. METHODS: From April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2-IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size <2 cm; (4) no lymphovascular space invasion; (5) depth of invasion <10 mm; (6) negative imaging for metastatic disease; and (7) negative conization margins. Cervical conization was performed to determine eligibility, with one repeat cone permitted. Eligible women desiring fertility preservation underwent a second surgery with pelvic lymph node assessment, consisting of sentinel lymph node biopsy and/or full pelvic lymph node dissection. Those not desiring fertility preservation underwent simple hysterectomy with lymph node assessment. Women who had undergone an 'inadvertent' simple hysterectomy with an unexpected post-operative diagnosis of cancer were also eligible if they met the above inclusion criteria and underwent a second surgery with pelvic lymph node dissection only. RESULTS: 100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23-67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients-that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0-68.3). Three patients developed recurrent disease within 2 years of surgery-that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). DISCUSSION: Our prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

Impact of COVID-19 Pandemic on Cancer-Related Hospitalizations in Brazil.

BACKGROUND: Alongside the SARS-CoV-2 (COVID-19) pandemic, Brazil also faces an ongoing rise in cancer burden. In 2020, there were approximately 592 000 new cancer cases and 260 000 cancer deaths. Considering the heterogeneities across Brazil, this study aimed to estimate the impact of the COVID-19 pandemic on cancer-related hospital admissions at a national and regional level. METHODS: The national, regional, and state-specific monthly average of cancer-related hospital admission rates per 100 000 inhabitants and 95% confidence intervals (95% CIs) were calculated from March to July (2019: pre-COVID-19; and 2020: COVID-19 period). Thematic maps were constructed to compare the rates between periods and regions. RESULTS: Cancer-related hospital admissions were reduced by 26% and 28% for clinical and surgical purposes, respectively. In Brazil, the average hospitalization rates decreased from 13.9 in 2019 to 10.2 in 2020 per 100,000 inhabitants, representing a rate difference of -3.7 (per 100,000 inhabitants; 95% CI: -3.9 to -3.5) for cancer-related (clinical) hospital admissions. Surgical hospital admissions showed a rate decline of -5.8 per 100,000 (95% CI: -6.0 to -5.5). The reduction in cancer-related admissions for the surgical procedure varies across regions ranging between -2.2 and -10.8 per 100 000 inhabitants, with the most significant decrease observed in the south and southeastern Brazil. CONCLUSIONS: We observed a substantial decrease in cancer-related hospital admissions during the COVID-19 pandemic with marked differences across regions. Delays in treatment may negatively impact cancer survival in the future; hence, cancer control strategies to mitigate the impact are needed.

Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the histologic response rate of high-grade squamous intraepithelial lesions (HSIL) of the cervix after topical application of 5% imiquimod cream. METHODS: In this phase II trial, women with cervical HSIL (cervical intraepithelial neoplasia [CIN] 2-3) were randomly assigned to 250 mg of 5% imiquimod cream applied to the cervix weekly for 12 weeks, followed by loop electrosurgical excision procedure (LEEP) without preceding treatment. The sample size was calculated based on the HSIL regression rates previously reported by Grimm et al. The primary outcome was rate of histologic regression (to CIN 1 or less) in LEEP specimens. Prespecified secondary endpoints included surgical margin status and adverse events. Outcomes were stratified by human papillomavirus type and lesion grade (CIN 2 or CIN 3). Results were reported according to per protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: Ninety women were enrolled: 49 in the experimental group and 41 in the control group. In the PP population, histologic regression was observed in 23 of 38 participants (61%) in the experimental group compared with 9 of 40 (23%) in the control group (P=.001). Surgical margins were negative for HSIL in 36 of 38 participants (95%) in the experimental group and 28 of 40 (70%) in the control group (P=.004). In the ITT population, rates of histologic regression also were significantly higher in the experimental group. Rates of adverse events in the experimental group were 74% (28/38) in the PP population and 78% (35/45) in the ITT population. Adverse events were mild, with abdominal pain being the most common. Three patients in the experimental group had grade 2 adverse events, including vaginal ulcer, vaginal pruritus with local edema, and moderate pelvic pain. CONCLUSION: Weekly topical treatment with imiquimod is effective in promoting regression of cervical HSIL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03233412.

MicroRNA Biomarkers of High-Grade Cervical Intraepithelial Neoplasia in Liquid Biopsy.

New prevention strategies are needed to detect cervical intraepithelial neoplasia (CIN). The microRNA expression analysis has already been reported as molecular biomarkers in the early detection of cervical cancer (CC) through minimally invasive samples, such as liquid biopsy, obtained through collection using liquid-based cytology (LBC). In this study, we aimed to identify molecular signatures of microRNAs in cervical precursor lesions from LBC cervical and the molecular pathways potentially associated with the CC progression. We analyzed 31 LBC cervical samples from women who underwent colposcopy. These samples were divided into two groups: the first group was composed of samples without precursor lesions of CC, considering the control group, referred to as healthy female subjects (HFS; n = 11). The second group corresponded to women diagnosed with cervical interepithelial neoplasia grade 3 (CIN 3; n = 20). We performed microRNA and gene expression profiling using the nCounter® miRNA Expression Assays (NanoString Technology) and PanCancer Pathways (NanoString Technology), respectively. A microRNA target prediction was performed by mirDIP, and molecular pathway interaction was constructed using Cytoscape. Bidirectional in silico analyses and Pearson's correlation were performed for associated the relation between genes, and miRNAs differentially expressed related cervical cancer progression were performed. We found that the expression of nine microRNAs was significantly higher, two were downregulated (miR-381-3p and miR-4531), and seven miRNAs were upregulated (miR-205-5p, miR-130a-3p, miR-3136-3p, miR-128-2-5p, let-7f-5p, miR-202-3p, and miR-323a-5p) in CIN 3 (fold change ≥ 2 and p ≤ 0.05). The miRNA expression patterns were independent of hr-HPV infection. We identified four miRNAs (miR-205-5p, miR-130a-3p, miR-4531, and miR-381-3p) that could be used as biomarkers for CIN 3 in LBC samples through multiple logistic regression analyses. We found 16 genes differentially expressed between CIN 3 and HSF samples (fold change ≥ 2 and p ≤ 0.05). We found the correlation between miR-130a-3p and CCND1(R = -0.52; p = 0.0029), miR-205-5p and EGFR (R = 0.53; p = 0.0021), and miR-4531 and SMAD2 (R = -0.54; p = 0.0016). In addition, we demonstrated the most significant pathways of the targets associated with cervical cancer progression (FDR-corrected p < 0.001). This study demonstrated that miRNA biomarkers may distinguish healthy cervix and CIN 3 and regulate important molecular pathways of carcinogenesis.

DNA Recovery Using Ethanol-Based Liquid Medium from FTA Card-Stored Samples for HPV Detection.

INTRODUCTION: Alternative methods of dry storage and transportation may be a viable alternative to the use of liquid storage medium for cervical samples, especially for screening programs in places with few resources. OBJECTIVE: The objective of this study is to verify the viability and efficacy of human papillomavirus DNA (HPV-DNA) detection in cervical cell samples collected and stored on a Flinders Technology Associates (FTA) card (Whatman Indicating FTA® Elute Micro Card) and subsequently recovered in ethanol-based liquid medium and to compare the results to those obtained using samples stored directly in ethanol-based liquid medium. STUDY DESIGN: Thirty-four women submitted to ETZ (excision of the transformation zone of the cervix) were included in this study. Before ETZ, 2 samples of exfoliated cervical cells were collected from each woman by a doctor and stored in ethanol-based liquid medium and on an FTA card. DNA recovery from FTA samples was performed using ethanol-based liquid medium. Detection of HPV-DNA in the samples was performed using the Cobas® 4800 HPV Test Platform. RESULTS AND CONCLUSIONS: The HPV-DNA detection positivity rates were 70.6% for the samples collected directly in liquid medium and 64.7% for the samples stored on the FTA card, with high detection accuracy in the DNA samples recovered from the FTA card (area under the curve = 0.958; 95% confidence interval = 0.890-1.000). The concordance between the results obtained using the 2 storage media was 94.1% (Kappa = 0.866). These preliminary results suggest that collection of cervical material on an FTA card may be an alternative to storage in liquid medium since the liquid medium has some limitations. In addition, DNA recovery from the card using ethanol-based liquid medium streamlines the workflow in the laboratory and reduces the cost associated with reagents, thereby facilitating access to the HPV test in places with few resources and potentially improving cervical cancer screening.

Cervical lesion assessment using real-time microendoscopy image analysis in Brazil: The CLARA study.

We conducted a prospective evaluation of the diagnostic performance of high-resolution microendoscopy (HRME) to detect cervical intraepithelial neoplasia (CIN) in women with abnormal screening tests. Study participants underwent colposcopy, HRME and cervical biopsy. The prospective diagnostic performance of HRME using an automated morphologic image analysis algorithm was compared to that of colposcopy using histopathologic detection of CIN as the gold standard. To assess the potential to further improve performance of HRME image analysis, we also conducted a retrospective analysis assessing performance of a multi-task convolutional neural network to segment and classify HRME images. One thousand four hundred eighty-six subjects completed the study; 435 (29%) subjects had CIN Grade 2 or more severe (CIN2+) diagnosis. HRME with morphologic image analysis for detection of CIN Grade 3 or more severe diagnoses (CIN3+) was similarly sensitive (95.6% vs 96.2%, P = .81) and specific (56.6% vs 58.7%, P = .18) as colposcopy. HRME with morphologic image analysis for detection of CIN2+ was slightly less sensitive (91.7% vs 95.6%, P < .01) and specific (59.7% vs 63.4%, P = .02) than colposcopy. Images from 870 subjects were used to train a multi-task convolutional neural network-based algorithm and images from the remaining 616 were used to validate its performance. There were no significant differences in the sensitivity and specificity of HRME with neural network analysis vs colposcopy for detection of CIN2+ or CIN3+. Using a neural network-based algorithm, HRME has comparable sensitivity and specificity to colposcopy for detection of CIN2+. HRME could provide a low-cost, point-of-care alternative to colposcopy and biopsy in the prevention of cervical cancer.