Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options.

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

Gynecologic Adnexal Tumors and Tumor-Like Lesions in Children and Adolescents: Experience at a Cancer Center.

Introduction. Tumors and tumor-like lesions of the uterine adnexa in children and adolescents are uncommon but may carry devastating consequences. Methods. We conducted an observational retrospective cohort study, to describe patients aged 0 to 19 years diagnosed with tumors and tumor-like lesions of the uterine adnexa at our institution between 2000 and 2018. Results. Eighty-nine patients with 105 adnexal lesions were included. Thirty-seven (42%) patients presented with benign tumors, 13 (15%) with borderline tumors, 25 (28%) with malignant tumors and 14 (16%) with tumor-like lesions. Germ cell tumors (n = 45|43%) were the most frequent, followed by epithelial tumors (n = 30|29%). No significant differences were found in the age distribution of the lesions by malignant potential or histologic group. Most patients (n = 80|90%) were treated primarily with conservative surgery, including cystectomy (n = 25|28%) and unilateral oophorectomy/adnexectomy (n = 54|61%). Thirty-four (38%) underwent surgical staging (partial omentectomy and peritoneal biopsies). Twenty (23%) patients with borderline and malignant tumors were submitted to chemotherapy. Four (5%) patients with borderline or malignant tumors relapsed, one of whom died from disease. Conclusion. Gynecological lesions in children and adolescents encompass a wide range of rare histological tumor subtypes, requiring evaluation by experienced pathologists. Most tumors were diagnosed at early stages, with low relapse and mortality rates. Conservative management, with fertility sparing surgery and limited use of adjuvant chemotherapy, is of utmost importance.

Expert Pathology for Gestational Trophoblastic Disease: Towards an International Multidisciplinary Team Meeting.

BACKGROUND: Gestational trophoblastic disease (GTD), comprising hydatidiform moles and gestational trophoblastic tumours, is extremely rare. Exact diagnosis is crucial to indicate the appropriate treatment and to prevent complications. The scarcity and variability in the number of cases available for reporting, lack of specialised training in GTD, and non-existence of refresher courses implies that the pathologist dealing with these rare and, at times, extremely challenging cases is not completely confident in their diagnosis. OBJECTIVES: The objective of this study was to explore the benefits of implementation of an international multidisciplinary conference (virtual) to aid diagnosis of difficult cases and support clinical management of GTD. METHODS: A short survey was circulated to all 46 members of the EOTTD pathology and genetics working party and further spread to other colleagues who practice GTD. This showed that the pathologists and geneticists working with GTD patients do not feel adequately supported and equipped with dealing with these rare diseases. OUTCOME: Virtual cross-border multidisciplinary team meetings (MDTs) were initiated in April 2022, bringing together participants from 11 European countries on a bi-yearly basis. Mean numbers of 3 patients are discussed during the MDTs followed by 3-4 quality assessment cases. A participant survey was conducted at the end of virtual meeting with an average satisfaction rate of 9.5. The pathologists felt supported and benefited from networking and clinical collaboration. CONCLUSIONS AND OUTLOOK: This international MDT continues to provide support in managing the uncertainty with difficult and rare cases and enhances the pathologists training and experience. The frequency of meetings and the number of cases discussed per meeting will be increased in 2023 given the positive response. This will empower individuals and organisations to work together and improve diagnosis and the prognosis for these young patients.

Practical guidelines of the EOTTD for pathological and genetic diagnosis of hydatidiform moles.

Hydatidiform moles are rare and thus most pathologists and geneticists have little experience with their diagnosis. It is important to promptly and correctly identify hydatidiform moles given that they are premalignant disorders associated with a risk of persistent gestational trophoblastic disease and gestational trophoblastic neoplasia. Improvement in diagnosis can be achieved with uniformization of diagnostic criteria and establishment of algorithms. To this aim, the Pathology and Genetics Working Party of the European Organisation for Treatment of Trophoblastic Diseases has developed guidelines that describe the pathological criteria and ancillary techniques that can be used in the differential diagnosis of hydatidiform moles. These guidelines are based on the best available evidence in the literature, professional experience and consensus of the experts' group involved in its development.

Endometrial Pipelle Biopsy Computer-Aided Diagnosis: A Feasibility Study.

Endometrial biopsies are important in the diagnostic workup of women who present with abnormal uterine bleeding or hereditary risk of endometrial cancer. In general, approximately 10% of all endometrial biopsies demonstrate endometrial (pre)malignancy that requires specific treatment. As the diagnostic evaluation of mostly benign cases results in a substantial workload for pathologists, artificial intelligence (AI)-assisted preselection of biopsies could optimize the workflow. This study aimed to assess the feasibility of AI-assisted diagnosis for endometrial biopsies (endometrial Pipelle biopsy computer-aided diagnosis), trained on daily-practice whole-slide images instead of highly selected images. Endometrial biopsies were classified into 6 clinically relevant categories defined as follows: nonrepresentative, normal, nonneoplastic, hyperplasia without atypia, hyperplasia with atypia, and malignant. The agreement among 15 pathologists, within these classifications, was evaluated in 91 endometrial biopsies. Next, an algorithm (trained on a total of 2819 endometrial biopsies) rated the same 91 cases, and we compared its performance using the pathologist's classification as the reference standard. The interrater reliability among pathologists was moderate with a mean Cohen's kappa of 0.51, whereas for a binary classification into benign vs (pre)malignant, the agreement was substantial with a mean Cohen's kappa of 0.66. The AI algorithm performed slightly worse for the 6 categories with a moderate Cohen's kappa of 0.43 but was comparable for the binary classification with a substantial Cohen's kappa of 0.65. AI-assisted diagnosis of endometrial biopsies was demonstrated to be feasible in discriminating between benign and (pre)malignant endometrial tissues, even when trained on unselected cases. Endometrial premalignancies remain challenging for both pathologists and AI algorithms. Future steps to improve reliability of the diagnosis are needed to achieve a more refined AI-assisted diagnostic solution for endometrial biopsies that covers both premalignant and malignant diagnoses.

Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndrome.

NTHL1 tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the NTHL1 gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial/personal history of multiple tumors (excluding multiple breast/ovarian/polyposis). Three NTHL1 tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic NTHL1 variants, as well as two index patients with one pathogenic or likely pathogenic NTHL1 variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the NTHL1 tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.

Practical lessons learned from real-world implementation of the molecular classification for endometrial carcinoma.

OBJECTIVES: This study aimed to explore the practical organisational aspects and difficulties in the implementation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification. METHODS: We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. RESULTS: Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group. CONCLUSIONS: Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification.

Short tandem repeat analysis: a practical tool to identify specimen mix-ups in the pathology laboratory.

Despite all precautions in pathology laboratories, contaminations and specimen mix-ups still occur and can negatively impact both patients and institutions. We present two cases in which short tandem repeat (STR) analysis was used to assert the correct identity of specimens. The first patient had a biopsy diagnosis of triple negative invasive carcinoma of no special type of the breast. Sample mix-up with another biopsy was suspected, because in her post-chemotherapy mastectomy specimen, a hormone receptor-positive lobular carcinoma was diagnosed. STR analysis displayed a complete common loci profile of the patient's biopsy and mastectomy, supporting that no mix-up occurred. The second patient underwent hysterectomy due to cervix squamous cell carcinoma. A fragment of adenocarcinoma was identified and confirmed by STR profile to be a contaminant. STR analysis is a fast, easy-to-perform, and widely available technique which can clarify contaminations and specimen mix-ups in pathology laboratories.

Molecular Classification of Endometrial Carcinoma: Protocol for a Cohort Study.

BACKGROUND: Endometrial carcinoma (EC) is the most common gynecologic malignancy in developed countries and the fourth most frequent in women worldwide. The cornerstone of treatment for EC is surgery. Clinicopathological features are currently used to help determine the individual risk of recurrence and the need for adjuvant treatment after surgery. Nonetheless, there is significant interobserver variability in assigning histologic subtype when using a morphological classification, revealing the need for a more unified approach. The Cancer Genome Atlas (TCGA) project identified 4 distinct prognostic EC subtypes based on genomic abnormalities. Surrogate assays including 3 immunohistochemical markers (p53, MSH6, and PMS2) and 1 molecular test (mutation analysis of the exonuclease domain of DNA polymerase epsilon; POLE) allowed the development and validation of a simplified molecular classifier that correlates with the TCGA classification, has prognostic value, and can easily be used in clinical practice. This molecular classification categorizes EC in 4 subtypes: POLE mutated, mismatch repair-deficient, p53 abnormal, and no specific molecular profile. Applying this classification in clinical practice will help tailor adjuvant treatment decisions. OBJECTIVE: The aim of this study is to retrospectively apply this novel molecular classification to a cohort of patients with EC treated in a comprehensive cancer center, to assess its applicability in clinical practice, to evaluate clinical outcomes by molecular subtypes, and to assess its prognostic value. METHODS: In this retrospective cohort study, patients with primary EC diagnosed during and after 2013 and treated or followed at our institution, after definite surgery, will be included. Demographic and clinicopathological data will be obtained from electronic health records and from pathology reports. Laboratory methods will include immunohistochemical study of p53 and mismatch repair proteins, as well as POLE mutational analysis by genetic sequencing. The primary end point is recurrence-free survival and secondary end points are disease-specific survival and overall survival. A descriptive analysis of variables will be carried out. Survival analysis will be performed using the Kaplan-Meier method and the groups will be compared using the log-rank test. RESULTS: This protocol was reviewed and approved by the Instituto Português de Oncologia do Porto, Portugal, ethics committee in October 2021; patient selection from our cancer registry began the same month. A total of 160 patients will be included. This work will present real-life results that will allow a better understanding of the Portuguese EC population and the distribution of the molecular subgroups throughout. We will use these results to understand the prognostic value of this classification in our population and its role in adjuvant therapy decisions. This study is anticipated to conclude in December 2022. CONCLUSIONS: This study will provide important information regarding these women's outcomes according to this new molecular classification and will support its use when discussing a patient's need for adjuvant treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34461.

Do Not Forget Poly (Adenosine Diphosphate-Ribose) Polymerase Inhibitors in Ovarian Carcinosarcoma.

Ovarian carcinosarcoma (OCS) is a rare entity with a poor prognosis and without evidence-based therapy. Here, we report the case of a 55-year-old woman with a germline BRCA1 mutation and a stage IV OCS who was proposed olaparib maintenance therapy after three platinum-based chemotherapies in relapsed disease. Currently, the patient has an overall survival of 102 months and progression-free survival of 60 months with olaparib, with a good quality of life and not experiencing any adverse events. Despite the lack of evidence for the use of poly (adenosine diphosphate-ribose) polymerase inhibitors in OCS, our case report proves that patients with a potential biomarker of response to these drugs (such as BRCA mutation and platinum-sensitive disease) derive great benefits from it.

Impressive and durable clinical responses obtained with dabrafenib and trametinib in low-grade serous ovarian cancer harbouring a BRAF V600E mutation.

Low-grade serous ovarian cancer (LGSOC) is now considered a different entity from high-grade serous ovarian cancer. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. Here we present a case report of two patients with a BRAF V600E mutation that achieved sustained clinical responses with combination treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor).

Next Generation Sequencing of Tumor and Matched Plasma Samples: Identification of Somatic Variants in ctDNA From Ovarian Cancer Patients.

Genetic testing to detect somatic alterations is usually performed on formalin-fixed paraffin-embedded tumor samples. However, tumor molecular profiling through ctDNA analysis may be particularly interesting with the emergence of targeted therapies for ovarian cancer (OC), mainly when tumor is not available and biopsy is not viable, also allowing representation of multiple neoplastic subclones. Using a custom panel of 27 genes, next-generation sequencing (NGS) was performed on tumor and matched plasma samples from 96 OC patients, which were combined in two groups (treatment naive and post-treatment). Overall, at least one somatic variant present in the tumor sample was also detected in the matched plasma sample in 35.6% of the patients, a percentage that increased to 69.6% of the treatment naive patients and 83.3% of those with stage IV disease, showing the potential of ctDNA analysis as an alternative to identify somatic variants in these patients, namely those that have predictive value for targeted therapy. In fact, of the two treatment-naive patients with somatic BRCA1 variants identified in tumor samples, in one of them we detected in ctDNA a BRCA1 somatic variant that was present in the tumor with a VAF of 53%, but not in the one that had a VAF of 5.4%. We also showed that ctDNA analysis has a complementary role to molecular unraveling of inter- and intra-tumor heterogeneity, as exemplified by one patient diagnosed with bilateral OC in which different somatic variants from both tumors were detected in ctDNA. Interestingly, as these bilateral tumors shared a rare combination of two of the three variants identified in ctDNA, we could conclude that these morphologically different tumors were clonally related and not synchronous independent neoplasias. Moreover, in the post-treatment group of patients with plasma samples collected after surgery, those with detectable somatic variants had poor prognosis when compared with patients with no detectable somatic variants, highlighting the potential of ctDNA analysis to identify patients at higher risk of recurrence. Concluding, this study demonstrated that somatic variants can be detected in plasma samples of a significant proportion of OC patients, supporting the use of NGS-based ctDNA testing for noninvasive tumor molecular profiling and to stratify patients according to prognosis.

Performance of DNA methylation-based biomarkers in the cervical cancer screening program of northern Portugal: A feasibility study.

Cervical cancer remains a health concern. Effective screening programs are critical to reduce the incidence and mortality. High-risk HPV (hr-HPV) testing as primary screening tool discloses high sensitivity but suboptimal specificity. Adequate triage tests to reduce unnecessary colposcopy referrals and overdiagnosis/overtreatment are crucial. Hence, we aimed to validate a panel of DNA methylation-based markers as triage test for women hr-HPV+ in the population-based Regional Cervical Cancer Screening Program of Northern Portugal. Firstly, CADM1, MAL, FAM19A4 and hsa-miR124-2 promoter methylation levels were assessed by multiplex QMSP in a testing set of 402 FFPE tissue samples (159 normal samples and 243 cervical lesions, including 39 low-grade intraepithelial squamous lesions [LSIL], 59 high-grade intraepithelial squamous lesions [HSIL] and 145 cancerous lesions). Then, preliminary validation was performed in 125 hr-HPV+ cervical scrapes (including 59 normal samples, 30 LSIL, 34 HSIL and 2 cancerous lesions). Higher MALme , FAM19A4me and hsa-miR124-2me methylation levels were disclosed in histological HSIL or worse (HSIL+) in testing set. Individually, markers depicted over 86% specificity for HSIL+ detection. In validation set, all these genes significantly differed between histological HSIL+ and low-grade squamous intraepithelial lesions or less. In combination, these markers reached 74% specificity and 61% sensitivity for identification of histological HSIL+. We concluded that host gene methylation might constitute a useful referral triage tool of hr-HPV+ women enrolled in the Cervical Cancer Screening Program of Northern Portugal.

The Impact of Routine Transvaginal Ultrasound Measurement of the Cervical Length on the Prediction of Preterm Birth: A Retrospective Study in a Tertiary Hospital.

Preterm birth (PTB) is a major obstetric problem associated with high rates of neonatal morbidity and mortality. The prevalence of PTB has not changed in the last decade; thus, the establishment of a screening test and effective treatment are warranted. Transvaginal ultrasound measurement of the cervical length (TUCL) has been proposed as an effective method to screen pregnant women at a higher risk of experiencing PTB. OBJECTIVE: To evaluate the applicability and usefulness of second-trimester TUCL to predict PTB in a cohort of Portuguese pregnant women. METHODS: Retrospective cross-sectional cohort study including all singleton pregnant women who performed their second-trimester ultrasound (between weeks 18 and 22 + 6 days) from January 2013 to October 2017 at Centro Hospitalar Universitário São João. RESULTS: Our cohort included 4,481 women. The prevalence of spontaneous PTB was of 4.0%, with 0.7% occurring before the 34th week of gestation. The mean TUCL was of 33.8 mm, and percentiles 3, 5 and 10 corresponded to TUCLs of 25.0 mm, 27.0 mm and 29.0 mm respectively. The multiple logistic regression analysis, including maternal age, previous PTB and cervical surgery showed a significant negative association between TUCL and PTB, with an odds ratio (OR) of 0.92 (95% confidence interval [95%CI]: 0.90-0.95; p < 0.001). The use of a TUCL of 20 mm is the best cut-off, when compared with the 25-mm cut-off, improving the prediction of risk. CONCLUSION: The present study showed an inverse association between TUCL and PTB, and that the inclusion of other risk factors like maternal age, previous PTB and cervical surgery can improve the screening algorithm. Furthermore, it emphasizes that the TUCL cut-off that defines short cervix can differ according to the population.

O parto pré-termo (PPT) é uma grande complicação obstétrica que se associa a elevadas taxas de morbimortalidade neonatal. A sua prevalência não tem alterado na última década, sendo esencial determinar uma forma de rastreio e tratamento eficaz. A medição ecográfica transvaginal do comprimento cervical tem sido proposta como um método eficaz de rastreio das grávidas com risco aumentado de PPT. OBJETIVO: Avaliar a aplicabilidade e utilidade da medição ecográfica transvaginal do comprimento cervical na previsão de PPT numa amostra de grávidas portuguesas. MéTODO: Estudo de coorte retrospectivo incluindo todas as grávidas com gestação unifetal que realizaram ecografia do 2° trimestre (de 18 a 22semanas + 6 dias) no Centro Hospitalar Universitário de São João entre janeiro de 2013 e outubro de 2017. RESULTADOS: A nossa amostra incluiu 4.481 mulheres. A prevalência de PPT espontâneo foi de 4,0%, sendo que 0,7% ocorreu antes das 34 semanas de gestação. A média do comprimento cervical por ecografia transvaginal foi 33,8 mm, e os percentis 3, 5 e 10 da amostra corresponderam a comprimentos cervicais de 25,0 mm, 27,0 mm e 29,0 mm, respetivamente. A regressão logística múltipla, que incluiu a idade materna, PPT anterior e antecedentes de conização, demonstrou uma associação estatisticamente significativa entre o comprimento cervical e o risco de PPT, com um risco relativo de 0,92 (intervalo de confiança de 95% [IC95%]: 0.90­0.95; p < 0.001). A utilização de um valor de referência de comprimento cervical de 20 mm, quando comparado com o valor de referência de 25 mm, melhora a previsão do risco de PPT. CONCLUSãO: Este estudo demostra uma associação entre o comprimento cervical avaliado por ecografia tranasvaginal e o risco de PPT, e salienta que a inclusão de outros fatores de risco, como idade materna, PPT anterior e antecedentes de conização podem melhorar o algoritmo de rastreio. Realça ainda que o valor de comprimento cervical utilizado para definir "colo curto" varia de acordo com a população em estudo.

The impact of routine transvaginal ultrasound measurement of the cervical length on the prediction of preterm birth: A retrospective study in a tertiary hospital / O impacto da medição por rotina do comprimento cervical por ecografia transvaginal na predição de parto pré-termo: Um estudo retrospetivo num hospital terciário

Abstract Pretermbirth (PTB) is a major obstetric problem associated with high rates of neonatal morbidity and mortality. The prevalence of PTB has not changed in the last decade; thus, the establishment of a screening test and effective treatment are warranted. Transvaginal ultrasoundmeasurement of the cervical length (TUCL) has been proposed as an effective method to screen pregnant women at a higher risk of experiencing PTB. Objective To evaluate the applicability and usefulness of second-trimester TUCL to predict PTB in a cohort of Portuguese pregnant women. Methods Retrospective cross-sectional cohort study including all singleton pregnant women who performed their second-trimester ultrasound (between weeks 18 and 22þ6 days) from January 2013 to October 2017 at Centro Hospitalar Universitário São João. Results Our cohort included 4,481 women. The prevalence of spontaneous PTB was of 4.0%, with 0.7% occurring before the 34th week of gestation. The mean TUCL was of 33.8mm,and percentiles 3, 5 and 10 corresponded toTUCLs of 25.0mm, 27.0mmand 29.0mmrespectively. The multiple logistic regression analysis, including maternal age, previous PTB and cervical surgery showed a significant negative association between TUCL and PTB, with an odds ratio (OR) of 0.92 (95% confidence interval [95%CI]: 0.90-0.95; p<0.001). The use of a TUCL of 20mm is the best cut-off, when compared with the 25-mm cut-off, improving the prediction of risk. Conclusion The present study showed an inverse association between TUCL and PTB, and that the inclusion of other risk factors like maternal age, previous PTB and cervical surgery can improve the screening algorithm. Furthermore, it emphasizes that the TUCL cut-off that defines short cervix can differ according to the population.

Resumo O parto pré-termo (PPT) é uma grande complicação obstétrica que se associa a elevadas taxas de morbimortalidade neonatal. A sua prevalência não tem alterado na última década, sendo esencial determinar uma forma de rastreio e tratamento eficaz. A medição ecográfica transvaginal do comprimento cervical tem sido proposta como um método eficaz de rastreio das grávidas com risco aumentado de PPT. Objetivo Avaliar a aplicabilidade e utilidade da medição ecográfica transvaginal do comprimento cervical na previsão de PPT numa amostra de grávidas portuguesas. Método Estudo de coorte retrospectivo incluindo todas as grávidas com gestação unifetal que realizaram ecografia do 2° trimestre (de 18 a 22semanasþ6 dias) no Centro Hospitalar Universitário de São João entre janeiro de 2013 e outubro de 2017. Resultados A nossa amostra incluiu 4.481 mulheres. A prevalência de PPT espontâneo foi de 4,0%, sendo que 0,7% ocorreu antes das 34 semanas de gestação. A média do comprimento cervical por ecografia transvaginal foi 33,8mm, e os percentis 3, 5 e 10 da amostra corresponderam a comprimentos cervicais de 25,0mm, 27,0mm e 29,0mm, respetivamente. A regressão logística múltipla, que incluiu a idade materna, PPT anterior e antecedentes de conização, demonstrou uma associação estatisticamente significativa entre o comprimento cervical e o risco de PPT, com um risco relativo de 0,92 (intervalo de confiança de 95% [IC95%]: 0.90-0.95; p<0.001). A utilização de um valor de referência de comprimento cervical de 20mm, quando comparado com o valor de referência de 25 mm, melhora a previsão do risco de PPT. Conclusão Este estudo demostra uma associação entre o comprimento cervical avaliado por ecografia tranasvaginal e o risco de PPT, e salienta que a inclusão de outros fatores de risco, como idade materna, PPT anterior e antecedentes de conização podem melhorar o algoritmo de rastreio. Realça ainda que o valor de comprimento cervical utilizado para definir "colo curto" varia de acordo com a população em estudo.

Placental site trophoblastic tumour: five challenges of patient clinical management.

Placental site trophoblastic tumour is a rare form of gestational trophoblastic disease accounting for about 1%-2% of all trophoblastic tumours. Diagnosis and management of placental site trophoblastic tumour can be difficult.We report a case of a 30-year-old woman diagnosed with a placental site trophoblastic tumour and identify the challenges in diagnosis and treatment of this rare situation. The presenting sign was abnormal vaginal bleeding that started 3 months after delivery. Image exams revealed an enlarged uterus with a heterogeneous mass, with vesicular pattern, and the increased vascularisation serum human chorionic gonadotropin level was above normal range. The histological diagnosis was achieved through hysteroscopic biopsy. Staging exams revealed pulmonary micronodules. The patient was successfully treated with hysterectomy and chemotherapy. The latest follow-up (37 months after diagnosis) was uneventful, and the patient exhibited no signs of recurrence or metastasis.

Influence of EPICardial adipose tissue in HEART diseases (EPICHEART) study: Protocol for a translational study in coronary atherosclerosis.

INTRODUCTION: Accumulation of epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) and increased risk of coronary events in asymptomatic subjects and low-risk patients, suggesting that EAT promotes atherosclerosis in its early stage. Recent studies have shown that the presence of CAD affects the properties of adjacent EAT, leading to dynamic changes in the molecular players involved in the interplay between EAT and the coronary arteries over the history of the disease. The role of EAT in late-stage CAD has not been investigated. OBJECTIVES: In a comparative analysis with mediastinal and subcutaneous adipose tissue, we aim to investigate whether the volume of EAT assessed by computed tomography and its proteome assessed by SWATH-MS mass spectrometry are associated with late stages of CAD in an elderly cohort of severe aortic stenosis patients. METHODS: The EPICHEART study (NCT03280433) is a prospective study enrolling patients with severe degenerative aortic stenosis referred for elective aortic valve replacement, whose protocol includes preoperative clinical, nutritional, echocardiographic, cardiac computed tomography and invasive coronary angiographic assessments. During cardiac surgery, samples of EAT and mediastinal and subcutaneous thoracic adipose tissue are collected for proteomics analysis by SWATH-MS. In addition, pericardial fluid and peripheral and coronary sinus blood samples are collected to identify circulating and local adipose tissue-derived biomarkers of CAD. CONCLUSION: We designed a translational study to explore the association of EAT quantity and quality with advanced CAD. We expect to identify new biochemical factors and biomarkers in the crosstalk between EAT and the coronary arteries that are involved in the pathogenesis of late coronary atherosclerosis, especially coronary calcification, which might be translated into new therapeutic targets and imaging tools by biomedical engineering.

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2.

Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants.