RESUMO
Consideration of risk-reducing bilateral salpingectomy has been recommended instead of tubal occlusive procedures for female sterilisation due to the role of the Fallopian tubes in the aetiology of serous ovarian malignancies. This study identified barriers to performing salpingectomy for permanent contraception. Twenty-two semi-structured interviews were conducted with Australian gynaecologists, and transcripts analysed qualitatively. Barriers to performing bilateral salpingectomy included: (a) patient factors (younger age and risk of regret); (b) operative complexity and complications (particularly risk of bleeding); (c) surgeon factors (lack of awareness of guidelines supporting salpingectomy; less comfort with laparoscopic surgery); and (d) practical system challenges (including cost and equipment availability).
Assuntos
Ginecologia , Neoplasias Ovarianas , Esterilização Tubária , Austrália , Anticoncepção , Tubas Uterinas , Feminino , Humanos , SalpingectomiaRESUMO
Enzymatic factors driving cancer-associated chromatin remodelling are of increasing interest as the role of the cancer epigenome in gene expression and DNA repair processes becomes elucidated. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) is a central histone modification that functions in histone cross-talk, transcriptional elongation, DNA repair, maintaining centromeric chromatin and replication-dependent histone mRNA 3'-end processing, as well as being required for the differentiation of stem cells. The loss of global H2Bub1 is seen in a number of aggressive malignancies and has been linked to tumour progression and/or a poorer prognosis in some cancers. Here, we analyse a large cohort of high-grade serous ovarian cancers (HGSOC) and show loss of global H2Bub1 in 77% (313 of 407) of tumours. Loss of H2Bub1 was seen at all stages (I-IV) of HGSOC, indicating it is a relatively early epigenomic event in this aggressive malignancy. Manipulation of key H2Bub1 E3 ubiquitin ligases, RNF20, RNF40 and BRCA1, in ovarian cancer cell line models modulated H2Bub1 levels, indicative of the role of these RING finger ligases in monoubiquitination of H2Bub1 in vitro. However, in primary HGSOC, loss of RNF20 protein expression was identified in just 6% of tumours (26 of 424) and did not correlate with global H2Bub1 loss. Similarly, germline mutation of BRCA1 did not show a correlation with the global H2Bub1 loss. We conclude that the regulation of tumour-associated H2Bub1 levels is complex. Aberrant expression of alternative histone-associated 'writer' or 'eraser' enzymes are likely responsible for the global loss of H2Bub1 seen in HGSOC.
Assuntos
Proteína BRCA1/genética , Neoplasias Ovarianas/genética , Ubiquitina-Proteína Ligases/biossíntese , Ubiquitinação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/biossíntese , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Código das Histonas/genética , Histonas/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
OBJECTIVES: The most widely used approach for the clinical management of women with high-grade serous ovarian cancer (HGSOC) is surgery, followed by platinum and taxane based chemotherapy. The degree of macroscopic disease remaining at the conclusion of surgery is a key prognostic factor determining progression free and overall survival. We sought to develop a non-invasive test to assist surgeons to determine the likelihood of achieving complete surgical resection. This knowledge could be used to plan surgical approaches for optimal clinical management. METHODS: We profiled 170 serum microRNAs (miRNAs) using the Serum/Plasma Focus miRNA PCR panel containing locked nucleic acid (LNA) primers (Exiqon) in women with HGSOC (N=56) and age-matched healthy volunteers (N=30). Additionally, we measured serum CA-125 levels in the same samples. The HGSOC cohort was further classified based on the degree of macroscopic disease at the conclusion of surgery. Stepwise logistic regression was used to identify predictive markers. RESULTS: We identified a combination of miR-375 and CA-125 as the strongest discriminator of healthy versus HGSOC serum, with an area under the curve (AUC) of 0.956. The inclusion of miR-210 increased the AUC to 0.984; however, miR-210 was affected by hemolysis. The combination of miR-34a-5p and CA-125 was the strongest predictor of completeness of surgical resection with an AUC of 0.818. CONCLUSION: A molecular test incorporating circulating miRNA to predict completeness of surgical resection for women with HGSOC has the potential to contribute to planning for optimal patient management, ultimately improving patient outcome.
Assuntos
Antígeno Ca-125/sangue , Cistadenocarcinoma Seroso/sangue , Proteínas de Membrana/sangue , MicroRNAs/sangue , Neoplasias Ovarianas/sangue , Idoso , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Valor Preditivo dos Testes , Cuidados Pré-Operatórios/métodos , Prognóstico , Resultado do TratamentoRESUMO
This is a case series of women presenting to a tertiary care centre with a diagnosis of interstitial pregnancy. Dilatation and evacuation was performed under ultrasound control with systemic methotrexate post-operatively. All women had successful termination of their interstitial pregnancy. Although described in the international literature, this is the first time that this technique has been documented in Australia, and it may ultimately prove to be a relatively safe and simple fertility preserving method of treating women with unruptured interstitial pregnancies.
Assuntos
Preservação da Fertilidade , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/cirurgia , Abortivos não Esteroides/uso terapêutico , Adulto , Gonadotropina Coriônica Humana Subunidade beta/sangue , Terapia Combinada , Dilatação , Extração Obstétrica , Feminino , Humanos , Metotrexato/uso terapêutico , Gravidez , Gravidez Ectópica/sangue , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: There is a critical need for improved diagnostic markers for high grade serous epithelial ovarian cancer (SEOC). MicroRNAs are stable in the circulation and may have utility as biomarkers of malignancy. We investigated whether levels of serum microRNA could discriminate women with high-grade SEOC from age matched healthy volunteers. METHODS: To identify microRNA of interest, microRNA expression profiling was performed on 4 SEOC cell lines and normal human ovarian surface epithelial cells. Total RNA was extracted from 500 µL aliquots of serum collected from patients with SEOC (n = 28) and age-matched healthy donors (n = 28). Serum microRNA levels were assessed by quantitative RT-PCR following preamplification. RESULTS: microRNA (miR)-182, miR-200a, miR-200b and miR-200c were highly overexpressed in the SEOC cell lines relative to normal human ovarian surface epithelial cells and were assessed in RNA extracted from serum as candidate biomarkers. miR-103, miR-92a and miR -638 had relatively invariant expression across all ovarian cell lines, and with small-nucleolar C/D box 48 (RNU48) were assessed in RNA extracted from serum as candidate endogenous normalizers. No correlation between serum levels and age were observed (age range 30-79 years) for any of these microRNA or RNU48. Individually, miR-200a, miR-200b and miR-200c normalized to serum volume and miR-103 were significantly higher in serum of the SEOC cohort (P < 0.05; 0.05; 0.0005 respectively) and in combination, miR-200b + miR-200c normalized to serum volume and miR-103 was the best predictive classifier of SEOC (ROC-AUC = 0.784). This predictive model (miR-200b + miR-200c) was further confirmed by leave one out cross validation (AUC = 0.784). CONCLUSIONS: We identified serum microRNAs able to discriminate patients with high grade SEOC from age-matched healthy controls. The addition of these microRNAs to current testing regimes may improve diagnosis for women with SEOC.
Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/genética , MicroRNAs/sangue , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Área Sob a Curva , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: To evaluate the initial experience and clinical utility of first-line adjuvant intensity-modulated whole abdominal radiation therapy (WART) in women with ovarian clear cell cancer (OCCC) referred to an academic center. METHODS: Progression-free and overall survival was analyzed in a pragmatic observational cohort study of histologically pure OCCC patients over-expressing HNF-1ß treated between 2013 and end-December 2018. An in-house intensity-modulated WART program was developed from a published pre-clinical model. Radiation dose-volume data was curated to American Association of Physics in Medicine (AAPM) Task Group 263 recommendations. A dedicated database prospectively recorded presenting characteristics and outcomes in a standardized fashion. RESULTS: Five women with FIGO (2018) stage IA to IIIA2 OCCC were treated with first-line WART. Median age was 58 years (range 47-68 years). At diagnosis CA-125 was elevated in 4 cases (median 56 kU/L: range 18.4-370 kU/L) before primary de-bulking surgery. Severe premorbid endometriosis was documented in 3 patients. At a median follow-up of 77 months (range 16-83 mo.), all patients remain alive and progression-free on clinical, biochemical (CA-125), and 18Fluoro-deoxyglucose (FDG) PET/CT re-evaluation. Late radiation toxicity was significant (G3) in 1 case who required a limited bowel resection and chronic nutritional support at 9 months post-WART; 2 further patients had asymptomatic (G2) osteoporotic fragility fractures of axial skeleton at 12 months post-radiation treated with anti-resorptive agents (denosumab). CONCLUSIONS: The clinical utility of intensity-modulated WART in OCCC over-expressing HNF-1ß was suggested in this small observational cohort study. The hypothesis that HNF-1ß is a portent of platinum-resistance and an important predictive biomarker in OCCC needs further confirmation. Curating multi-institutional cohort studies utilizing WART by means of "Big Data" may improve OCCC care standards in the future.
Assuntos
Abdome/efeitos da radiação , Adenocarcinoma de Células Claras/mortalidade , Imunofenotipagem/métodos , Neoplasias Ovarianas/mortalidade , Radioterapia Adjuvante/mortalidade , Radioterapia de Intensidade Modulada/mortalidade , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/radioterapia , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Dosagem Radioterapêutica , Taxa de SobrevidaRESUMO
OBJECTIVE: The purpose of this study was to describe the use of a staged procedure that involved femoral artery catheterization, classic cesarean section delivery, and uterine and placental embolization before hysterectomy for placenta accreta. STUDY DESIGN: We conducted a cohort study of retrospective and prospective data from cases of histologically identified placenta accreta at a tertiary teaching hospital with access to interventional radiology. RESULTS: Twenty-six cases of placenta accreta were identified histologically (7 accretas, 5 incretas, and 14 percretas); 8 cases were successful staged embolization procedures. These cases had significant reductions in blood loss (553 vs 4517 mL; P = .0001), need for transfusion (2 vs 16; P = .001), and units of blood transfused (0.5 vs 7.9; P = .0013). The total operation time was no different between the 2 groups, but there was a longer length of anesthesia (2.7 vs 6.6 hours; P = .0001). There were nonsignificant reductions in admission to the intensive care unit and length of hospital stay. CONCLUSION: We found that the successful use of a staged embolization hysterectomy procedure for placenta accreta is associated with decreased maternal morbidity.
Assuntos
Parto Obstétrico/métodos , Placenta Acreta/cirurgia , Adolescente , Adulto , Cateterismo , Embolização Terapêutica , Feminino , Humanos , Histerectomia , Artéria Ilíaca/diagnóstico por imagem , Tempo de Internação , Pessoa de Meia-Idade , Gravidez , Pregnanolona , Radiografia Intervencionista , Estudos Retrospectivos , Ultrassonografia Doppler Dupla , Adulto JovemRESUMO
OBJECTIVE: To determine the rate of occult malignancy in patients undergoing prophylactic bilateral salpingo-oophorectomy in Northern Sydney. METHODS: A retrospective case series of 45 consecutive patients who underwent prophylactic bilateral salpingo-oophorectomy between 2004 and March 2008. RESULTS: Five (11%) cases of occult neoplasia were found in 45 patients. This included 3 cases of micro-invasive serous carcinoma of the fallopian tube, 1 case of in situ carcinoma in the fallopian tube and 1 case of metastatic breast cancer in the ovary. All cases of primary neoplasia were in the fimbrial end of the fallopian tube. CONCLUSIONS: The importance of complete removal of the fallopian tubes and ovaries and the rigorous systematic pathological examination of these specimens are demonstrated in this case series. It supports emerging evidence that the fimbrial end of the fallopian tube is an important site of genesis of cancer in BRCA1/2 mutation carriers.
Assuntos
Carcinoma in Situ/diagnóstico , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias das Tubas Uterinas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Ovariectomia , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma in Situ/genética , Carcinoma in Situ/prevenção & controle , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/prevenção & controle , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/prevenção & controle , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Somatic mutation of the tumor suppressor gene TP53 is reported in at least 50% of human malignancies. Most high-grade serous ovarian cancers (HGSC) have a mutant TP53 allele. Accurate detection of these mutants in heterogeneous tumor tissue is paramount as therapies emerge to target mutant p53. We used a Fluidigm Access Array™ System with Massively Parallel Sequencing (MPS) to analyze DNA extracted from 76 serous ovarian tumors. This dataset has been made available to researchers through the European Genome-phenome Archive (EGA; EGAS00001002200). Herein, we present analyses of this dataset using HaplotypeCaller and MuTect2 through the Broad Institute's Genome Analysis Toolkit (GATK). We anticipate that this TP53 mutation dataset will be useful to researchers developing and testing new software to accurately determine high and low frequency variant alleles in heterogeneous aneuploid tumor tissue. Furthermore, the analysis pipeline we present provides a valuable framework for determining somatic variants more broadly in tumor tissue.
Assuntos
Genes p53 , Mutação , Neoplasias Ovarianas/genética , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
The tumour suppressor p53 is mutated in cancer, including over 96% of high-grade serous ovarian cancer (HGSOC). Mutations cause loss of wild-type p53 function due to either gain of abnormal function of mutant p53 (mutp53), or absent to low mutp53. Massively parallel sequencing (MPS) enables increased accuracy of detection of somatic variants in heterogeneous tumours. We used MPS and immunohistochemistry (IHC) to characterise HGSOCs for TP53 mutation and p53 expression. TP53 mutation was identified in 94% (68/72) of HGSOCs, 62% of which were missense. Missense mutations demonstrated high p53 by IHC, as did 35% (9/26) of non-missense mutations. Low p53 was seen by IHC in 62% of HGSOC associated with non-missense mutations. Most wild-type TP53 tumours (75%, 6/8) displayed intermediate p53 levels. The overall sensitivity of detecting a TP53 mutation based on classification as 'Low', 'Intermediate' or 'High' for p53 IHC was 99%, with a specificity of 75%. We suggest p53 IHC can be used as a surrogate marker of TP53 mutation in HGSOC; however, this will result in misclassification of a proportion of TP53 wild-type and mutant tumours. Therapeutic targeting of mutp53 will require knowledge of both TP53 mutations and mutp53 expression.