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OBJECTIVE: To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. METHODS: A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. RESULTS: Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. CONCLUSION: In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population.
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OBJECTIVE: Anemia is prevalent in patients with gynecologic cancers and is associated with increased peri-operative morbidity. We aimed to characterize risk factors for pre-operative anemia and describe outcomes among patients undergoing surgery by a gynecologic oncologist to identify potential areas for impactful intervention. METHODS: We analyzed major surgical cases performed by a gynecologic oncologist in the National Surgical Quality Improvement Program (NSQIP) database from 2014 to 2019. Anemia was defined as hematocrit <36%. Demographic characteristics and peri-operative variables for patients with and without anemia were compared using bivariable tests. Odds of peri-operative complications in patients stratified by pre-operative anemia were calculated using logistic regression models. RESULTS: Among 60 017 patients undergoing surgery by a gynecologic oncologist, 23.1% had pre-operative anemia. Women with ovarian cancer had the highest rate of pre-operative anemia at 39.7%. Patients with advanced-stage cancer had a higher risk of anemia than early-stage disease (42.0% vs 16.3%, p≤0.001). In a logistic regression model adjusting for potential demographic, cancer-related, and surgical confounders, patients with pre-operative anemia had increased odds of infectious complications (odds ratio (OR) 1.16, 95% CI 1.07 to 1.26), thromboembolic complications (OR 1.39, 95% CI 1.15 to 1.68), and blood transfusion (OR 5.78, 95% CI 5.34 to 6.26). CONCLUSIONS: There is a high rate of anemia in patients undergoing surgery by a gynecologic oncologist, particularly those with ovarian cancer and/or advanced malignancy. Pre-operative anemia is associated with increased odds of peri-operative complications. Interventions designed to screen for and treat anemia in this population have the potential for significant impact on surgical outcomes.
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Anemia , Neoplasias dos Genitais Femininos , Oncologistas , Neoplasias Ovarianas , Humanos , Feminino , Complicações Pós-Operatórias/etiologia , Anemia/complicações , Anemia/epidemiologia , Fatores de Risco , Neoplasias dos Genitais Femininos/cirurgia , Neoplasias Ovarianas/complicações , Estudos RetrospectivosRESUMO
INTRODUCTION AND HYPOTHESIS: The objective was to study the effect of immediate pre-operative warm-up using virtual reality simulation on intraoperative robot-assisted laparoscopic hysterectomy (RALH) performance by gynecology trainees (residents and fellows). METHODS: We randomized the first, non-emergent RALH of the day that involved trainees warming up or not warming up. For cases assigned to warm-up, trainees performed a set of exercises on the da Vinci Skills Simulator immediately before the procedure. The supervising attending surgeon, who was not informed whether or not the trainee was assigned to warm-up, assessed the trainee's performance using the Objective Structured Assessment for Technical Skill (OSATS) and the Global Evaluative Assessment of Robotic Skills (GEARS) immediately after each surgery. RESULTS: We randomized 66 cases and analyzed 58 cases (30 warm-up, 28 no warm-up), which involved 21 trainees. Attending surgeons rated trainees similarly irrespective of warm-up randomization with mean (SD) OSATS composite scores of 22.6 (4.3; warm-up) vs 21.8 (3.4; no warm-up) and mean GEARS composite scores of 19.2 (3.8; warm-up) vs 18.8 (3.1; no warm-up). The difference in composite scores between warm-up and no warm-up was 0.34 (95% CI: -1.44, 2.13), and 0.34 (95% CI: -1.22, 1.90) for OSATS and GEARS respectively. Also, we did not observe any significant differences in each of the component/subscale scores within OSATS and GEARS between cases assigned to warm-up and no warm-up. CONCLUSION: Performing a brief virtual reality-based warm-up before RALH did not significantly improve the intraoperative performance of the trainees.
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Laparoscopia , Procedimentos Cirúrgicos Robóticos , Robótica , Feminino , Humanos , Simulação por Computador , Histerectomia , Competência ClínicaRESUMO
BackgroundImmune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study.MethodsEligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m2) on days 1-4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment.ResultsAmong 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%-49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8+ T cells and CD20+ B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR.ConclusionEpigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC.Trial registrationClinicalTrials.gov NCT02901899.FundingUS Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.
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Recidiva Local de Neoplasia , Neoplasias Ovarianas , Protocolos de Quimioterapia Combinada Antineoplásica , Epigênese Genética , Epigenômica , Feminino , Humanos , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
Understanding the regulatory programs enabling cancer stem cells (CSCs) to self-renew and drive tumorigenicity could identify new treatments. Through comparative chromatin-state and gene expression analyses in ovarian CSCs versus non-CSCs, we identified FOXK2 as a highly expressed stemness-specific transcription factor in ovarian cancer. Its genetic depletion diminished stemness features and reduced tumor initiation capacity. Our mechanistic studies highlight that FOXK2 directly regulated IRE1α (encoded by ERN1) expression, a key sensor for the unfolded protein response (UPR). Chromatin immunoprecipitation and sequencing revealed that FOXK2 bound to an intronic regulatory element of ERN1. Blocking FOXK2 from binding to this enhancer by using a catalytically inactive CRISPR/Cas9 (dCas9) diminished IRE1α transcription. At the molecular level, FOXK2-driven upregulation of IRE1α led to alternative XBP1 splicing and activation of stemness pathways, while genetic or pharmacological blockade of this sensor of the UPR inhibited ovarian CSCs. Collectively, these data establish what we believe is a new function for FOXK2 as a key transcriptional regulator of CSCs and a mediator of the UPR, providing insight into potentially targetable new pathways in CSCs.
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Fatores de Transcrição Forkhead , Neoplasias Ovarianas , Resposta a Proteínas não Dobradas , Endorribonucleases/genética , Endorribonucleases/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/genética , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
Sleep difficulties, particularly symptoms of insomnia and circadian disruption, are among the primary complaints of gynecologic cancer survivors before, during, and after treatment. Moreover, difficulty sleeping has been linked to poorer health-related quality of life and elevated symptom burden in this population. Although leading behavioral sleep interventions have demonstrated efficacy among cancer survivors, up to 50% of survivors are non-adherent to these treatments, likely because these interventions require labor-intensive behavior and lifestyle changes. Therefore, there is a need for more effective and acceptable approaches to diminish sleep disturbance among cancer survivors. This manuscript describes the methodology of a two-part study guided by the Multiphase Optimization Strategy (MOST) framework to identify a streamlined behavioral sleep intervention for gynecologic cancer survivors. Three candidate intervention components previously shown to decrease sleep disturbance will be evaluated, including sleep restriction, stimulus control, and systematic bright light exposure. Participants will be adult women with a history of non-metastatic gynecologic cancer who have completed primary treatment and who report current poor sleep quality. Fifteen participants will be recruited for Part 1 of the study, which will utilize qualitative methods to identify barriers to and facilitators of intervention adherence. Results will inform changes to the delivery of the candidate intervention components to promote adherence in Part 2, where 80 participants will be recruited and randomized to one of eight conditions reflecting every possible combination of the three candidate intervention components in a full factorial design. Participants will complete assessments at baseline, post-intervention, and 3-months post-intervention. Part 2 results will identify the combination of candidate intervention components that yields the most efficacious yet efficient 6-week intervention for diminishing sleep disturbance. This is the first known study to apply the MOST framework to optimize a behavioral sleep intervention and will yield a resource-efficient treatment to diminish sleep disturbance, improve health-related quality of life, and decrease symptom burden among gynecologic cancer survivors. ClinicalTrials.gov Identifier: NCT05044975.
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Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with overall benign clinical course. It has histologic features showing focal or diffuse nuclear atypia surrounded by usual type leiomyoma. Uterine leiomyosarcomas (LMS) are a group of rare and aggressive malignancies with limited treatment options available. The potential association between LM-BN with LMS is largely unknown. In this study, we report 2 cases of uterine smooth muscle tumor with typical histologic and molecular evidence of LM-BN, which are associated with its progression to the malignant counterpart of LMS. We summarize the detailed histologic, morphologic, and genomic characteristics of these 2 sets of cases. Our findings suggest that LMS progressing from preexisting LM-BN can be one of the tumor pathogenesis pathways in uterine leiomyosarcomas.
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Leiomioma , Leiomiossarcoma , Neoplasias Pélvicas , Tumor de Músculo Liso , Neoplasias Uterinas , Feminino , Humanos , Leiomiossarcoma/patologia , Leiomioma/patologia , Neoplasias Uterinas/patologia , Tumor de Músculo Liso/patologia , GenômicaRESUMO
OBJECTIVE: Plasma energy ablation vaporizes tissues similar to carbon dioxide laser ablation, but is not hindered by the unique hazards and regulation of laser technology. We aimed to evaluate the complication rate and effectiveness of plasma versus laser ablation in the treatment of vulvovaginal high-grade squamous intra-epithelial lesions (HSIL). METHODS: We performed a retrospective cohort study of women treated with plasma or carbon dioxide laser ablation for histologically proven HSIL of the vulva or vagina from January 2014 to October 2019 at a single institution. Demographic factors, surgical characteristics, and complications were compared by ablation type using Fisher's exact tests. Recurrence-free survival was evaluated by ablation type using Kaplan-Meier curves, weighted log-rank tests, and Cox proportional hazards ratio estimates. RESULTS: Forty-two women were included; 50% underwent plasma and 50% underwent carbon dioxide laser ablation. Demographic factors were similar between the groups. 50% (n=21) were immunosuppressed, 45.2% (n=19) had prior vulvovaginal HSIL treatment, and 35.7% (n=15) were current smokers. Most women (n=25, 59.5%) were treated for vulvar HSIL, 38.1% (n=16) for vaginal HSIL. Complication rates did not differ by treatment: 9.5% (n=2) for laser ablation versus 4.8% (n=1) for plasma ablation (p=1.0). Over a median follow-up time of 29.3 months (IQR 11.0-45.0 months), recurrence rates were similar: 28.6% in the laser ablation group versus 33.3% in the plasma ablation group (weighted log rank p=0.43; 24-month HR 0.54, 95% CI 0.15 to 2.01). CONCLUSION: Plasma energy ablation of vulvovaginal HSIL has similar complication rates and recurrence risk to carbon dioxide laser ablation. This technique could be considered as an alternative treatment modality for vulvovaginal HSIL and warrants further investigation.
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Carcinoma de Células Escamosas/cirurgia , Terapia a Laser/métodos , Lasers de Gás/uso terapêutico , Neoplasias Vaginais/cirurgia , Neoplasias Vulvares/cirurgia , Adulto , Feminino , Humanos , Terapia a Laser/efeitos adversos , Lasers de Gás/efeitos adversos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Purpose: To determine how young patients with early-stage endometrial cancer are counseled regarding fertility preserving therapy and pregnancy options by gynecologic oncology and reproductive endocrinology and infertility (REI) providers. Methods: Anonymous online survey of Society of Gynecology Oncology (SGO) and the Society for Reproductive Endocrinology and Infertility (SREI) members; data were analyzed using chi-square and t-tests. Results: Twelve percent (169/1433) of SGO and 6.5% (60/927) of SREI members responded to the survey request. Most providers manage fewer than 10 fertility preservation patients annually. All gynecologic oncologists offer conservative management to patients with grade 1 endometrial cancer without evidence of invasion, and 40% would offer it to patients with grade 2 or <50% invasion. Magnetic resonance imaging was the most common method of assessing invasion, and the progesterone intrauterine device was the preferred first-line treatment. Two-thirds of providers would recommend hysterectomy if no endometrial response was noted by 12 months, two-thirds would continue conservative management for more than a year if a partial response was noted, and 70% would recommend hysterectomy after a patient completes childbearing. Comparatively, 60% of REI providers would recommend hysterectomy after childbearing. More gynecologic oncologists than REI providers recommend attempting spontaneous conception and for longer durations before initiating fertility treatments. Conclusion: Heterogeneous management styles exist among and between gynecologic oncology and REI providers for patients with early-stage endometrial cancer desiring future pregnancy. Improved guidelines are needed regarding treatment and monitoring surrounding trials of conception and pregnancy.
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Neoplasias do Endométrio , Preservação da Fertilidade , Infertilidade , Oncologistas , Neoplasias do Endométrio/terapia , Feminino , Humanos , Histerectomia , GravidezRESUMO
Human epidermal growth factor receptor 2 (HER-2) targeted therapy shows promising results in HER-2-positive uterine serous carcinoma (USC). HER-2 scoring criteria for USC and its associated noninvasive lesion, serous endometrial intraepithelial carcinoma (SEIC), are not well-established. Here, we compare the breast and gastric (GI) HER-2 immunohistochemistry (IHC) scoring criteria for HER-2 with HER-2/neu fluorescence in situ hybridization (FISH) in 68 tumors (17 USC with SEIC, 30 USC, 18 SEIC, 3 metastatic USC). The majority (97%) of lesions displayed intratumoral HER-2 IHC heterogeneity. Breast or GI IHC scoring criteria were performed equivalently. The breast and GI IHC criteria classified 51% and 47% USC as HER-2 negative (IHC 0/1+), 40% and 45% as equivocal (IHC 2+), and 9% each as HER-2 positive (IHC 3+). A quarter of USC classified as HER-2 negative or positive with the breast (25%, n=7/28) or GI IHC criteria (23%, n=6/26) was discordant by FISH. Specifically, 13% to 14% of IHC 0/1+ USC were FISH amplified; 50% of IHC 3+ USC were FISH negative. The majority (77% to 83%) of SEIC were HER-2 IHC 0/1+, and no SEIC was HER-2 IHC 3+. A minority (4% to 7%) of IHC 0/1+ SEIC were FISH positive. Discordant HER-2 status was observed between half (47%,bn=7/15) of synchronous SEIC and USC. In conclusion, USC displays HER-2 intratumoral heterogeneity, a high IHC/FISH discordance rate, and variation in HER-2 status between the SEIC and invasive components. Caution is required when evaluating HER-2 in small biopsies, which should be repeated on excisions. Both IHC and FISH should be performed on USC until clinical trials correlate HER-2 status with clinical response to HER-2-targeted therapy.
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Biomarcadores Tumorais/genética , Carcinoma in Situ/genética , Neoplasias do Endométrio/genética , Amplificação de Genes , Neoplasias Císticas, Mucinosas e Serosas/genética , Receptor ErbB-2/genética , Neoplasias Uterinas/genética , Biópsia , Carcinoma in Situ/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Císticas, Mucinosas e Serosas/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Neoplasias Uterinas/patologiaRESUMO
Defining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH+ cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7+ from FZD7- cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7+ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7-ß-catenin-Tp63-GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential "persister cancer cell" phenotype. SIGNIFICANCE: Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.
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Biomarcadores Tumorais/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Receptores Frizzled/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Receptores Frizzled/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Trillions of dollars pass to physicians from industry-related businesses annually, leading to many opportunities for financial conflicts of interest. The Open Payments Database (OPD) was created to ensure transparency. We describe the industry relationships as reported in the OPD for presenters at the 2019 Society of Gynecologic Oncology (SGO) Annual Meeting and evaluate concordance between author disclosures of their financial interests and information provided by the OPD. METHODS: This is an observational, cross-sectional study. Disclosure data were collected from authors with oral and featured abstract presentations in the 2019 SGO annual conference. These disclosures were compared to data available for each author in the 2018 OPD, which included the amount and nature of industry payments. RESULTS: We examined the disclosures of 301 authors who met inclusion criteria. Of 161 authors who had disclosure statements on their presentations,147 reported "no disclosures," and 14 disclosed industry relationships. The remaining 140 did not list any disclosure information. Sixty percent (184/301) of authors had industry relationships in the 2018 OPD, including 173 of 287 (60.3%) of authors who either reported no disclosures or did not have disclosure data available in their presentations. These transactions totaled over 43 million USD from 122 different companies, with most payments (46%) categorized as "Research or Associated Research." Accurate disclosure reporting was associated with receiving higher payments or research payments, and being a presenting author. CONCLUSIONS: Most authors at the SGO annual conference did not correctly disclose their industry relationships when compared with their entries in the OPD.
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Congressos como Assunto/economia , Revelação , Neoplasias dos Genitais Femininos , Setor de Assistência à Saúde/economia , Médicos/economia , Autoria , Conflito de Interesses , Congressos como Assunto/ética , Estudos Transversais , Ética em Pesquisa , Feminino , Ginecologia/economia , Ginecologia/ética , Setor de Assistência à Saúde/ética , Humanos , Oncologia/economia , Oncologia/ética , Médicos/ética , Publicações/economiaRESUMO
Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.
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Antropometria/métodos , Neoplasias dos Genitais Femininos/terapia , Extremidade Inferior/patologia , Linfedema/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Quimioterapia Adjuvante/efeitos adversos , Espectroscopia Dielétrica/métodos , Espectroscopia Dielétrica/normas , Feminino , Neoplasias dos Genitais Femininos/complicações , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Humanos , Excisão de Linfonodo/efeitos adversos , Linfedema/etiologia , Linfedema/patologia , Linfedema/terapia , Tamanho do Órgão , Radioterapia Adjuvante/efeitos adversos , Fatores de Risco , Biópsia de Linfonodo Sentinela/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: To estimate receipt of recommended gynecologic care, including cancer screening and menstrual care, among women with Down syndrome in the United States. METHODS: We conducted a retrospective cohort study of women participating in DS-Connect, the National Institute of Health's registry of women with Down syndrome. Using 2013-2019 survey data, we estimated the proportion of women receiving recommended age-appropriate well-woman care (Pap tests, mammogram, breast examination, pelvic examination) and compared receipt of gynecologic care to receipt of other preventive health care. We also estimated proportion receiving care for menstrual regulation. RESULTS: Of 70 participants with Down syndrome, 23% (95% CI 13-33) of women received all recommended gynecologic components of a well-woman examination. Forty-four percent (95% CI 32-56) of women aged 18 years and older reported ever having a gynecologic examination, and 26% (95% CI 15-37) reported ever having a Pap test. Of women aged 40 years or older, 50% (95% CI 22-78) had had a mammogram. Fifty-two percent (95% CI 41-65) had tried medication for menstrual regulation, and 89% (95% CI 81-96) received all recommended components of nongynecologic routine health care. CONCLUSION: Women with Down syndrome received gynecologic care, including cancer screening, at lower-than-recommended rates and at substantially lower rates than other forms of health care. Efforts to improve gynecologic care in this vulnerable population are needed.
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Síndrome de Down , Doenças dos Genitais Femininos/prevenção & controle , Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Serviços de Saúde para Pessoas com Deficiência/estatística & dados numéricos , Serviços Preventivos de Saúde/estatística & dados numéricos , Serviços de Saúde Reprodutiva/estatística & dados numéricos , Adulto , Idoso , Estudos de Coortes , Síndrome de Down/complicações , Feminino , Doenças dos Genitais Femininos/complicações , Humanos , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Estados Unidos , Adulto JovemRESUMO
N 6-Methyladenosine (m6A) is the most abundant modification of mammalian mRNAs. RNA methylation fine tunes RNA stability and translation, altering cell fate. The fat mass- and obesity-associated protein (FTO) is an m6A demethylase with oncogenic properties in leukemia. Here, we show that FTO expression is suppressed in ovarian tumors and cancer stem cells (CSC). FTO inhibited the self-renewal of ovarian CSC and suppressed tumorigenesis in vivo, both of which required FTO demethylase activity. Integrative RNA sequencing and m6A mapping analysis revealed significant transcriptomic changes associated with FTO overexpression and m6A loss involving stem cell signaling, RNA transcription, and mRNA splicing pathways. By reducing m6A levels at the 3'UTR and the mRNA stability of two phosphodiesterase genes (PDE1C and PDE4B), FTO augmented second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) signaling and suppressed stemness features of ovarian cancer cells. Our results reveal a previously unappreciated tumor suppressor function of FTO in ovarian CSC mediated through inhibition of cAMP signaling. SIGNIFICANCE: A new tumor suppressor function of the RNA demethylase FTO implicates m6A RNA modifications in the regulation of cyclic AMP signaling involved in stemness and tumor initiation.
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Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Sistemas do Segundo Mensageiro , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas/genética , Adenosina/genética , Adenosina/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Processamento Alternativo , Animais , Ascite/metabolismo , Carcinogênese/metabolismo , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Regulação para Baixo , Tubas Uterinas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Análise de Sequência de RNA , Esferoides Celulares , Análise Serial de Tecidos , Transcriptoma , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVE: Women with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460). METHODS: Volunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 109 colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS). RESULTS: Among 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3-12.1) and median PFS was 2.8 months (95% CI: 2.6-3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment. CONCLUSION: At the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma.
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Vacinas Anticâncer/administração & dosagem , Listeria monocytogenes/imunologia , Proteínas E7 de Papillomavirus/imunologia , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologiaRESUMO
OBJECTIVE: Our objectives were 1) to compare the efficacy of progestin therapy combined with metformin (Prog-Met) to Prog alone as primary fertility sparing treatment in women with atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or early-stage endometrioid carcinoma (EC), and 2) to analyze the proportion of women achieving live birth following treatment. METHODS: A retrospective cohort study of all reproductive-aged women with AH/IN or EC treated with Prog ± Met from 1999-2018 was conducted. Complete response (CR) was assessed and Kaplan-Meier analysis used to calculate time to CR. Comparison of potential response predictors was performed with multivariable Cox regression models. RESULTS: Ninety-two women met criteria; 59% (n = 54) were treated for AH/EIN and 41% (n = 38) for EC. Their median age, body mass index, and follow up time was 35 years, 37.7 kg/m2, and 28.4 months, respectively. Fifty-eight women (63%) received Prog and 34 (37%) received Prog-Met. Overall, 79% (n = 73) of subjects responded to treatment with a CR of 69% (n = 63). There was no difference in CR (p = 0.90) or time to CR (p = 0.31) between the treatment cohorts. Overall, 22% experienced a disease recurrence. On multivariable analysis, EC histology was the only covariate associated with a decreased Prog response (HR 0.48; p = 0.007). Only 17% of the cohort achieved a live-birth pregnancy, the majority of which required assisted reproductive technologies (81%) and occurred in the Prog treatment group. CONCLUSIONS: Our study does not support the use of Prog-Met therapy for treatment of AH/EIN or EC. Additionally, fewer than 20% of women achieved a live-birth pregnancy during the study period, with most requiring ART.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma in Situ/tratamento farmacológico , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade/métodos , Nascido Vivo , Adulto , Carcinoma in Situ/patologia , Estudos de Coortes , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Metformina/administração & dosagem , Recidiva Local de Neoplasia/patologia , Gravidez , Resultado da Gravidez , Progestinas/administração & dosagem , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVES: Recent studies demonstrating decreased survival following minimally invasive surgery (MIS) for cervical cancer have generated concern regarding oncologic efficacy of MIS. Our objective was to evaluate the association between surgical approach and 5-year survival following resection of abdominopelvic malignancies. METHODS: Patients with stage I or II adenocarcinoma of the prostate, colon, rectum, and stage IA2 or IB1 cervical cancer from 2010-2015 were identified from the National Cancer Data Base. The association between surgical approach and 5-year survival was assessed using propensity-score-matched cohorts. Distributions were compared using logistic regression. Hazard ratio for death was estimated using Cox proportional-hazard models. RESULTS: The rate of deaths at 5 years was 3.4% following radical prostatectomy, 22.9% following colectomy, 18.6% following proctectomy, and 6.8% following radical hysterectomy. Open surgery was associated with worse survival following radical prostatectomy (HR, 1.18; 95% CI, 1.05-1.33; P = .005), colectomy (HR, 1.45; 95% CI, 1.39-1.51; P < .001), and proctectomy (HR, 1.28; 95% CI, 1.10-1.50; P = .002); however, open surgery was associated with improved survival following radical hysterectomy (HR, 0.61; 95% CI, 0.44-0.82; P = .003). CONCLUSIONS: These results suggest that MIS is an acceptable approach in selected patients with prostate, colon, and rectal cancers, while concerns regarding MIS resection of cervical cancer appear warranted.
Assuntos
Neoplasias Abdominais/mortalidade , Neoplasias Abdominais/cirurgia , Neoplasias Pélvicas/mortalidade , Neoplasias Pélvicas/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Colectomia/mortalidade , Colectomia/estatística & dados numéricos , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Feminino , Humanos , Histerectomia/mortalidade , Histerectomia/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Protectomia/mortalidade , Protectomia/estatística & dados numéricos , Prostatectomia/mortalidade , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Neoplasias Retais/mortalidade , Neoplasias Retais/cirurgia , Análise de Sobrevida , Estados Unidos/epidemiologia , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/cirurgiaRESUMO
OBJECTIVE: The study purpose was to report the outcomes of patients undergoing endometrial cancer surgical staging with laparoscopic abdominal access entry using a left upper quadrant (LUQ) access technique. METHODS: This was a retrospective cohort study conducted from 1 January 2013 to 1 January 2018. The setting was an academic, single institution gynecologic oncology service with a high volume of minimally invasive surgery (MIS). The patient cohort included obese (defined as BMIâ¯>â¯30â¯kg/m2) or morbidly obese (BMIâ¯>â¯40â¯kg/m2) women undergoing MIS for endometrial cancer staging. All patients underwent laparoscopic abdominal access via a 5-mm or 10-mm optical trocar system using a LUQ technique. RESULTS: In total, 317 patients were included with a median age of 54 years (range, 24-79) and median BMI 42.5â¯kg/m2 (range, 32-70); 60 % morbidly obese. Successful LUQ access was achieved in 98.1 %. Of those with a failed LUQ approach, two had undergone previous LUQ surgery and 4 had ≥1 previous midline vertical incisions. There was one LUQ trocar-related visceral injury (0.3 %) and no vascular injuries during the study period. CONCLUSION: A LUQ abdominal technique is a safe and reliable method of laparoscopic access in morbidly obese women undergoing MIS for endometrial cancer staging. This may be the preferred method of laparoscopic access for women with a panniculus or central adiposity, given the caudal displacement of the umbilicus and poor correlation with intraperitoneal anatomic landmarks in this setting.
Assuntos
Neoplasias do Endométrio/cirurgia , Procedimentos Cirúrgicos em Ginecologia/métodos , Laparoscopia/métodos , Obesidade Mórbida/complicações , Adulto , Idoso , Neoplasias do Endométrio/complicações , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
STUDY OBJECTIVE: To determine the frequency with which Commission on Cancer-accredited hospitals met a metric of ≥80% minimally invasively performed hysterectomies for endometrial cancer and to compare the clinical outcomes of hospitals meeting this metric with those that did not. DESIGN: Retrospective cohort study. SETTING: Hospitals caring for ≥20 endometrial cancer patients per year recorded in the National Cancer Database in 2015 were included. PATIENTS: Women who had undergone hysterectomy for endometrial cancer and had an epithelial histology, a Charlson comorbidity score of 0, and stage I to III disease. INTERVENTION: Patient characteristics, patterns of care, and outcomes were compared between hospitals performing ≥80% minimally invasive hysterectomies and hospitals not meeting this metric. MEASUREMENTS AND MAIN RESULTS: The hospitals (nâ¯=â¯510) treated 20 670 women with endometrial cancer. In 283 (55%) hospitals ≥80% of hysterectomies were minimally invasively performed (high-minimally invasive surgery [MIS] hospitals, overall MIS rate 89%). In the 227 hospitals that did not meet this metric, 61% of hysterectomies for endometrial cancer were performed using a minimally invasive approach. In high-MIS hospitals, patients were more likely to be white (87% vs 82%, p<.001), privately insured (53% vs 49%, p <.001), and have stage I disease (84% vs 82%, pâ¯=â¯.002) and an endometrioid histology (79% vs 76%, p <.001). Surgery was more often performed robotically (80% vs 71%), and conversion to laparotomy was less likely (1.5% vs 3.2%, adjusted odds ratio [aOR], 0.47; 95% confidence interval [CI], 0.39-0.57) (both p <.001). Patients treated at high-MIS hospitals were more likely to have undergone lymph node assessment at the time of surgery (76% vs 69%; aOR, 1.43; 95% CI, 1.35-1.53) and been discharged on the same or next day (74% vs 57%; aOR, 2.27; 95% CI, 2.13-2.42) and were less likely to have an unplanned 30-day readmission (1.8% vs 2.9%; aOR, 0.64; 95% CI, 0.53-0.77). CONCLUSION: An MIS rate of ≥80% for endometrial cancer is feasible on a national scale and is associated with other hospital-level measurements of high-quality care.