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1.
Gynecol Oncol ; 186: 126-136, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38669767

RESUMO

OBJECTIVE: Overweight/obesity is the strongest risk factor for endometrial cancer (EC), and weight management can reduce that risk and improve survival. We aimed to establish the differential benefits of intermittent energy restriction (IER) and low-fat diet (LFD), alone and in combination with paclitaxel, to reverse the procancer effects of high-fat diet (HFD)-induced obesity in a mouse model of EC. METHODS: Lkb1fl/flp53fl/fl mice were fed HFD or LFD to generate obese and lean phenotypes, respectively. Obese mice were maintained on a HFD or switched to a LFD (HFD-LFD) or IER (HFD-IER). Ten weeks after induction of endometrial cancer, mice in each group received paclitaxel or placebo for 4 weeks. Body and tumor weights; tumoral transcriptomic, metabolomic and oxylipin profiles; and serum metabolic hormones and chemocytokines were assessed. RESULTS: HFD-IER and HFD-LFD, relative to HFD, reduced body weight; reversed obesity-induced alterations in serum insulin, leptin and inflammatory factors; and decreased tumor incidence and mass, often to levels emulating those associated with continuous LFD. Concurrent paclitaxel, versus placebo, enhanced tumor suppression in each group, with greatest benefit in HFD-IER. The diets produced distinct tumoral gene expression and metabolic profiles, with HFD-IER associated with a more favorable (antitumor) metabolic and inflammatory environment. CONCLUSION: In Lkb1fl/flp53fl/fl mice, IER is generally more effective than LFD in promoting weight loss, inhibiting obesity-related endometrial tumor growth (particularly in combination with paclitaxel), and reversing detrimental obesity-related metabolic effects. These findings lay the foundation for further investigations of IER as an EC prevention and treatment strategies in overweight/obesity women.


Assuntos
Dieta Hiperlipídica , Neoplasias do Endométrio , Camundongos Transgênicos , Obesidade , Paclitaxel , Animais , Feminino , Paclitaxel/farmacologia , Paclitaxel/administração & dosagem , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Camundongos , Obesidade/metabolismo , Dieta Hiperlipídica/efeitos adversos , Restrição Calórica/métodos , Modelos Animais de Doenças , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem
2.
Gynecol Oncol ; 164(2): 304-310, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34922769

RESUMO

BACKGROUND: Despite significant increase in COVID-19 publications, characterization of COVID-19 infection in patients with gynecologic cancer remains limited. Here we present an update of COVID-19 outcomes among people with gynecologic cancer in New York City (NYC) during the initial surge of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]). METHODS: Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 NYC area hospital systems between March and June 2020. Multivariable logistic regression was utilized to estimate associations between factors and COVID-19 related hospitalization and mortality. RESULTS: Of 193 patients with gynecologic cancer and COVID-19, the median age at diagnosis was 65.0 years (interquartile range (IQR), 53.0-73.0 years). One hundred six of the 193 patients (54.9%) required hospitalization; among the hospitalized patients, 13 (12.3%) required invasive mechanical ventilation, 39 (36.8%) required ICU admission. Half of the cohort (49.2%) had not received anti-cancer treatment prior to COVID-19 diagnosis. No patients requiring mechanical ventilation survived. Thirty-four of 193 (17.6%) patients died of COVID-19 complications. In multivariable analysis, hospitalization was associated with an age ≥ 65 years (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.11, 4.07), Black race (OR 2.53, CI 1.24, 5.32), performance status ≥2 (OR 3.67, CI 1.25, 13.55) and ≥ 3 comorbidities (OR 2.00, CI 1.05, 3.84). Only former or current history of smoking (OR 2.75, CI 1.21, 6.22) was associated with death due to COVID-19 in multivariable analysis. Administration of cytotoxic chemotherapy within 90 days of COVID-19 diagnosis was not predictive of COVID-19 hospitalization (OR 0.83, CI 0.41, 1.68) or mortality (OR 1.56, CI 0.67, 3.53). CONCLUSIONS: The case fatality rate among patients with gynecologic malignancy with COVID-19 infection was 17.6%. Cancer-directed therapy was not associated with an increased risk of mortality related to COVID-19 infection.


Assuntos
COVID-19/complicações , COVID-19/mortalidade , Carcinoma/complicações , Carcinoma/mortalidade , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/mortalidade , Hospitalização/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/terapia , Carcinoma/terapia , Feminino , Neoplasias dos Genitais Femininos/terapia , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Gravidade do Paciente , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
3.
Gynecol Oncol ; 167(2): 146-151, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36154761

RESUMO

OBJECTIVES: Patients with gynecologic malignancies may have varied responses to COVID-19 infection. We aimed to describe clinical courses, treatment changes, and short-term clinical outcomes for gynecologic oncology patients with concurrent COVID-19 in the United States. METHODS: The Society of Gynecologic Oncology COVID-19 and Gynecologic Cancer Registry was created to capture clinical courses of gynecologic oncology patients with COVID-19. Logistic regression models were employed to evaluate factors for an association with hospitalization and death, respectively, within 30 days of COVID-19 diagnosis. RESULTS: Data were available for 348 patients across 7 institutions. At COVID-19 diagnosis, 125 patients (36%) had active malignancy. Delay (n = 88) or discontinuation (n = 10) of treatment due to COVID-19 infection occurred in 28% with those on chemotherapy (53/88) or recently receiving surgery (32/88) most frequently delayed. In addition to age, performance status, diabetes, and specific COVID symptoms, both non-White race (adjusted odds ratio (aOR) = 3.93, 95% CI 2.06-7.50) and active malignancy (aOR = 2.34, 95% CI 1.30-4.20) were associated with an increased odds of hospitalization. Eight percent of hospitalized patients (8/101) died of COVID-19 complications and 5% (17/348) of the entire cohort died within 30 days after diagnosis. CONCLUSIONS: Gynecologic oncology patients diagnosed with COVID-19 are at risk for hospitalization, delay of anti-cancer treatments, and death. One in 20 gynecologic oncology patients with COVID-19 died within 30 days after diagnosis. Racial disparities exist in patient hospitalizations for COVID-19, a surrogate of disease severity. Additional studies are needed to determine long-term outcomes and the impact of race.


Assuntos
COVID-19 , Neoplasias dos Genitais Femininos , Humanos , Feminino , Estados Unidos/epidemiologia , COVID-19/terapia , Neoplasias dos Genitais Femininos/terapia , Teste para COVID-19 , Hospitalização , Sistema de Registros , Estudos Retrospectivos
4.
Cancer ; 127(7): 1057-1067, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33294978

RESUMO

BACKGROUND: Mounting evidence suggests disproportionate coronavirus disease 2019 (COVID-19) hospitalizations and deaths because of racial disparities. The association of race in a cohort of gynecologic oncology patients with severe acute respiratory syndrome-coronavirus 2 infection is unknown. METHODS: Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 New York City area hospital systems. A multivariable mixed-effects logistic regression model accounting for county clustering was used to analyze COVID-19-related hospitalization and mortality. RESULTS: Of 193 patients who had gynecologic cancer and COVID-19, 67 (34.7%) were Black, and 126 (65.3%) were non-Black. Black patients were more likely to require hospitalization compared with non-Black patients (71.6% [48 of 67] vs 46.0% [58 of 126]; P = .001). Of 34 (17.6%) patients who died from COVID-19, 14 (41.2%) were Black. Among those who were hospitalized, compared with non-Black patients, Black patients were more likely to: have ≥3 comorbidities (81.1% [30 of 37] vs 59.2% [29 of 49]; P = .05), to reside in Brooklyn (81.0% [17 of 21] vs 44.4% [12 of 27]; P = .02), to live with family (69.4% [25 of 36] vs 41.6% [37 of 89]; P = .009), and to have public insurance (79.6% [39 of 49] vs 53.4% [39 of 73]; P = .006). In multivariable analysis, among patients aged <65 years, Black patients were more likely to require hospitalization compared with non-Black patients (odds ratio, 4.87; 95% CI, 1.82-12.99; P = .002). CONCLUSIONS: Although Black patients represented only one-third of patients with gynecologic cancer, they accounted for disproportionate rates of hospitalization (>45%) and death (>40%) because of COVID-19 infection; younger Black patients had a nearly 5-fold greater risk of hospitalization. Efforts to understand and improve these disparities in COVID-19 outcomes among Black patients are critical.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , COVID-19/etnologia , Neoplasias dos Genitais Femininos/etnologia , Disparidades nos Níveis de Saúde , População Branca/estatística & dados numéricos , Adulto , Idoso , COVID-19/complicações , COVID-19/virologia , Feminino , Neoplasias dos Genitais Femininos/complicações , Hospitalização/estatística & dados numéricos , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Cidade de Nova Iorque , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/fisiologia , Análise de Sobrevida
5.
Cancer ; 126(4): 800-807, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730714

RESUMO

BACKGROUND: Racial disparities in cancer outcomes are increasingly recognized, but comprehensive analyses, including molecular studies, are limited. The objective of the current study was to perform a pan-cancer clinical and epigenetic molecular analysis of outcomes in African American (AA) and European American (EA) patients. METHODS: Cross-platform analyses using cancer databases (the Surveillance, Epidemiology, and End Results program database and the National Cancer Data Base) and a molecular database (The Cancer Genome Ancestry Atlas) were performed to evaluate clinical and epigenetic molecular differences between AA and EA patients based on genetic ancestry. RESULTS: In the primary pan-cancer survival analysis using the Surveillance, Epidemiology, and End Results database (2,045,839 patients; 87.5% EA and 12.5% AA), AA patients had higher mortality rates for 28 of 42 cancer types analyzed (hazard ratio, >1.0). AAs continued to have higher mortality in 13 cancer types after adjustment for socioeconomic variables using the National Cancer Database (5,150,023 patients; 11.6% AA and 88.4% EA). Then, molecular features of 5,283 tumors were analyzed in patients who had genetic ancestry data available (87.2% EA and 12.8% AA). Genes were identified with altered DNA methylation along with increased microRNA expression levels unique to AA patients that are associated with cancer drug resistance. Increased miRNAs (miR-15a, miR-17, miR-130-3p, miR-181a) were noted in common among AAs with breast, kidney, thyroid, or prostate carcinomas. CONCLUSIONS: The current results identified epigenetic features in AA patients who have cancer that may contribute to higher mortality rates compared with EA patients who have cancer. Therefore, a focus on molecular signatures unique to AAs may identify actionable molecular abnormalities.


Assuntos
Negro ou Afro-Americano/genética , Epigênese Genética/genética , Disparidades nos Níveis de Saúde , MicroRNAs/genética , Neoplasias/genética , População Branca/genética , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/etnologia , Programa de SEER/estatística & dados numéricos , Análise de Sobrevida , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricos
6.
Cancer ; 126(19): 4294-4303, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32729142

RESUMO

BACKGROUND: New York City (NYC) is the epicenter of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) in the United States. Clinical characteristics and outcomes of vulnerable populations, such as those with gynecologic cancer who develop COVID-19 infections, is limited. METHODS: Patients from 6 NYC-area hospital systems with known gynecologic cancer and a COVID-19 diagnosis were identified. Demographic and clinical outcome data were abstracted through a review of electronic medical records. RESULTS: Records for 121 patients with gynecologic cancer and COVID-19 were abstracted; the median age at the COVID-19 diagnosis was 64.0 years (interquartile range, 51.0-73.0 years). Sixty-six of the 121 patients (54.5%) required hospitalization; among the hospitalized patients, 45 (68.2%) required respiratory intervention, 20 (30.3%) were admitted to the intensive care unit, and 9 (13.6%) underwent invasive mechanical ventilation. Seventeen patients (14.0%) died of COVID-19 complications. No patient requiring mechanical ventilation survived. On multivariable analysis, hospitalization was associated with an age ≥64 years (risk ratio [RR], 1.73; 95% confidence interval [CI], 1.18-2.51), African American race (RR, 1.56; 95% CI, 1.13-2.15), and 3 or more comorbidities (RR, 1.43; 95% CI, 1.03-1.98). Only recent immunotherapy use (RR, 3.49; 95% CI, 1.08-11.27) was associated with death due to COVID-19 on multivariable analysis; chemotherapy treatment and recent major surgery were not predictive of COVID-19 severity or mortality. CONCLUSIONS: The case fatality rate among gynecologic oncology patients with a COVID-19 infection is 14.0%. Recent immunotherapy use is associated with an increased risk of mortality related to COVID-19 infection. LAY SUMMARY: The case fatality rate among gynecologic oncology patients with a coronavirus disease 2019 (COVID-19) infection is 14.0%; there is no association between cytotoxic chemotherapy and cancer-directed surgery and COVID-19 severity or death. As such, patients can be counseled regarding the safety of continued anticancer treatments during the pandemic. This is important because the ability to continue cancer therapies for cancer control and cure is critical.


Assuntos
COVID-19/mortalidade , COVID-19/terapia , Neoplasias dos Genitais Femininos/epidemiologia , Idoso , COVID-19/epidemiologia , COVID-19/etiologia , Comorbidade , Feminino , Neoplasias dos Genitais Femininos/terapia , Hospitalização , Humanos , Imunoterapia , Unidades de Terapia Intensiva , Pessoa de Meia-Idade , Cidade de Nova Iorque , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
7.
Gynecol Oncol ; 159(3): 618-622, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33019984

RESUMO

OBJECTIVE: Elevated inflammatory markers are predictive of COVID-19 infection severity and mortality. It is unclear if these markers are associated with severe infection in patients with cancer due to underlying tumor related inflammation. We sought to further understand the inflammatory response related to COVID-19 infection in patients with gynecologic cancer. METHODS: Patients with a history of gynecologic cancer hospitalized for COVID-19 infection with available laboratory data were identified. Admission laboratory values and clinical outcomes were abstracted from electronic medical records. Severe infection was defined as infection requiring ICU admission, mechanical ventilation, or resulting in death. RESULTS: 86 patients with gynecologic cancer were hospitalized with COVID-19 infection with a median age of 68.5 years (interquartile range (IQR), 59.0-74.8). Of the 86 patients, 29 (33.7%) patients required ICU admission and 25 (29.1%) patients died of COVID-19 complications. Fifty (58.1%) patients had active cancer and 36 (41.9%) were in remission. Patients with severe infection had significantly higher ferritin (median 1163.0 vs 624.0 ng/mL, p < 0.01), procalcitonin (median 0.8 vs 0.2 ng/mL, p < 0.01), and C-reactive protein (median 142.0 vs 62.3 mg/L, p = 0.02) levels compared to those with moderate infection. White blood cell count, lactate, and creatinine were also associated with severe infection. D-dimer levels were not significantly associated with severe infection (p = 0.20). CONCLUSIONS: The inflammatory markers ferritin, procalcitonin, and CRP were associated with COVID-19 severity in gynecologic cancer patients and may be used as prognostic markers at the time of admission.


Assuntos
Proteína C-Reativa/análise , COVID-19/diagnóstico , Neoplasias dos Genitais Femininos/imunologia , Inflamação/diagnóstico , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Feminino , Neoplasias dos Genitais Femininos/sangue , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/diagnóstico , Humanos , Inflamação/sangue , Inflamação/imunologia , Contagem de Leucócitos , Pessoa de Meia-Idade , Admissão do Paciente , Prognóstico , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença
8.
Int J Gynecol Cancer ; 28(8): 1485-1490, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30036226

RESUMO

OBJECTIVE: Establishing an accurate histologic diagnosis is essential for determining the appropriate course of therapy for ovarian cancer. This study sought to investigate and describe nonovarian cancer pathologies discovered during the systematic laparoscopic workup of presumed advanced ovarian cancer. METHODS: A retrospective cohort of patients with presumed advanced ovarian cancer (based on elevated CA125 and/or imaging) presenting to our center without confirmed pathologic diagnosis were identified and characterized. Patients without ovarian cancer on final pathology were described and compared with those with confirmed epithelial ovarian cancer using standard statistical methods. RESULTS: Nonovarian cancer was found in 26 (7.1%) of 365 cases over 3.5 years of study, and included benign ovarian pathology, and metastatic uterine, breast, and gastrointestinal cancers. Most nonovarian cancer cases could not be diagnosed with percutaneous biopsy, and instead used diagnostic laparoscopy or assessment at the time of laparotomy for diagnosis (58%). No patient received inappropriate treatment. Nonovarian cancer cases were more likely to be nonwhite (P = 0.003), have a better Eastern Cooperative Oncology Group performance status (P < 0.001), and have a lower CA125 value (P < 0.001), and were less likely to have pleural effusions (P = 0.04). CONCLUSIONS: A systematic laparoscopic triage approach to advanced-stage ovarian cancer eliminates incorrect neoadjuvant chemotherapy administration and inappropriate laparotomy. This algorithm identified a population of women who are more likely to have nonovarian cancer pathology. Increasing screening efforts should be focused on conclusive diagnosis with the least invasive testing possible.


Assuntos
Doenças Ovarianas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Laparoscopia/métodos , Pessoa de Meia-Idade , Doenças Ovarianas/patologia , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Adulto Jovem
9.
Clin Lymphoma Myeloma Leuk ; 24(7): 478-483, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38555259

RESUMO

BACKGROUND: Multiple myeloma (MM) is a disease with unspecific initial symptoms which may lead into a delay in the diagnosis, seemingly increasing the risk of complications and in turn reducing the overall survival (OS). OBJECTIVE: To analyze the consequences of a delayed diagnosis of MM in both the OS and the progression-free survival (PFS) of the patients in a single center in México. METHODS: The study included patients with MM who were diagnosed at Clínica Ruiz, Puebla, México, between 1983 and 2022. According to the time elapsed between the onset of symptoms to the establishment of the definite diagnosis of MM, 4 groups were constructed: 1) Less than 3 months, 2) 3-6 months, 3) 6-12 months, and 4) More than 12 months. RESULTS: About 136 patients had a complete clinical record and at least a 3-month follow up period. A delay in the diagnosis of MM (more than 3 months from the onset of symptoms) was recorded in 92/136 persons (68%). The median follow-up for the whole group was 24.7 months, median OS was 131.4 months, whereas median PFS was 85.4 months. There was a significant trend for being in earlier stages of the disease and being diagnosed within 3 months from the onset of symptoms (P = .049). Both OS and PFS were similar in the patients diagnosed before or after 3 months from the symptoms onset (P = .772). The 6-12 months group was the group with the better median both OS (197.4 months) and DFS (197.4) from the diagnosis. The median OS for the other groups were similar among them. CONCLUSION: A delay in the diagnosis of MM is very frequent in México (68% of cases); despite the fact that there was a significant trend for being in earlier stages of the disease and being diagnosed within 3 months from the onset of symptoms, we did not find a relationship between a delay on the diagnosis of the disease and a higher risk of complications and/or poor prognosis. Possible explanations to these findings are discussed.


Assuntos
Diagnóstico Tardio , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Prevalência , Adulto , Idoso de 80 Anos ou mais , México/epidemiologia
10.
Int J Lab Hematol ; 46(4): 620-626, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38421242

RESUMO

INTRODUCTION: Biomarkers that help to evaluate the immune system and could be useful in multiple sclerosis (MS) are the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII). The objective of this work is to evaluate the significance of the SII index, PLR, and NLR before and after transplantation in individuals with MS who underwent autologous hematopoietic stem cell transplant (aHSCT) at a single institution. METHODS: Patients with MS who received an aHSCT between 2017 and 2022 were included in the study. NLR, PLR, and SII index were calculated prior to the transplant and 100 days after, and evaluation of the expanded disability status scale (EDSS) was done before the transplant and 12 months after. The cohort was divided into two groups: aHSCT responders (R) and nonresponders (NR). RESULTS: Fifty-eight individuals were examined: 37 patients in the responders group R group and 21 in NR group. There was no statistically significant difference in the SII, NLR, and PLR prior to the transplant, however at 100 days post-HSCT, NLR in the R group was 1.8 versus 3.1 in the NR group (p = 0.003), PLR was 194 versus 295, respectively (p = 0.024), meanwhile SII index was 489.5 versus 729.3 (p < 0.001). CONCLUSION: High NLR and SII index values after the aHSCT were associated with a worsening in the EDSS score. However, since this is the first ever study that compared NLR and SII index with the aHSCT response in persons with MS, further studies must be performed to corroborate this information.


Assuntos
Biomarcadores , Transplante de Células-Tronco Hematopoéticas , Linfócitos , Esclerose Múltipla , Neutrófilos , Transplante Autólogo , Humanos , Feminino , Masculino , Adulto , Esclerose Múltipla/terapia , Esclerose Múltipla/sangue , Biomarcadores/sangue , Pessoa de Meia-Idade , Inflamação/sangue , Contagem de Linfócitos
11.
Cancer Res Commun ; 2(2): 99-109, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35992327

RESUMO

The difference in cancer morbidity and mortality between individuals of different racial groups is complex. Health disparities provide a framework to explore potential connections between poor outcomes and individuals of different racial backgrounds. This study identifies genomic changes in African-American patients with gynecologic malignancies, a population with well-established disparities in outcomes. Our data explore whether social health disparities might mediate interactions between the environment and tumor epigenomes and genomes that can be identified. Using The Cancer Genetic Ancestry Atlas, which encodes data from The Cancer Genome Atlas by ancestry and allows for systematic analyses of sequencing data by racial group, we performed large-scale, comparative analyses to identify novel targets with alterations in methylation, transcript, and microRNA expression between tumors from women of European American or African American racial groups across all gynecologic malignancies. We identify novel discrete genomic changes in these complex malignancies and suggest a framework for identifying novel therapeutic targets for future investigation.


Assuntos
Neoplasias dos Genitais Femininos , Humanos , Feminino , Neoplasias dos Genitais Femininos/genética , Grupos Raciais , Negro ou Afro-Americano/genética , Genômica , Brancos
12.
Cell Rep ; 36(7): 109549, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34407412

RESUMO

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.


Assuntos
Vesículas Extracelulares/metabolismo , Tetraspanina 30/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Animais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Vesículas Extracelulares/ultraestrutura , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Ovarianas/tratamento farmacológico , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
13.
Oncotarget ; 11(29): 2819-2833, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32754300

RESUMO

BACKGROUND: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in gynecologic cancer models. MATERIALS AND METHODS: Murine orthotopic models of ovarian (OVCAR5 and SKOV3ip1) and uterine (Hec1a) cancer were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2. FINDINGS: Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer (OVCAR5, SKOV3ip1) by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Treatment with L-Grb2 and paclitaxel led to the greatest decrease in tumor weight (mean ± SEM, 0.17 g ± 0.10 g) compared with that in control mice (0.99 g ± 0.35 g). We also observed a reduction in tumor burden after treatment with L-Grb2 and the anti-VEGF antibody B-20 (86% decrease in tumor weight compared with that in controls). Ovarian cancer cells with ErbB2 amplification (OVCAR8 and SKOV3ip1) were the most sensitive to Grb2 downregulation. Reverse phase protein array analysis identified significant dysregulation of metabolites (LDHA, GAPDH, and TCA intermediates) in ovarian cancer cells after Grb2 downregulation. INTERPRETATION: L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. These findings support further clinical development of L-Grb2.

14.
Cell Rep ; 31(2): 107502, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32294438

RESUMO

The diversity and heterogeneity within high-grade serous ovarian cancer (HGSC), which is the most lethal gynecologic malignancy, is not well understood. Here, we perform comprehensive multi-platform omics analyses, including integrated analysis, and immune monitoring on primary and metastatic sites from highly clinically annotated HGSC samples based on a laparoscopic triage algorithm from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT) with excellent or poor response. We identify significant distinct molecular abnormalities and cellular changes and immune cell repertoire alterations between the groups, including a higher rate of NF1 copy number loss, and reduced chromothripsis-like patterns, higher levels of strong-binding neoantigens, and a higher number of infiltrated T cells in the R0 versus the NACT groups.


Assuntos
Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Adulto , Feminino , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Humanos , Metabolômica/métodos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética
15.
Sci Rep ; 9(1): 17589, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772388

RESUMO

The prognostic and therapeutic value of the tumor microenvironment (TME) in various cancer types is of major interest. Characterization of the TME often relies on a small representative tissue sample. However, the adequacy of such a sample for assessing components of the TME is not yet known. Here, we used immunohistochemical (IHC) staining and 7-color multiplex staining to evaluate CD8 (cluster of differentiation 8), CD68, PD-L1 (programmed death-ligand 1), CD34, FAP (fibroblast activation protein), and cytokeratin in 220 tissue cores from 26 high-grade serous ovarian cancer samples. Comparisons were drawn between a larger tumor specimen and smaller core biopsies based on number and location (central tumor vs. peripheral tumor) of biopsies. Our analysis found that the correlation between marker-specific cell subsets in larger tumor versus smaller core was stronger with two core biopsies and was not further strengthened with additional biopsies. Moreover, this correlation was consistently strong regardless of whether the biopsy was taken at the center or at the periphery of the original tumor sample. These findings could have a substantial impact on longitudinal assessment for detection of biomarkers in clinical trials.


Assuntos
Biópsia com Agulha de Grande Calibre , Cistadenocarcinoma Seroso/patologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral/imunologia , Algoritmos , Biópsia com Agulha de Grande Calibre/métodos , Contagem de Células , Cistadenocarcinoma Seroso/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Ovarianas/imunologia , Coloração e Rotulagem/métodos , Células Estromais/imunologia , Células Estromais/patologia , Análise Serial de Tecidos
16.
Oncotarget ; 9(38): 25115-25126, 2018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29861857

RESUMO

Primary debulking surgery followed by adjuvant chemotherapy is the standard treatment for ovarian cancer. Residual disease after primary surgery is associated with poor patient outcome. Previously, we discovered ADH1B to be a molecular biomarker of residual disease. In the current study, we investigated the functional role of ADH1B in promoting ovarian cancer cell invasiveness and contributing to residual disease. We discovered that ADH1B overexpression leads to a more infiltrative cancer cell phenotype, promotes metastasis, increases the adhesion of cancer cells to mesothelial cells, and increases extracellular matrix degradation. Live cell imaging revealed that ADH1B-overexpressing cancer cells efficiently cleared the mesothelial cell layer compared to control cells. Moreover, gene array analysis revealed that ADH1B affects several pathways related to the migration and invasion of cancer cells. We also discovered that hypoxia increases ADH1B expression in ovarian cancer cells. Collectively, these findings indicate that ADH1B plays an important role in the pathways that promote ovarian cancer cell infiltration and may increase the likelihood of residual disease following surgery.

18.
Rev. enferm. Inst. Mex. Seguro Soc ; 19(1): 29-34, Enero–Abr. 2011. tab, ilus
Artigo em Espanhol | LILACS, BDENF - enfermagem (Brasil) | ID: biblio-1031135

RESUMO

Resumen


Objetivo: evaluar la estrategia educativa de visita del profesor para mejorar la calidad en la toma de citología cervical del programa DOCCACU en IMSS Zona Xalapa, Veracruz.


Metodología: en la primera fase se aplicó un instrumento con preguntas abiertas y una lista de verificación que describe la técnica, al personal que toma las muestras. En la segunda fase se desarrolló la intervención educativa visita de profesor y en la tercera fase nuevamente se aplicó la misma herramienta con observación directa del procedimiento. El impacto se midió comparando la proporción de laminillas adecuadas antes del estudio y tres meses después de la intervención educativa.


Resultados: se evaluaron 89 enfermeras antes de la capacitación con una media de aciertos de seis, después de la capacitación la media fue de 11, con un valor de p < 0.05. En cuanto al impacto de la capacitación sobre el programa, encontramos que en el 2009 de junio a septiembre, las muestras inadecuadas fueron 208, en el 2010 en el mismo periodo de tiempo, después de la estrategia educativa fueron 151, con un valor de p < 0.05.


Conclusión: dentro de las instituciones del sector salud existen indicadores que nos hablan de cobertura e impacto en la población pero muy pocos que nos hablen de la calidad de los procesos, lo cual se ve reflejado en las tasas de mortalidad. La estrategia educativa de visita del profesor mejora la calidad de la toma de la muestra al disminuir el número de muestras inadecuadas y aumentar la detección de lesiones así como mejora el conocimiento en los alumnos.


Summary


Objective: to evaluate the educational strategy of teacher’s visit to improve the quality of the specimen collection for Cervicovaginal Cytology of the Program Opportune detection of Cervico-uterine Cancer in the units of Familiar Medicine of the Instituto Mexicano del Seguro Social (IMSS) of the Zone Xalapa, Veracruz, Mexico.


Methodology: in the first phase a questionnaire was applied by opened questions and a list of check that describes the technique, to the personnel that takes the slides. The second phase developed the educational intervention (the visit of the teacher) and in the third phase again the same tool was applied by direct observation of the procedure. The impact was measured up comparing the proportion of good technique realized slides before the study and the ones realized 3 months after the educational intervention


Results: there were evaluated a total of 89 nurses finding before the training an average of successes of 6 slides, and after the training an average of 11, with a value of p minor of 0.05. As for the impact of the training on the program, we find that in 2009 from June to September, the inadequate technique realized slides samples were 208, in 2010 in the same period of time, after the educational strategy they were 151, with a value of p of 0.001.


Conclusion: the Health Sector has documents that indicate about coverage and Impact in the population but very few ones which speak about the quality of the process, which seems reflected in the rates of mortality. The educational strategy of teacher’s visit improves the quality of the specimen collection, decreasing the number of inadequate specimen collection and increasing the detection of injuries, as well as it improves the knowledge in the pupils.


Assuntos
Humanos , Biologia Celular , Coleta de Dados , Detecção Precoce de Câncer , Estratégias de Saúde , Neoplasias , Neoplasias Vaginais , Neoplasias do Colo do Útero , México , Humanos
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