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1.
Gynecol Oncol ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31703813

RESUMO

Early endometrial cancer has an overall survival of greater than 80% (1). One of the poor prognostic factors that may be associated with the 20% who do not survive 5 years is the presence of lymphovascular space invasion (LVSI). LVSI is associated with increased nodal metastasis and decreased progression free survival (PFS) and overall survival (OS). (2-8). Therefore, unstaged, LVSI positive early endometrial cancer requires additional management with either completion of staging with lymphadenectomy or adjuvant radiation. We focus on reviewing the management of natural history and management of early endometrial cancer followed by the prognostic impact of LVSI, management options and recommendations.

2.
Am J Clin Oncol ; 42(11): 813-817, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31592805

RESUMO

OBJECTIVES: In endometrial cancer, the appropriate sequence of adjuvant chemotherapy (aCT) and adjuvant radiation therapy (aRT) is unclear. We aim evaluated whether early chemotherapy is associated with improved overall survival (OS) and cancer-specific survival (CSS). METHODS: Endometrial cancer patients that received aCT and aRT were selected from the SEER-Medicare database. Early chemotherapy was defined as receiving aCT before aRT, with or without additional aCT ("sandwich" regimens). All other patients received a full course of aRT before chemotherapy with or without concurrent chemotherapy. Univariate and multivariate Cox proportional hazards regression was utilized to assess the impact of clinical and demographic factors on OS. RESULTS: We selected 597 patients for analysis. Median age and was 72 years; 85% of patients were white. Overall, 68% of women had FIGO (International Federation of Gynecology and Obstetrics) stage III disease and 77% received 4 to 6 cycles of chemotherapy. Five-year OS (66.6% vs. 62.4%, P=0.46) and 5-year CSS (71.1% vs. 71.2%, P=0.88) was not significantly improved among those receiving early chemotherapy. In addition, early chemotherapy did not improve OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]: 0.56-1.34, P=0.53) or CSS (HR=1.21; 95% CI: 0.82-1.79, P=0.34) on multivariate analysis. Compared with 1 to 3 cycles, receiving 4 to 6 (HR=0.48, 95% CI: 0.26-0.87, P=0.02), and ≥7 cycles (HR=0.42, 95% CI: 0.20-0.89, P=0.02) of chemotherapy was associated with improved OS. CONCLUSION: No differences in OS or CSS were noted among endometrial patients receiving early chemotherapy. However, the number of chemotherapy cycles was associated with prolonged survival.

3.
N Engl J Med ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31562800

RESUMO

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

4.
Lancet Oncol ; 20(10): 1409-1419, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31474354

RESUMO

BACKGROUND: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. METHODS: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131. FINDINGS: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. INTERPRETATION: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. FUNDING: Nordic Society of Gynaecological Oncology and Tesaro.

5.
J Natl Compr Canc Netw ; 17(8): 896-909, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390583

RESUMO

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

6.
BMC Public Health ; 19(1): 921, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291920

RESUMO

BACKGROUND: Endometrial cancer is the second most common cancer among female cancer survivors in the US and is increasing in incidence. Rural endometrial cancer patients experience lower survival rates but the reasons for the lower survival are not known. The aim of this study is to examine whether prognostic factors are different for rural and urban patients in a population-based cohort. METHODS: Endometrial cancer patients diagnosed 1997-2012 were identified through the Utah Cancer Registry and Utah Population Database. The address at cancer diagnosis was used to classify patients in rural or urban residences. Demographic and cancer-specific characteristics were examined as prognostic factors for both all-cause and endometrial cancer-specific mortality using Cox proportional hazards models. RESULTS: There were 2,994 endometrial cancer patients and 14.1% of these patients lived in rural areas at diagnosis. Rural endometrial cancer patients were older at cancer diagnosis and did not appear to be different in terms of obesity or overweight at cancer diagnosis. There were no differences for treatment or stage at diagnosis although rural patients had higher proportions of higher grade. Age at diagnosis, poverty, education, and histology were significant prognostic factors for all-cause death. Rural patients with more advanced stages of cancer had significantly increased risks of all-cause and endometrial cancer-specific death than urban patients. Rural endometrial cancer patients diagnosed at advanced stage had a 17-fold increase in the risk of all-cause death compared to an 8-fold increase in death for urban patients. CONCLUSIONS: Rural endometrial cancer patients in Utah were older at diagnosis, had higher grade and higher comorbidities. While urban and rural endometrial cancer patients shared many prognostic factors, the risk of mortality is greater among rural patients with advanced stage endometrial cancer. Future studies should examine where patients are receiving treatment and how that impacts their survival and how to reduce the mortality rates of high risk patients.


Assuntos
Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/terapia , População Rural/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida , Utah/epidemiologia
7.
Am J Clin Oncol ; 42(7): 549-554, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31169554

RESUMO

OBJECTIVES: Lymphovascular space invasion (LVSI) is a known prognostic factor for endometrial carcinomas. However, LVSI as a determinant of treatment benefit has not been fully elucidated. METHODS AND MATERIALS: Data from the National Cancer Database for endometrial cancer from 2004 to 2012 was obtained. Univariate and multivariate analysis was performed to assess the impact of LVSI on overall survival (OS). Survival analysis was performed utilizing log-rank and Kaplan-Meier analyses. The difference in OS between external beam radiation therapy (EBRT) and vaginal brachytherapy (VBT) in LVSI-positive patients was analyzed with propensity score matching. RESULTS: A total of 32,150 patients with surgical stage I to III endometrial carcinomas were available for analysis with a median follow-up of 30 months. Twenty-nine percent were LVSI positive and received adjuvant radiotherapy (aRT) more often than if LVSI negative (57% vs. 37%). On multivariate analysis, LVSI (hazard ratio, 1.94; P<0.01) was associated with an increased risk of death. aRT improved OS for LVSI-negative patients (87% without aRT, 90% with aRT; P=0.006). aRT was particularly effective in LVSI-positive patients: all stages of LVSI-positive patients were associated with an OS benefit (P<0.01), whereas among LVSI-negative patients, only stage III benefited from aRT (P<0.01). After propensity score match, there was no OS difference between EBRT and VBT among LVSI-positive patients (hazard ratio, 1.15; P=0.44). CONCLUSIONS: LVSI is an independent prognostic factor in locoregional endometrial carcinomas. aRT benefited all stages of LVSI-positive patients, but only stage III of LVSI-negative patients. Among LVSI-positive patients, we did not find an OS difference between adjuvant EBRT versus VBT.

8.
Gynecol Oncol ; 154(1): 38-44, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31029507

RESUMO

OBJECTIVE: To analyze our institutional experience and oncologic outcomes for salvage treatment for the recurrence of early-stage endometrial cancer patients. METHODS: We included women of all ages diagnosed with FIGO stage I-II, any grade endometrial cancer from 2000 to 2016 at our institutions who were treated with at least a hysterectomy. Recurrences in the pelvis and/or vagina were considered locoregional recurrences (LRR). Overall survival (OS) was assessed using Kaplan-Meier survival analysis. Univariate (UV) and multivariate (MV) Cox proportional hazards modeling was also used. RESULTS: A total of 2691 women were analyzed. The majority had endometrioid histology (91%), stage IA disease (61%), and were grade 1 (57%). With a median follow-up of 6.1 years, the overall rate of recurrence was 7.2%, and the rate of LRR was 3.7%. Women with vaginal-only recurrences had a longer median OS after recurrence (14.0 years) compared to both pelvic (1.2 years) and distant (1.0 year) failures. For women with vaginal-only recurrences, salvage radiotherapy (RT) was the only factor associated with improved OS on MVA (HR 0.1, p = .04). For women with pelvic recurrences, salvage surgery (HR 0.3, p = .01), salvage RT (HR 0.3, p < .01), and salvage chemotherapy (HR 0.4, p = .03) were associated with improved OS. CONCLUSIONS: Failure rates for women with early-stage endometrial cancer are low. Women with vaginal-only recurrences have improved OS compared to pelvic or distant recurrences. Salvage RT appears to be an important factor for treatment of women with vaginal-only recurrences. Aggressive multimodality treatment may be beneficial for women with pelvic recurrences.


Assuntos
Neoplasias do Endométrio/terapia , Recidiva Local de Neoplasia/terapia , Terapia de Salvação/métodos , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Quimioterapia Adjuvante , Neoplasias do Endométrio/patologia , Feminino , Humanos , Histerectomia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Radioterapia Adjuvante , Resultado do Tratamento
9.
Brachytherapy ; 18(4): 453-461, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31005603

RESUMO

PURPOSE: We sought to retrospectively examine clinical outcomes for three adjuvant vaginal high-dose-rate (HDR) brachytherapy regimens after hysterectomy for early-stage endometrial cancer. METHODS: Included were women of all ages from two independent hospital systems diagnosed with Stage I-II endometrial cancer of any grade between 2000 and 2016 who underwent hysterectomy followed by adjuvant vaginal cylinder HDR brachytherapy with either 7.0 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, 6.5 Gy × 3 fractions prescribed to 0.5 cm vaginal depth, or 6.0 Gy × 5 fractions prescribed to the vaginal surface. Outcomes included vaginal recurrence (VR), pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival. RESULTS: Of the 348 women, 45 (13%) received 7.0 Gy × 3 fractions, 259 (74%) received 6.5 Gy × 3 fractions, and 44 (13%) received 6.0 Gy × 5 fractions. Women receiving 5-fraction brachytherapy were more likely to be younger with a higher performance status. At a median follow-up of 4.5 years, VR rates were 2.2%, 0.8%, and 4.5%, respectively. Multivariate analysis revealed no significant differences in the risks for VR among brachytherapy regimens. Risks for VR, pelvic recurrence, distant recurrence, locoregional recurrence, recurrence-free survival, and overall survival did not differ between propensity score-matched five- and 3-fraction brachytherapy cohorts. CONCLUSIONS: VR rates after hysterectomy and adjuvant vaginal brachytherapy for early-stage endometrial cancer were low and not significantly different by HDR dose fractionation.

10.
Int J Cancer ; 145(7): 1798-1808, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30680712

RESUMO

PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.

11.
Gynecol Oncol ; 151(3): 547-554, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30301561

RESUMO

One woman dies from cervix cancer every 2 min, adding up to over 270,000 deaths globally per year. This cancer affects a young population, and hence, the loss of life is staggering. There are many aspects of prevention, screening, and care that are suboptimal. A great deal is known about HPV induced carcinogenesis, yet clinical outcomes have been stagnant over decades. There has been no improvement in cervix cancer survival in the US since the mid-1970s [1]. With increased knowledge of the disease and greater worldwide resources including prevention, screening, and improved therapeutics, there is significant promise for fewer women to die from this virally induced cancer. We focus here on the major problems in prevention, screening, and delivery of care for cervix cancer and provide concrete solutions. With appropriate focus, a major improvement in survival from cervix cancer could be achieved in a short time span.

12.
J Natl Cancer Inst ; 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29741696

RESUMO

Background: Endometrial cancer is the second most common cancer among female cancer survivors in the United States. Cardiovascular disease is the leading cause of death among endometrial cancer survivors. Studies that examine long-term cardiovascular outcomes among endometrial cancer survivors are critical. Methods: Cohorts of 2648 endometrial cancer survivors diagnosed between 1997 and 2012 and 10 503 age-matched women from the general population were identified. Cardiovascular disease diagnoses were identified from electronic medical records and statewide ambulatory surgery and statewide inpatient data. Cox regression models were used to estimate hazard ratios (HRs) at one to five years, more than five to 10 years, and more than 10 years after cancer diagnosis. Results: Between one and five years after diagnosis, increased cardiovascular risks among endometrial cancer survivors were observed for phlebitis, thrombophlebitis, and thromboembolism (HR = 2.07, 99% confidence interval [CI] = 1.57 to 2.72), pulmonary heart disease (HR = 1.74, 99% CI = 1.26 to 2.40), and atrial fibrillation (HR = 1.50, 99% CI = 1.07 to 2.11). At more than five to 10 years, some elevated risk persisted for cardiovascular diseases. Compared with patients who had surgery, patients who additionally had radiation therapy and/or chemotherapy were at increased risk for heart and circulatory system disorders between one and five years after cancer diagnosis. Older age and obesity were also risk factors for hypertension and heart disease among endometrial cancer survivors. Conclusions: Endometrial cancer survivors are at higher risk for various adverse long-term cardiovascular outcomes compared with women from the general population. This study suggests that increased monitoring for cardiovascular diseases may be necessary for endometrial cancer patients for 10 years after cancer diagnosis.

13.
Cancer Med ; 7(6): 2360-2369, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29733524

RESUMO

The poly(ADP-ribose) polymerase-1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended-release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib-ER up to 800 mg once daily or 600 mg twice daily. Dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28-day cycles). Seventy-one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single-dose veliparib-ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration-time curve compared with veliparib immediate-release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib-ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment-related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib-ER, versus veliparib-IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA-mutated breast cancers.

14.
Nat Commun ; 9(1): 572, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402882

RESUMO

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.

15.
Gynecol Oncol ; 148(3): 499-506, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29289418

RESUMO

OBJECTIVE: With the increasing incidence of endometrial cancer, the high survival rate, and the large number of endometrial cancer survivors, investigations of long-term genitourinary outcomes are important for the management of these outcomes among endometrial cancer survivors. METHODS: Cohorts of 2648 endometrial cancer survivors diagnosed in the state of Utah between 1997 and 2012 and 10,503 general population women were identified. All ICD-9 diagnosis codes were collected from the state's two largest healthcare systems and statewide databases. Multivariate Cox regression models were used to estimate hazard ratios at 1-5years and >5-10years after endometrial cancer diagnosis for genitourinary outcomes. RESULTS: Endometrial cancer survivors were at elevated risk for urinary system disorders between 1 and 5years (HR: 1.64, 95% CI: 1.50-1.78) and >5-10years (HR: 1.40, 95% CI: 1.26-1.56) and genital organ disorders between 1 and 5years (HR: 1.71, 95% CI: 1.58-2.03) and >5-10years (HR: 1.33, 95% CI: 1.19-1.49). Significantly elevated risk was observed among endometrial cancer survivors for renal failure, chronic kidney disease, urinary tract infections, and nonmalignant breast conditions, persisting between >5-10years. Between 1 and 5years after cancer diagnosis, those with higher stage, higher grade, older age and treated with radiation or chemotherapy were at higher risk for urinary disorders. CONCLUSIONS: Endometrial cancer survivors were at higher risk for many genitourinary outcomes compared to women from the general population. This study presents evidence suggesting the necessity of increased monitoring and counseling for genitourinary disorders for endometrial cancer patients both immediately after treatment cessation and for years afterwards.


Assuntos
Adenocarcinoma/terapia , Antineoplásicos/uso terapêutico , Doenças Mamárias/epidemiologia , Neoplasias do Endométrio/terapia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Radioterapia/métodos , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal/epidemiologia , Infecções Urinárias/epidemiologia , Adenocarcinoma/patologia , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Sobreviventes de Câncer , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Estudos de Coortes , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/patologia , Modelos de Riscos Proporcionais , Fatores de Risco , Utah/epidemiologia
16.
Am J Clin Oncol ; 41(8): 784-791, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28121642

RESUMO

OBJECTIVES: Uterine carcinosarcoma (UCS) is a rare and aggressive cancer with poor survival. Our purpose was to evaluate the patterns-of-care and overall survival (OS) benefit of adjuvant chemoradiation (aCRT) compared with adjuvant chemotherapy (aCT) among UCS patients. METHODS: A query was made in the National Cancer Database to identify patients with UCS diagnosed between 2004 and 2012. Factors predictive of OS were determined using univariate and multivariate Cox regression analysis, as well as Kaplan-Meier and log-rank analysis. Propensity-score matching was employed to decrease the potential influence of selection bias. RESULTS: A total of 3538 patients were identified for analysis, consisting of 1787 patients (50.5%) receiving aCT and 1751 (49.5%) receiving aCRT. The median age of patients was 65 years. The majority of patients in our cohort were white (68.6%), on Medicare insurance (47.9%), with >5 cm tumor size (59.9%), and received a lymph node surgery (87.9%). The following factors were predictive of aCRT use: undergoing lymph node surgery (odds ratio, 1.59, P=0.01), and FIGO stage II (odds ratio, 1.71, P=0.01). Median survival for the aCT and aCRT groups was 24 months and 31.3 months, respectively. When compared with aCT alone, aCRT was associated with a benefit in OS on multivariate analysis (hazard ratio, 0.65, P<0.01). CONCLUSIONS: When compared with aCT alone, the use of aCRT in UCS patients was associated with a significant OS benefit. Multiple demographic and clinical factors significantly influence the choice of adjuvant therapy in this setting.

17.
Int J Gynecol Cancer ; 28(1): 152-160, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28953502

RESUMO

OBJECTIVES: AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFß), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). This study evaluates the efficacy of AL3818 studying tumor regression in an orthotopic murine endometrial cancer model. METHODS: We tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model. AL3818 was administered daily per os either alone or in combination with carboplatin and paclitaxel, which represent the current standard of adjuvant care for endometrial cancer. RESULTS: AL3818 significantly reduces AN3CA cell number in vitro, characterized by high expression of a mutated FGFR2 protein. Daily oral administration of AL3818 (5 mg/kg) resulted in a complete response in 55% of animals treated and in a reduced tumor volume, as well as decreased tumor weights of AN3CA tumors by 94% and 96%, respectively, following a 29-day treatment cycle. Whereas carboplatin and paclitaxel failed to alter tumor growth, the combination with AL3818 did not seem to exhibit a superior effect when compared with AL3818 treatment alone. CONCLUSIONS: AL3818 shows superior efficacy for the treatment of endometrial cancer irresponsive to conventional carboplatin and paclitaxel combination and warrants further investigation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Indóis/farmacologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Animais , Carboplatina/administração & dosagem , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Endométrio/enzimologia , Feminino , Humanos , Indóis/administração & dosagem , Camundongos , Camundongos Nus , Paclitaxel/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Distribuição Aleatória , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Nat Commun ; 8(1): 1231, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093439

RESUMO

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Evolução Clonal , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Mama/patologia , Células Cultivadas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Fenótipo , Transdução de Sinais/genética , Análise de Célula Única/métodos
19.
J Cell Sci ; 130(19): 3347-3359, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28751496

RESUMO

DNA double-strand breaks are typically repaired through either the high-fidelity process of homologous recombination (HR), in which BRCA1 plays a key role, or the more error-prone process of non-homologous end joining (NHEJ), which relies on 53BP1. The balance between NHEJ and HR depends, in part, on whether 53BP1 predominates in binding to damage sites, where it protects the DNA ends from resection. The nucleoporin Nup153 has been implicated in the DNA damage response, attributed to a role in promoting nuclear import of 53BP1. Here, we define a distinct requirement for Nup153 in 53BP1 intranuclear targeting to damage foci and report that Nup153 likely facilitates the role of another nucleoporin, Nup50, in 53BP1 targeting. The requirement for Nup153 and Nup50 in promoting 53BP1 recruitment to damage foci induced by either etoposide or olaparib is abrogated in cells deficient for BRCA1 or its partner BARD1, but not in cells deficient for BRCA2. Together, our results further highlight the antagonistic relationship between 53BP1 and BRCA1, and place Nup153 and Nup50 in a molecular pathway that regulates 53BP1 function by counteracting BRCA1-mediated events.


Assuntos
Proteína BRCA1/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Proteína BRCA1/genética , Células HeLa , Humanos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas Nucleares/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
20.
Clin Breast Cancer ; 17(7): 503-509, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28579139

RESUMO

BACKGROUND: The aims of this study were to assess the safety and tolerability of nanoparticle albumin bound paclitaxel (nab-paclitaxel), doxorubicin, and cyclophosphamide as combination therapy for breast cancer patients in the neoadjuvant setting and to assess the overall clinical response and pathologic complete response (pCR). PATIENTS AND METHODS: Twenty-six women with newly diagnosed stage II to III histologically or cytologically proven adenocarcinoma of the breast with negative HER2 status were enrolled. Patients were treated with nab-paclitaxel 100 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 on day 1 and nab-paclitaxel 100 mg/m2 on day 8 in a 21-day cycle for 6 cycles total. RESULTS: Most adverse events attributed to treatment were decreased white blood cell count, neutropenia, anemia, thrombocytopenia, and lymphopenia with a median duration of 8 days. Fifteen of 23 (65.2%; 95% confidence interval [CI], 45.7%-84.6%) had a complete clinical response and 8 of 23 (34.7%; 95% CI, 15.2%-54.1%) had a partial clinical response for an overall clinical response rate of 100%. Thirteen of 23 patients (56.5%; 95% CI, 36.2%-76.7%) had a pCR. All 10 triple-negative breast cancer (TNBC) patients (100%) achieved a pCR. CONCLUSION: The regimen of nab-paclitaxel, doxorubicin, and cyclophosphamide chemotherapy was well tolerated and resulted in high clinical as well as pathologic responses, particularly in TNBC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Adulto , Idoso , Albuminas/administração & dosagem , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico
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