RESUMEN
VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.
Asunto(s)
Diabetes Mellitus , Preeclampsia , Femenino , Humanos , Recién Nacido , Embarazo , Número de Embarazos , Oxitocina/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Proteómica , Receptores de Oxitocina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: To describe the incidence, complications, and trends associated with ureteral surgeries on a gynecologic oncology service in the context of a fellowship training program over a 24-year period. METHODS: We conducted a retrospective cohort analysis of ureteral surgeries by gynecologic oncologists at either Moffitt Cancer Center or Tampa General Hospital from 1997 to 2020. Patient characteristics, predisposing factors, location and type of injury, repair method, postoperative management and complications were abstracted from the medical record. The recent cohort (2005-2020) was compared to our prior series (1997-2004). RESULTS: Eighty-eight cases were included. The average number of ureteral surgeries per year decreased from 5.75 (1997-2004) to 2.63 (2005-2020). Of 46 iatrogenic injuries, 45 were recognized and repaired intraoperatively. Ureteral transection was the most common type (85% [39 of 46]) and the distal 5 cm was the most common location of injury (63% [29 of 46]). Ureteroneocystostomy was the most common method of repair (83% [73 of 88]). Postoperative management, including stenting and imaging, has not changed significantly. Length of urinary catheter usage decreased in the recent cohort without associated complications. Five patients had major postoperative complications and 4 involved the urinary tract. Of those with follow-up, 96% (66 of 69) of ureteroneocystostomies and 75% (9 of 12) of ureteroureterostomies had radiologically normal urinary tracts. CONCLUSIONS: Ureteral surgery is necessary in the case of injury or involvement with invasive disease. There has been a decrease in number of procedures. Ureteroneocystostomy has remained the most common method of reconstruction for both injury and resection with acceptable postoperative complication rates.
Asunto(s)
Neoplasias de los Genitales Femeninos/cirugía , Uréter/cirugía , Estudios de Cohortes , Cistostomía/métodos , Cistostomía/tendencias , Femenino , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Ginecológicos/tendencias , Humanos , Estudios Retrospectivos , Uréter/lesiones , Ureterostomía/métodos , Ureterostomía/tendenciasRESUMEN
BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood. METHODS: GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy - Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time. RESULTS: Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO. CONCLUSIONS: HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.
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Detección Precoz del Cáncer/métodos , Neoplasias Ováricas/prevención & control , Salpingooforectomía/métodos , Adulto , Anciano , Estudios de Cohortes , Detección Precoz del Cáncer/psicología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/psicología , Neoplasias Ováricas/cirugía , Estudios Prospectivos , Calidad de Vida , Salpingooforectomía/psicologíaRESUMEN
BACKGROUND: Male spouses and partners play an important role in determining a woman's willingness to participate in cervical cancer screening. However, the attitudes and behaviors by which they influence a woman's decision to undergo Pap testing remain poorly understood. METHODS: A series of semi-structured, qualitative interviews were conducted in Spanish with 19 recent Latino immigrants in Houston, Texas. The interview format was designed to establish each individual's pattern of engagement with the United States healthcare system, assess baseline knowledge of cervical cancer screening and evaluate attitudes and patterns of communication with their female partners regarding health care. Interview questions were constructed using principles of the Theory of Reasoned Action. All interviews were conducted in Spanish. After translation, responses were coded and scored with the goal of identifying themes and key observations. RESULTS: Most subjects reported few, if any, interactions with the healthcare system since their arrival in the United States. Although most participants reported being aware that women should be seen by their doctors regularly, fewer than half could clearly indicate the purpose of a Pap test or could state with certainty the last time their female partner had undergone screening. Multiple subjects expressed a general distrust of the health care system and concern for its costs. Approximately half of subjects reported that they accompanied their female partner to the health care provider's office and none of the participants reported that they were present in examination rooms at the time their partner underwent screening. Multiple participants endorsed that there may be some concerns within their community regarding women receiving frequent gynecologic care and distrust of the healthcare system. Almost all interviewed subjects stated that while they would allow their female partners to see male physicians, they also expressed the opinion that other men might be uncomfortable with this and that women would likely be more comfortable with female physicians. CONCLUSIONS: Strategies to enhance knowledge of HPV and cancer screening and improve trust in the health care system among male spouses or partners should be explored with the goal of promoting cervical cancer screening among immigrant Latinx populations.
Asunto(s)
Emigrantes e Inmigrantes , Conocimientos, Actitudes y Práctica en Salud/etnología , Tamizaje Masivo/psicología , Neoplasias del Cuello Uterino/diagnóstico , Detección Precoz del Cáncer , Femenino , Hispánicos o Latinos/psicología , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Entrevistas como Asunto , Masculino , Prueba de Papanicolaou , Investigación Cualitativa , Texas/epidemiología , Neoplasias del Cuello Uterino/etnología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/psicología , Frotis Vaginal/psicologíaRESUMEN
PURPOSE: A simple measure to predict chemotherapy tolerance in elderly patients would be useful. We prospectively tested the association of baseline Instrumental Activities of Daily Living (IADL) score with ability to complete 4 cycles of first line chemotherapy without dose reductions or >7days delay in elderly ovarian cancer patients. PATIENTS AND METHODS: Patients' age ≥70 along with their physicians chose between two regimens: CP (Carboplatin AUC 5, Paclitaxel 135mg/m2) or C (Carboplatin AUC 5), both given every 3weeks either after primary surgery or as neoadjuvant chemotherapy (NACT) with IADL and quality of life assessments performed at baseline, pre-cycle 3, and post-cycle 4. RESULTS: Two-hundred-twelve women were enrolled, 152 selecting CP and 60 selecting C. Those who selected CP had higher baseline IADL scores (p<0.001). After adjusting for age and PS, baseline IADL was independently associated with the choice of regimen (p=0.035). The baseline IADL score was not found to be associated with completion of 4 cycles of chemotherapy without dose reduction or delays (p=0.21), but was associated with completion of 4 cycles of chemotherapy regardless of dose reduction and delay (p=0.008) and toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17% (OR: 0.83; 95%CI: 0.72-0.96; p=0.013) for each additional activity in which the patient was independent. After adjustment for chemotherapy regimen, IADL was also associated with overall survival (p=0.019) for patients receiving CP. CONCLUSION: Patients with a higher baseline IADL score (more independent) were more likely to complete 4 cycles of chemotherapy and less likely to experience grade 3 or higher toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patologíaRESUMEN
OBJECTIVES: Women at increased genetic risk of ovarian cancer (OC) are recommended to have risk-reducing salpingo-oophorectomy (RRSO) after completion of reproductive planning. Effective screening has not been established, and novel screening modalities are being evaluated. METHODS: Participants chose either RRSO or a novel OC screening regimen (OCS) as their risk management option, and provided demographic and other data on BRCA mutation status, cancer worry, perceived intervention risks/benefits, perceived cancer risk, and quality-of-life at enrollment. We performed univariate and multivariate analyses to evaluate factors influencing decision between RRSO and OCS. RESULTS: Of 2287 participants enrolled, 904 (40%) chose RRSO and 1383 (60%) chose OCS. Compared with participants choosing OCS, participants choosing RRSO were older (p<0.0001), more likely to carry deleterious BRCA1/2 mutations (p<0.0001), perceive RRSO as effective, be more concerned about surgical harms and OCS limitations, and report higher perceived OC risk and OC-related worry. OCS participants were more likely to perceive screening as effective, be more concerned about menopausal symptoms, infertility, and loss of femininity, and report better overall quality-of-life. Twenty-four percent of participants believed they would definitely develop OC, and half estimated their lifetime OC risk as >50%, both higher than objective risk estimates. CONCLUSIONS: Cancer worry, BRCA1/2 mutation status, and perceived intervention-related risks and benefits were associated with choosing between RRSO and OCS. Efforts to promote individualized, evidence-based, shared medical decision-making among high-risk women facing management choices should focus on conveying accurate OC risk estimates, clarifying the current understanding of intervention-related benefits and limitations, and addressing OC worry.
Asunto(s)
Conducta de Elección , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/prevención & control , Ovariectomía , Procedimientos Quirúrgicos Profilácticos , Salpingectomía , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Detección Precoz del Cáncer , Escolaridad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Análisis Multivariante , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Percepción , Estudios Prospectivos , Calidad de Vida , Riesgo , Conducta de Reducción del RiesgoRESUMEN
Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.
Asunto(s)
Variaciones en el Número de Copia de ADN , Mutación , Neoplasias Uterinas/genética , Secuencia de Aminoácidos , Animales , Disparidad de Par Base , Femenino , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de AminoácidoRESUMEN
Identification of micrometastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in Claudin-3- and -4-overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naïve and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDXs) were treated with the carboxyl-terminal binding domain of the Clostridium perfringens enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneally (IP) or intravenously (IV). We found tumor fluorescence to plateau at 30 min after IP injection of both the FITC-c-CPE and the CW800-c-CPE peptides and to be significantly higher than in healthy organs (p < 0.01). After IV injection of CW800-c-CPE, tumor fluorescence plateaued at 6 hr while the most favorable tumor-to-background fluorescence ratio (TBR) was found at 48 hr in both mouse models. Importantly, fluorescent c-CPE was highly sensitive for the in vivo visualization of peritoneal micrometastatic tumor implants and the identification of ovarian tumor spheroids floating in malignant ascites that were otherwise not detectable by conventional visual observation. The use of the fluorescent c-CPE peptide may represent a novel and effective optical approach at the time of primary debulking surgery for the real-time detection of micrometastatic ovarian disease overexpressing the Claudin-3 and -4 receptors or the identification of residual disease at the time of interval debulking surgery after neoadjuvant chemotherapy treatment.
Asunto(s)
Enterotoxinas/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Micrometástasis de Neoplasia/patología , Neoplasias Ováricas/patología , Animales , Claudina-3/metabolismo , Claudina-4/metabolismo , Femenino , Humanos , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS: EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays. RESULTS: EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001). CONCLUSIONS: Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM.
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Anticuerpos Biespecíficos/farmacología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Biespecíficos/inmunología , Antígenos de Neoplasias/biosíntesis , Antígenos de Neoplasias/inmunología , Complejo CD3/inmunología , Carcinoma Epitelial de Ovario , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos , Resistencia a Antineoplásicos , Molécula de Adhesión Celular Epitelial , Femenino , Citometría de Flujo , Humanos , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/inmunología , Neoplasias Ováricas/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: A patient with early-stage endometrial cancer may possibly have microscopic metastasis in the omentum, which is associated with a poor prognosis. The purpose of this study was to identify risk factors for microscopic omental metastasis in patients with clinical stage I endometrial cancer to establish the indications for selective omentectomy. METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for published studies from inception to August 2014, using terms such as 'endometrial cancer' or 'uterine cancer' for disease, 'omentectomy' or 'omental biopsy' for intervention, and 'metastasis' for outcome. Two reviewers independently identified the studies that matched the selection criteria. We calculated the pooled risk ratios (RRs) with 95 % confidence intervals (CI) of each surgicopathologic finding for microscopic omental metastases in clinical stage I endometrial cancer. We also calculated the prevalence of microscopic omental metastases. RESULTS: Among 1163 patients from ten studies, 22 cases (1.9 %) of microscopic omental metastases were found, which accounted for 26.5 % of all omental metastases. Positive lymph nodes (RR 8.71, 95 % CI 1.38-54.95), adnexal metastases (RR 16.76, 95 % CI 2.60-107.97), and appendiceal implants (RR 161.67, 95 % CI 5.16-5061.03) were highly associated with microscopic omental metastases. CONCLUSIONS: Microscopic omental metastases were not negligible in patients with clinical stage I endometrial cancer. Those with a risk factor of microscopic omental metastases were recommended for selective omentectomy.
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Neoplasias del Apéndice/secundario , Neoplasias Endometriales/patología , Neoplasias de las Trompas Uterinas/secundario , Micrometástasis de Neoplasia/patología , Epiplón/patología , Neoplasias Ováricas/secundario , Femenino , Humanos , Metástasis Linfática , Estadificación de Neoplasias , Epiplón/cirugía , Factores de RiesgoRESUMEN
Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 µM in FISH+ versus 1.498 ± 0.2209 µM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.
Asunto(s)
Cistadenocarcinoma Seroso/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinonas/administración & dosificación , Receptor ErbB-2/genética , Neoplasias Uterinas/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Femenino , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
OBJECTIVE: Clinical validation of a chemoresponse assay was recently published, demonstrating a significant increase in overall survival in recurrent ovarian cancer patients treated with therapies to which their tumor was sensitive in the assay. The current study investigates the cost effectiveness of using the assay at the time of ovarian cancer recurrence from the payer's perspective. METHODS: Using a Markov state transition model, patient characteristics and survival data from the recent clinical study, the cumulative costs over the study horizon (71 months) for both the baseline (no assay) and intervention (assay consistent, hypothetical) cohorts were evaluated. RESULTS: The assay consistent cohort had an incremental cost effectiveness ratio (ICER) of $6206 per life year saved (LYS), as compared to the baseline cohort. Cost-effectiveness was further demonstrated in platinum-sensitive and platinum-resistant populations treated with assay-sensitive therapies, with ICERs of $2773 per LYS and $2736 per LYS, respectively. CONCLUSIONS: The use of a chemoresponse assay to inform treatment decisions in recurrent ovarian cancer patients has the potential to be cost-effective in both platinum-sensitive and platinum-resistant patients.
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Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/economía , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/economía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/economía , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Análisis Costo-Beneficio , Resistencia a Antineoplásicos , Femenino , Procedimientos Quirúrgicos Ginecológicos/economía , Humanos , Cadenas de Markov , Modelos Económicos , Recurrencia Local de Neoplasia/cirugía , Neoplasias Glandulares y Epiteliales/cirugía , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/economía , Neoplasias Ováricas/cirugía , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Estados UnidosRESUMEN
OBJECTIVE: To describe the clinical outcome and tolerability of weekly ixabepilone (16-20mg/m(2) days 1, 8, 15 of a 28-day cycle)±biweekly bevacizumab (10mg/kg days 1 and 15) in patients with recurrent/persistent uterine or ovarian/primary peritoneal/fallopian tube cancers. METHODS: A single-institution retrospective review was performed inclusive of all patients who received ≥2cycles from 01/2010 to 06/2014. Progression-free (PFS) and overall (OS) survival were determined using the Kaplan-Meier method. Toxicities were graded according to CTCAEv4.0. Best response was categorized using RECIST or by CA-125 criteria. RESULTS: A total of 60 patients (24 uterine and 36 ovarian cancers) were identified. Patients had received a median of 3.5 (range:1-10) prior lines of chemotherapy. Patients completed a mean of 4.7±2.9cycles of ixabepilone; 66.7% (16/24) and 91.7% (33/36) of patients with uterine and ovarian cancers received concurrent bevacizumab. For uterine cancers, objective response rate (ORR) was 41.7% (12.5% complete, 29.2% partial); median duration of response or stabilization was 7months (range:2-30). Median PFS and OS were 5.2 and 9.6months, respectively. PFS and OS were improved in the setting of concurrent bevacizumab (6.5 versus 3.0months, p=0.01, HR 0.2, 95% CI 0.05-0.77; 9.6 versus 4.2months, p=0.02, HR 0.58, 95% CI 0.04-0.74). Similar ORR was observed among ovarian cancers; median PFS/OS were not yet reached. Most toxicities were grade 1/2. CONCLUSIONS: Weekly ixabepilone with or without biweekly bevacizumab has promising activity and acceptable toxicity in patients with platinum-/taxane-resistant endometrial and ovarian cancers. This combination warrants further prospective study in these populations.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Epotilonas/uso terapéutico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab , Supervivencia sin Enfermedad , Esquema de Medicación , Epotilonas/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
OBJECTIVE: Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma. METHODS: The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts. RESULTS: Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014µM±0.004vs.0.164µM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039). CONCLUSIONS: Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.
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Carcinosarcoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Animales , Carcinosarcoma/enzimología , Carcinosarcoma/genética , Carcinosarcoma/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Amplificación de Genes , Humanos , Ratones , Ratones SCID , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA). METHODS: Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha=10% (at a 10% assumed null response probability). RESULTS: The median age of the 50 eligible patients was 57years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n=3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events >10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18months. CONCLUSIONS: The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation.
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Bencimidazoles/uso terapéutico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2/genética , Bencimidazoles/efectos adversos , Carcinoma Epitelial de Ovario , Neoplasias de las Trompas Uterinas/genética , Femenino , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genéticaRESUMEN
OBJECTIVE: The aim of this study was to evaluate outcomes of patients with stage III endometrial adenocarcinoma treated with surgery followed by adjuvant chemotherapy and vaginal cuff brachytherapy. METHODS: We retrospectively identified 83 patients treated for 1988 International Federation of Gynecology and Obstetrics (FIGO) stage III endometrial adenocarcinoma at our institution between 2003 and 2010. All patients underwent comprehensive surgical staging. Adjuvant therapy was carboplatin and paclitaxel for 6 cycles and vaginal cuff brachytherapy. For analysis, patients were grouped into type I (FIGO grade 1-2 endometrioid histology, n = 41) or type II (FIGO grade 3, clear cell or papillary serous histology, n = 42) disease. Forty-three patients (52%) had node-positive disease, with similar node-positive rates for type I (n = 21, 51.2%) and type II (n = 22, 52.4%). RESULTS: The median follow-up was 38.6 months. There were no isolated vaginal failures. The estimated 3-year disease-free survival (DFS) and overall survival (OS) for type I versus type II were 92.4% versus 58.0% (P = 0.001) and 97.2% versus 65.8% (P = 0.002), respectively. The 3-year DFS and OS for node negative versus node positive were 85.0% versus 63.6% (P = 0.02) and 84.2% versus 78.0% (P = 0.02), respectively. Associations between type I histology and node-negative disease with improved DFS and OS persisted on multivariate analysis. CONCLUSIONS: Our institutional approach of adjuvant chemotherapy and vaginal cuff brachytherapy for stage III endometrial cancer seemed acceptable for patients with low-risk histology or node-negative disease. In contrast, higher rates of failure among those with high-risk histology and/or node-positive disease support intensification of therapy in these subsets.
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Adenocarcinoma/secundario , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia/métodos , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Recurrencia Local de Neoplasia/patología , Anciano , Carboplatino/administración & dosificación , Quimioradioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Histerectomía , Ganglios Linfáticos/patología , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Tasa de Supervivencia , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Mature cystic teratoma (MCT) is the most common germ cell tumor. It accounts for 10% to 20% of all ovarian masses. The likelihood of malignancy arising from within an MCT is low, and prognosis is poor. METHODS: A single-institution retrospective chart review was completed of all cases of MCT from 2004 to 2012. Multiple variables were examined including procedure performed, residual disease after surgery, surgical stage, histologic type, site of primary disease, date of recurrence, whether or not adjuvant chemotherapy was given, and whether or not there was death secondary to disease. RESULTS: During the study period, 1.2% of MCTs exhibited malignant transformation. The average age at presentation was 53.7 years. Mean follow-up time was 23 months. The most common presenting symptoms were bloating and abdominal pain. The average tumor size was 18 cm. Of note, 33% of cases were at least surgical stage IIIC at the time of presentation, whereas the remainder were stage IC or lower. Four (44.4%) of the 9 cases were identified as mucinous adenocarcinoma in addition to 1 case each of malignant melanoma, squamous cell carcinoma, and poorly differentiated adenocarcinoma. Only 1 patient experienced recurrence. One patient had a known MCT that was being managed expectantly and exhibited malignant transformation to a mucinous adenocarcinoma. CONCLUSIONS: A large ovarian mass that is suspected to be a mature teratoma should be managed more aggressively in older patients. Our data suggest that although malignancy arising from mature teratomas is rare, it is more likely when patients are older than 40 years, the mass is greater than 18 cm, and there is any suspicion for a mucinous tumor. Like most ovarian tumors, these tumors most often present at later stages and, thus, can be difficult to treat. It is unclear what role chemotherapy or radiation plays in the management of these tumors.
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Adenocarcinoma Mucinoso/patología , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/patología , Quiste Dermoide/patología , Neoplasias Ováricas/patología , Teratoma/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Quiste Dermoide/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Teratoma/tratamiento farmacológico , Adulto JovenRESUMEN
INTRODUCTION AND HYPOTHESIS: There is a growing body of evidence demonstrating frailty as an important predictor of surgical outcomes in older adults undergoing major surgeries. The age-related onset of many symptoms of female pelvic floor dysfunction (PFD) in women suggests that many women seeking treatment for PFD may also have a high prevalence of frailty, which could potentially impact the risks and benefits of surgical treatment options. Our primary objective was to determine the prevalence of frailty, cognitive impairment, and functional disability in older women seeking treatment for PFD. METHODS: We conducted a cross-sectional study with prospective recruitment between September 2011 and September 2012. Women, age 65 years and older, were recruited at the conclusion of their new patient consultation for PFD at a tertiary center. A comprehensive geriatric screening including frailty measurements (Fried Frailty Index), cognitive screening (Saint Louis University Mental Status score), and functional status evaluation for activities of daily living (Katz ADL score) was conducted. RESULTS: Sixteen percent (n/N = 25/150) of women were categorized as frail according to the Fried Frailty Index score. After adjusting for education level, 21.3 % of women (n/N = 32/150) screened positive for dementia and 46 (30.7 %) reported functional difficulty or dependence in performing at least one Katz ADL. Sixty-nine women (46.0 %) chose surgical options for treatment of their PFD at the conclusion of their new patient visit with their physician. CONCLUSIONS: Frailty, cognitive impairment, and functional disability are common in older women seeking treatment for PFD.
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Actividades Cotidianas , Trastornos del Conocimiento/epidemiología , Anciano Frágil/estadística & datos numéricos , Trastornos del Suelo Pélvico/epidemiología , Prolapso de Órgano Pélvico/epidemiología , Anciano , Anciano de 80 o más Años , Comorbilidad , Estudios Transversales , Femenino , Evaluación Geriátrica , Humanos , Trastornos del Suelo Pélvico/terapia , Prolapso de Órgano Pélvico/terapiaRESUMEN
BACKGROUND: Borderline ovarian tumors are staged similarly to invasive ovarian tumors. AIMS: We wanted to better understand which tumors were associated with disease recurrence. METHODS: We performed a retrospective cohort analysis at a single institution between 1984 and 2005. Cases were confirmed by pathology report. Multivariate analysis was done to evaluate factors associated with recurrence. RESULTS: 143 cases were identified. Mean follow-up was 73.5 months. The overall risk of recurrence was 12%. The hazard ratio for risk of recurrence was highest among seromucinous tumors at 4.04 and lowest among mucinous tumors at 0.53. Only 4% of mucinous tumors, 15.5% of serous tumors and 28.6% of seromucinous tumors recurred. 2% of mucinous tumors had an appendix positive for metastasis. No mucinous tumor had nodal disease. CONCLUSIONS: Based on our data, a low rate of appendiceal or lymph node involvement was observed in mucinous tumors, as was a low risk of recurrence. Less aggressive staging may be considered if a mucinous tumor is identified on frozen section with a normal-appearing appendix in the absence of pseudomyxoma peritonei. In patients with a serous or a seromucinous tumor, complete surgical staging is recommended. © 2015 S. Karger AG, Basel.
RESUMEN
OBJECTIVE: To evaluate the efficacy of taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification. METHODS: Sensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model. RESULTS: Four USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean±SEM=0.042±0.006µM in FISH+ versus 0.38±0.06µM in FISH-tumors, P<0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P=0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P<0.0001). CONCLUSIONS: Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.