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A major, unprecedented improvement in the durability of polymer electrolyte membrane fuel cells is obtained by tuning the properties of the interface between the catalyst and the ionomer by choosing the appropriate dispersing medium. While a fuel cell cathode prepared from aqueous dispersion showed 90 mV loss at 0.8 A cm(-2) after 30,000 potential cycles (0.6-1.0 V), a fuel cell cathode prepared from glycerol dispersion exhibited only 20 mV loss after 70,000 cycles. This minimum performance loss occurs even though there was an over 80% reduction of electrochemical surface area of the Pt catalyst. These findings indicate that a proper understanding and control of the catalyst-water-ionomer (three-phase) interfaces is even more important for maintaining fuel cell durability in typical electrodes than catalyst agglomeration, and this opens up a novel path for tailoring the functional properties of electrified interfaces.
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Some of the most effective anti-mitotic microtubule-binding agents, such as paclitaxel (Taxus brevifolia) were originally discovered through robust National Cancer Institute botanical screenings. In this study, a high-through put microarray format was utilized to screen 897 aqueous extracts of commonly used natural products (0.00015-0.5 mg/mL) relative to paclitaxel for anti-mitotic effects (independent of toxicity) on proliferation of MDA-MB-231 cells. The data obtained showed that less than 1.34 % of the extracts tested showed inhibitory growth (IG50 ) properties <0.0183 mg/mL. The most potent anti-mitotics (independent of toxicity) were Mandrake root (Podophyllum peltatum), Truja twigs (Thuja occidentalis), Colorado desert mistletoe (Phoradendron flavescens), Tou Gu Cao [symbol: see text] Speranskia herb (Speranskia tuberculata), Bentonite clay, Bunge root (Pulsatilla chinensis), Brucea fruit (Brucea javanica), Madder root (Rubia tinctorum), Gallnut of Chinese Sumac (Melaphis chinensis), Elecampane root (Inula Helenium), Yuan Zhi [symbol: see text] root (Polygala tenuifolia), Pagoda Tree fruit (Melia Toosendan), Stone root (Collinsonia Canadensis), and others such as American Witchhazel, Arjun, and Bladderwrack. The strongest tumoricidal herbs identified from amongst the subset evaluated for anti-mitotic properties were wild yam (Dioscorea villosa), beth root (Trillium Pendulum), and alkanet root (Lithospermum canescens). Additional data was obtained on a lesser-recognized herb: (S. tuberculata), which showed growth inhibition on BT-474 (human ductal breast carcinoma) and Ishikawa (human endometrial adenocarcinoma) cells with ability to block replicative DNA synthesis, leading to G2 arrest in MDA-MB-231 cells. In conclusion, these findings present relative potency of anti-mitotic natural plants that are effective against human breast carcinoma MDA-MB-231 cell division.
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Neoplasias de la Mama/patología , Magnoliopsida/química , Mitosis/efectos de los fármacos , Extractos Vegetales/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Extractos Vegetales/química , Plantas Medicinales/químicaRESUMEN
BACKGROUND: The decision to choose surgical cytoreduction in patients with newly diagnosed ovarian cancer may be influenced by their age. We compared perioperative morbidity and mortality of octogenarians compared with younger patients undergoing surgical cytoreduction. METHODS: A retrospective chart review identified patients who underwent primary surgical cytoreduction for ovarian cancer between January 2005 and December 2009. Patients were divided into 2 cohorts: younger than 80 years and 80 years or older (octogenarian). Patient demographics, surgical procedures, 30-day readmission, length of stay, 30-day mortality rates, and chemotherapy administration were examined. Student t test and χ test were used to evaluate statistical significance. RESULTS: Three hundred eighty-four patients who underwent surgical cytoreduction for ovarian cancer were identified. Three hundred fifty-two patients (91.7%) were younger than 80 years, whereas 32 patients (8.3%) were 80 years or older. Two hundred thirty-six women (67.0%) in the younger cohort had optimal cytoreduction (<1 cm) compared with 17 women (53.1%) in the older cohort (P = 0.12). Thirty-day readmission rates and postoperative complications were similar. More patients in the older cohort required preoperative admission for medical clearance (P < 0.01). Mean length of stay was significantly longer in the older cohort (10.0 vs 7.5; P = 0.02). The number of patients who received adjuvant chemotherapy was significantly lower in the older cohort (71.9% vs 93.8%; P < 0.01). The 30-day mortality rate was significantly higher in the older cohort (18.8% vs 4.0%; P < 0.01). CONCLUSIONS: Although octogenarians with ovarian cancer have similar surgical complication rates as their younger counterparts, they require more medical clearance and have a longer hospital stay. Older patients are less likely to undergo chemotherapy and have a higher 30-day mortality rate than are younger patients.
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Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma Mucinoso/mortalidad , Carcinoma Papilar/mortalidad , Cistadenocarcinoma Seroso/mortalidad , Neoplasias Endometriales/mortalidad , Neoplasias Ováricas/mortalidad , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Morbilidad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Readmisión del Paciente , Periodo Perioperatorio , Complicaciones Posoperatorias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
AIMS: Lactate dehydrogenase (LDH)-A is highly expressed in diverse human malignant tumors, parallel to aggressive metastatic disease, resistance to radiation/chemotherapy and clinically poor outcome. Although this enzyme constitutes a plausible target in treatment of advanced cancer, there are few known LDH-A inhibitors. STUDY DESIGN: In this work, we utilized a high-throughput enzyme micro-array format to screen and evaluate > 900 commonly used medicinal plant extracts (0.00001-.5 mg/ml) for capacity to inhibit activity of recombinant full length human LDHA; EC .1.1.1.27. METHODOLOGY: The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis- MALDI-TOF-MS/MS, enzyme activity was validated by oxidation of NADH (500µM) and kinetic inhibition established in the presence of a known inhibitor (Oxalic Acid). RESULTS: Of the natural extracts tested, the lowest IC50s [<0.001 mg/ml] were obtained by: Chinese Gallnut (Melaphis chinensis gallnut), Bladderwrack (Fucus vesiculosus), Kelp (Laminaria Japonica) and Babul (Acacia Arabica). Forty-six additional herbs contained significant LDH-A inhibitory properties with IC50s [<0.07 mg/ml], some of which have common names of Arjun, Pipsissewa, Cinnamon, Pink Rose Buds/Petals, Wintergreen, Cat's Claw, Witch Hazel Root and Rhodiola Root. CONCLUSION: These findings reflect relative potency by rank of commonly used herbs and plants that contain human LDH-A inhibitory properties. Future research will be required to isolate chemical constituents within these plants responsible for LDH-A inhibition and investigate potential therapeutic application.
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OBJECTIVES: To determine the efficacy and toxicity of radiation therapy and concurrent weekly cisplatin chemotherapy in achieving a complete clinical and pathologic response when used for the primary treatment of locally-advanced vulvar carcinoma. METHODS: Patients with locally-advanced (T3 or T4 tumors not amenable to surgical resection via radical vulvectomy), previously untreated squamous cell carcinoma of the vulva were treated with radiation (1.8 Gy daily × 32 fractions=57.6 Gy) plus weekly cisplatin (40 mg/m(2)) followed by surgical resection of residual tumor (or biopsy to confirm complete clinical response). Management of the groin lymph nodes was standardized and was not a statistical endpoint. Primary endpoints were complete clinical and pathologic response rates of the primary vulvar tumor. RESULTS: A planned interim analysis indicated sufficient activity to reopen the study to a second stage of accrual. Among 58 evaluable patients, there were 40 (69%) who completed study treatment. Reasons for prematurely discontinuing treatment included: patient refusal (N=4), toxicity (N=9), death (N=2), other (N=3). There were 37 patients with a complete clinical response (37/58; 64%). Among these women there were 34 who underwent surgical biopsy and 29 (78%) who also had a complete pathological response. Common adverse effects included leukopenia, pain, radiation dermatitis, pain, or metabolic changes. CONCLUSIONS: This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Cisplatino/administración & dosificación , Neoplasias de la Vulva/tratamiento farmacológico , Neoplasias de la Vulva/radioterapia , Adulto , Anciano , Antineoplásicos/efectos adversos , Carcinoma de Células Escamosas/cirugía , Cisplatino/efectos adversos , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Radioterapia/efectos adversos , Radioterapia/métodos , Neoplasias de la Vulva/cirugíaRESUMEN
PURPOSE: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), has clinical activity in multiple tumor types. We conducted a phase II trial to assess the activity and tolerability of single-agent bevacizumab in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS: Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status of ≤ 2. Treatment consisted of bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression or prohibitive toxicity. VEGF-A was assessed by immunohistochemistry in archival tumor and by enzyme-linked immunosorbent assay in pretreatment plasma. Primary end points were progression-free survival (PFS) at 6 months and overall response rate. RESULTS: Fifty-six patients were enrolled. Fifty-two patients were eligible and evaluable. Median age was 62 years, and prior treatment consisted of one or two regimens in 33 (63.5%) and 19 (36.5%) patients, respectively. Twenty-nine patients (55.8%) received prior radiation. Adverse events were consistent with those expected with bevacizumab treatment. No GI perforations or fistulae were seen. Seven patients (13.5%) experienced clinical responses (one complete response and six partial responses; median response duration, 6.0 months), and 21 patients (40.4%) survived progression free for at least 6 months. Median PFS and overall survival times were 4.2 and 10.5 months, respectively. Suggested associations were observed between high VEGF-A and adjusted hazard of death or tumor response when evaluated in tumor/plasma or plasma, respectively. CONCLUSION: Bevacizumab is well tolerated and active based on PFS at 6 months in recurrent or persistent EMC and warrants further investigation.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Bevacizumab , Supervivencia sin Enfermedad , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa/métodos , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
OBJECTIVE: To evaluate factors that place epithelial ovarian cancer (EOC) patients at increased risk for hospital readmission. METHODS: A retrospective review of patients diagnosed with EOC undergoing surgical cytoreduction at the University of Alabama at Birmingham from 2001 to 2008 was performed. Patients who required readmission were identified. Demographic data, comorbidities, surgical data including bowel resections, and hospital length of stay were evaluated. RESULTS: A total of 207 patients were identified. The mean age at diagnosis was 64 years (range, 32-89 years), 58% had optimal debulking (n=120), and the mean number of comorbidities was 1.3 (range, 0-6). Readmission within 30 days of discharge occurred in 33 (16%) of 207 patients. The readmission group had a statistically higher number of comorbidities (1.75 vs 1.01, P=0.025). The most common reasons for readmission were small bowel obstruction/ileus, wound complications, and thromboembolic events. CONCLUSIONS: The most common reason for readmission after cytoreductive surgery for EOC is small bowel obstruction/ileus. Studies assessing postoperative disease management programs including nursing telephone follow-up, administration of outpatient intravenous fluids, and continuation of antithrombotic agents may offer opportunities to reduce readmissions.
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Carcinoma/cirugía , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos , Neoplasias Glandulares y Epiteliales/cirugía , Neoplasias Ováricas/cirugía , Admisión del Paciente/estadística & datos numéricos , Readmisión del Paciente/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Alabama , Carcinoma/epidemiología , Carcinoma Epitelial de Ovario , Femenino , Humanos , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Ováricas/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-Δ24-Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases. EXPERIMENTAL DESIGN: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 10(9) to 1 × 10(12) viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response. RESULTS: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent. CONCLUSIONS: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted.
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Adenoviridae/genética , Adenoviridae/fisiología , Vacunas contra el Cáncer/uso terapéutico , Carcinoma/terapia , Neoplasias de los Genitales Femeninos/terapia , Tropismo Viral/genética , Replicación Viral/genética , Adenoviridae/patogenicidad , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/genética , Carcinoma/complicaciones , Carcinoma/virología , Femenino , Neoplasias de los Genitales Femeninos/complicaciones , Neoplasias de los Genitales Femeninos/virología , Humanos , Persona de Mediana Edad , Oligopéptidos/genética , Viroterapia Oncolítica/métodos , Organismos Modificados Genéticamente , Recurrencia , Células Tumorales Cultivadas , Vacunas de ADN/efectos adversos , Vacunas de ADN/genética , Vacunas de ADN/uso terapéuticoRESUMEN
PURPOSE: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. EXPERIMENTAL DESIGN: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. RESULTS: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. CONCLUSIONS: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
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Adenoviridae/metabolismo , Terapia Genética/efectos adversos , Vectores Genéticos/efectos adversos , Vectores Genéticos/metabolismo , Adenoviridae/genética , Animales , Ensayos Clínicos Fase I como Asunto , Cricetinae , Femenino , Ganciclovir/farmacología , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Mesocricetus , Receptores de Somatostatina/metabolismoRESUMEN
OBJECTIVES: To determine the maximum tolerated dose (MTD), spectrum of toxicities, clinical activity, and pharmacokinetics of carboplatin given in combination with lapatinib in women with a first recurrence of platinum sensitive epithelial ovarian carcinoma. METHODS: Patients with measurable, platinum sensitive recurrent epithelial ovarian carcinoma were eligible. Cohorts of 3-6 patients were to receive up to 6 cycles of intravenous carboplatin AUC of 6 every 21 days in combination with escalating dosages of oral lapatinib (starting at a dose of 750 mg daily). Toxicity was assessed using NCI CTC for Adverse Events. Clinical response was monitored using RECIST criteria. Pharmacokinetic (PK) analysis was performed for the second cohort of patients. RESULTS: Twelve patients were enrolled. No dose limiting toxicity was noted. Two of 6 patients in the first cohort had unanticipated excessive delays in treatment due to non-dose limiting G3 neutropenia. Therefore, the study was modified to reduce the carboplatin dose in the second cohort. The median number of courses administered to the 11 evaluable patients in these two cohorts was 2.8 (range 1-6). Drug-related grade 3 or 4 toxicities included non-dose limiting G4 thrombocytopenia (n=1), and non-dose limiting G3 neutropenia (n=3). Of the 11 patients who received >or=1 course of therapy, 3 (27%) had a partial response, and 3 (27%) had stable disease. The pharmacokinetics of carboplatin were not significantly altered by concomitant administration of lapatinib. CONCLUSIONS: This regimen of lapatinib and carboplatin was associated with unacceptable non-dose limiting toxicities, excessive treatment delays and limited clinical responses.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lapatinib , Persona de Mediana Edad , Recurrencia Local de Neoplasia/sangre , Neoplasias Ováricas/sangre , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinéticaRESUMEN
OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6-19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III.
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Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenosina Trifosfatasas/metabolismo , Adulto , Enzimas Reparadoras del ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Inmunohistoquímica , Inestabilidad de Microsatélites , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/metabolismo , Estudios RetrospectivosRESUMEN
OBJECTIVE: This study aimed at evaluating the expression of tyrosine kinase receptors c-kit, (platelet-derived growth factor receptor-alpha (PDGFR-alpha), and PDGFR-beta in ovarian granulosa cell tumors (GCTs). STUDY DESIGN: Primary ovarian GCT specimens were obtained for immunohistochemical staining.The expressions of c-kit, PDGFR-alpha, and PDGFR-beta were analyzed and scored by a semiquantitative (SQ) method. Normal ovarian tissue from the same patients' specimens served as internal controls. RESULTS: A total of 21 specimens were available for evaluation. C-kit was expressed in only 2 samples, whereas both PDGFR-alpha and PDGFR-beta stained positive in 100% of tumors. PDGFR targets demonstrated strong positive expression in intensity and amount of tissue stained. Normal ovarian tissue demonstrated complete absence of staining for all 3 antibodies evaluated. CONCLUSIONS: The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.
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Regulación Neoplásica de la Expresión Génica , Tumor de Células de la Granulosa/enzimología , Neoplasias Ováricas/enzimología , Proteínas Proto-Oncogénicas c-kit/biosíntesis , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Adolescente , Adulto , Anciano , Benzamidas , Niño , Sistemas de Liberación de Medicamentos , Epitelio/enzimología , Epitelio/patología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tumor de Células de la Granulosa/tratamiento farmacológico , Tumor de Células de la Granulosa/patología , Humanos , Mesilato de Imatinib , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células del Estroma/enzimología , Células del Estroma/patología , Adulto JovenRESUMEN
PURPOSE: This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. PATIENTS AND METHODS: Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. RESULTS: Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). CONCLUSIONS: Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Carboplatino/administración & dosificación , Cetuximab , Esquema de Medicación , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Neoplasias Hormono-Dependientes/metabolismo , Neoplasias Hormono-Dependientes/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Resultado del TratamientoRESUMEN
OBJECTIVE: Authors have suggested that chemotherapy-induced neutropenia could represent a surrogate parameter of cancer stem cell response to treatment. Thus, the aim of this study was to evaluate the association of relative chemotherapy-induced neutropenia with survival in advanced epithelial ovarian cancer (EOC). METHODS: A computerized database identified patients for primary advanced EOC with 6 cycles of platinum-taxane-based chemotherapy. Data collected included demographics, chemotherapy administration, laboratory evaluation, and survival outcomes. Relative neutropenia, defined as an absolute neutrophil count (ANC) <1000/mm3 at chemotherapy cycle nadir, was evaluated and correlated to PFS, OS, and platinum sensitivity (recurrence >6 months from completion of chemotherapy). RESULTS: 255 patients were identified. Patients with neutropenia (n=203) during treatment were similar to patients who never had neutropenia (n=52) in regards to age, race, body mass index (BMI), stage, histology, grade, and debulking status. Neutropenic patients demonstrated improvements in PFS (14 vs. 6 months; p=0.01), OS (45 vs. 29 months; p=0.03) and platinum sensitivity rates (69% vs. 44%; p=0.001). As the number of neutropenic episodes increased, improvements in PFS (range 6 to 17 months; p=0.07) and platinum sensitivity (range 44% to 90%; p=0.002) was demonstrated. When stratified by debulking status, neutropenia conferred a survival advantage in suboptimally debulked patients, but only demonstrated marginal improvements in optimally debulked patients. CONCLUSIONS: Our data demonstrates that patients with chemotherapy-induced neutropenia is associated with a survival advantage in ovarian cancer, especially in suboptimally debulked patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neutropenia/inducido químicamente , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Taxoides/administración & dosificación , Taxoides/efectos adversosRESUMEN
OBJECTIVE: To determine the response rate, progression-free survival and toxicity associated with weekly topotecan administered to patients with platinum-sensitive recurrent epithelial ovarian (EOC) in the third-line setting. METHODS: Patients with measurable platinum-sensitive EOC following failure of second-line chemotherapy were eligible for this phase II study. All patients were initially treated with cytoreductive surgery and platinum/paclitaxel-based chemotherapy. Continuous, weekly topotecan was administered at a starting dose of 4 mg/m(2). Toxicity and efficacy were assessed at various time points after initiation of therapy. RESULTS: Twenty nine patients were enrolled in this prospective study. Toxicity was acceptable with grade 1/2 nausea being the most commonly experienced side effect (52%). Nine patients (31%) had grade 3/4 leukopenia; however, only 3 patients had febrile neutropenia. Thirteen patients had a treatment delay and six required dose reductions. Twenty two patients were evaluable for efficacy. The overall response rate for weekly topotecan was 13.6% [95% CI; -0.7-27.9%] with 1 complete response, and 2 partial responses. Twelve patients (54.5%), including 2 with minor responses, had stable disease for a median duration of 18 weeks. CONCLUSIONS: Weekly topotecan at the current schedule in the third-line setting in patients with platinum-sensitive recurrent EOC has modest clinical activity. Toxicity associated with this regimen is acceptable but growth factor support, dose reductions, or schedule alterations may need to be considered in many of these patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Topotecan/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Esquema de Medicación , Resistencia a Antineoplásicos , Células Epiteliales/patología , Femenino , Humanos , Persona de Mediana Edad , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/patología , Topotecan/efectos adversosRESUMEN
BACKGROUND: Our goal was to determine the morbidity, disease-free survival, and overall survival of patients with bowel resection at primary cytoreductive surgery for advanced epithelial ovarian carcinoma in the era of platinum and taxane chemotherapy. STUDY DESIGN: We performed a retrospective study of patients undergoing bowel resection at the time of primary cytoreduction for advanced epithelial ovarian carcinoma, who subsequently received platinum and taxane chemotherapy, from 1996 to 2001. Data collected included demographics, stage, histology, debulking status, surgical morbidity, recurrence, and survival. Survival analysis and comparisons were performed using the Kaplan-Meier method and log-rank test. RESULTS: Of 48 patients (45 stage III; 3 stage IV), 25 patients (52%) were optimally debulked to < 1 cm of residual disease; the remaining 23 patients had residual disease > 1 cm. Four-year disease-free survival in the optimally debulked group was 24% versus 12% in the suboptimally debulked group (p=0.009). Four-year overall survival was 81% in the optimally debulked group versus 54% in the suboptimally debulked group (p=0.162). Five patients (10%) experienced a major postoperative complication including stroke, small bowel obstruction, anastomotic leak, entercutaneous fistula, and pelvic abscess. Two perioperative deaths occurred in the suboptimally debulked group. CONCLUSIONS: Patients with advanced epithelial ovarian carcinoma who undergo bowel resection as part of optimal cytoreduction and receive platinum and taxane chemotherapy have improved disease-free survival and a trend toward improved overall survival. Bowel resection at the time of primary cytoreductive surgery is associated with acceptable perioperative morbidity.
Asunto(s)
Carcinoma/mortalidad , Carcinoma/cirugía , Intestinos/cirugía , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/cirugía , Adulto , Anciano , Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Platino/uso terapéutico , Estudios Retrospectivos , Tasa de Supervivencia , Taxoides/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate our experience with the use of bevacizumab in patients with heavily pretreated recurrent ovarian carcinoma who have symptomatic ascites. METHODS: Four patients were identified who were previously heavily pretreated for recurrent ovarian carcinoma. Each had symptomatic ascites and required frequent therapeutic paracenteses. Each was treated with bevacizumab with the intent to palliate symptomatic ascites. Clinical data including demographic data and clinicopathologic variables was abstracted. RESULTS: The four patients demonstrated symptomatic relief of ascites. Toxicity was manageable in all patients with no grade 3/4 toxicity observed. In addition to symptomatic relief of ascites, no therapeutic paracenteses were required after initiation of therapy with bevacizumab. CONCLUSIONS: Bevacizumab may be a viable palliative option in patients with end stage ovarian carcinoma who have symptomatic ascites.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Ascitis/tratamiento farmacológico , Carcinoma/complicaciones , Neoplasias Ováricas/complicaciones , Anticuerpos Monoclonales Humanizados , Bevacizumab , Femenino , Humanos , Recurrencia Local de Neoplasia , Cuidados Paliativos , Factor A de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
OBJECTIVE: To assess the feasibility of using pegylated liposomal doxorubicin (PLD) as a consolidation therapy in patients with advanced ovarian cancer who have attained a clinically defined complete response to initial platinum/paclitaxel-based chemotherapy. METHODS: Patients diagnosed with suboptimally debulked stage IIIC/IV epithelial ovarian cancer who attained a clinically defined complete response at the completion of platinum/paclitaxel-based chemotherapy were eligible for this protocol. Patients were treated with PLD at a dose of 40 mg/m(2) every 28 days for four cycles. A survival analysis was calculated using the Kaplan-Meier method. RESULTS: Of the 30 patients enrolled, 29 were evaluable. Twenty-three patients (79%) completed all four cycles of consolidation therapy. Palmar-plantar erythrodysesthesia was the most common toxicity. Six patients remained clinically without evidence of disease with a median follow-up of 35 months from the completion of primary chemotherapy. The median progression-free interval was 15 months, and median overall survival time was 31 months, with 47% of patients achieving a 4-year survival. CONCLUSIONS: Consolidation therapy with PLD chemotherapy administered to women with advanced epithelial ovarian cancer after initial chemotherapy appears feasible based on its toxicity profile. Considering the tolerability of this agent, further investigation is needed to depict the optimal dose and schedule needed for consolidation therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Carcinoma/patología , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Platino (Metal)/administración & dosificación , Platino (Metal)/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Factores de TiempoRESUMEN
OBJECTIVES: KW-2170 is a novel DNA intercalating agent whose mechanism of action is similar to doxorubicin HCl, yet is associated with less cardiac toxicity. The objective of this study was to evaluate the activity and toxicity of this novel chemotherapeutic agent in patients with recurrent ovarian carcinoma. METHODS: A prospective phase II trial was performed in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma and measurable disease. Patients could have platinum-sensitive or refractory disease and could have received any number of prior treatments. One treatment cycle consisted of KW-2170 administered at a dose of 18 mg/m(2) weekly for 3 weeks followed by a 21-day rest period. Toxicity was assessed using the NCI Common Toxicity Criteria (Version 2.0), and dose reduction was allowed for significant toxicity. Response to therapy was assessed in patients who completed at least 2 cycles using RECIST criteria. RESULTS: A total of 28 patients were enrolled in this phase II trial at 5 separate centers. Of the 28 patients evaluated, all had stage III/IV disease at initial diagnosis. The median number of prior therapeutic regimens in these patients was 4 (range 1-8). The median number of KW-2170 cycles administered was 2 (range 1-5). Treatment-related toxicity in this heavily pretreated population was acceptable as only 6 patients (21%) had grade 3-4 neutropenia. Dose reductions occurred in 6 patients (21%) for grades 1-4 neutropenia, and no patient had febrile neutropenia. Four patients completed less than 1 cycle; 3 secondary to progressive disease, and one due to Gram-positive sepsis. Of patients receiving at least 2 full cycles, 10 patients (55%) had stable disease with a median of 4.5 months (range 3-10) to disease progression. All other patients were removed from the study after 1-2 cycles of therapy with no significant clinical effect noted. CONCLUSIONS: Although associated with relatively little toxicity, KW-2170 at the dose and schedule evaluated demonstrated little clinical activity in this heavily pretreated population of recurrent ovarian cancer patients. Whether KW-2170 would have greater clinical activity in a more treatment naive group of patients at an increased dose awaits clinical trial evaluation.