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OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.
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BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.
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Neoplasias Ováricas , Humanos , Femenino , Carboplatino , Trabectedina , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/etiología , Platino (Metal)/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Doxorrubicina , Polietilenglicoles , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for â¼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.
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Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Bevacizumab , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Antineoplásicos/uso terapéutico , Ftalazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Quimioterapia de MantenciónRESUMEN
PURPOSE: The two main etiological factors for vulvar squamous cell carcinoma (vSCC) are the vulvar dermatosis lichen sclerosus (LS) and high-risk human papillomavirus (hrHPV). Serpin A1 (α1-antitrypsin) is a serine protease inhibitor, which plays a role in the tumorigenesis of various cancer types. The aim of the study was to evaluate the expressions of Serpin A1 in LS, premalignant vulvar lesions, and vSCC using immunohistochemistry (IHC) and serum analysis, and to compare Serpin A1 stainings to the tumor markers p53 and p16. METHODS: In total, 120 samples from 74 patients were studied with IHC for Serpin A1, p53 and p16: 18 normal vulvar skin, 53 LS, 9 premalignant vulvar lesions (dVIN/HSIL) and 40 vSCC samples. Serum concentrations of Serpin A1 were analyzed from 30 LS, 44 vSCC and 10 control patients. Expressions were compared to clinical data. RESULTS: Tumor cell-specific Serpin A1 overexpression was detected in 88% of vSCC samples, independent of the etiology. The intensity of Serpin A1 expression was significantly higher in vSCC than in healthy vulvar skin, LS, or premalignant vulvar lesions. Serpin A1 showed an association with p53 positivity. No difference in overall survival was found between Serpin A1-, p53-, or p16-positive vSCC patients. Serum concentrations of Serpin A1 were equal in the LS, vSCC, and control groups. CONCLUSION: Tumor cell-specific Serpin A1 overexpression is a potential biomarker in vSCC.
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Carcinoma de Células Escamosas/genética , Neoplasias de la Vulva/genética , alfa 1-Antitripsina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Vulva/patologíaRESUMEN
This manuscript reports the consensus statements regarding recurrent ovarian cancer (ROC), reached at the fifth Ovarian Cancer Consensus Conference (OCCC), which was held in Tokyo, Japan, in November 2015. Three important questions were identified: (i) What are the subgroups for clinical trials in ROC? The historical definition of using platinum-free interval (PFI) to categorise patients as having platinum-sensitive/resistant disease was replaced by therapy-free interval (TFI). TFI can be broken down into TFIp (PFI), TFInp (non-PFI) and TFIb (biological agent-free interval). Additional criteria to consider include histology, BRCA mutation status, number/type of previous therapies, outcome of prior surgery and patient reported symptoms. (ii) What are the control arms for clinical trials in ROC? When platinum is considered the best option, the control arm should be a platinum-based therapy with or without an anti-angiogenic agent or a poly (ADP-ribose) polymerase (PARP) inhibitor. If platinum is not considered the best option, the control arm could include a non-platinum drug, either as single agent or in combination. (iii) What are the endpoints for clinical trials in ROC? Overall survival (OS) is the preferred endpoint for patient cohorts with an expected median OS < or = 12 months. Progression-free survival (PFS) is an alternative, and it is the preferred endpoint when the expected median OS is > 12 months. However, PFS alone should not be the only endpoint and must be supported by additional endpoints including pre-defined patient reported outcomes (PROs), time to second subsequent therapy (TSST), or time until definitive deterioration of quality of life (TUDD).
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Recurrencia Local de Neoplasia/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Proyectos de Investigación , Femenino , HumanosRESUMEN
Targeting Poly (ADP-ribose) polymerase 1 (PARP-1) involved in base excision repair (BER) has been shown to be a clinically effective treatment strategy in epithelial ovarian cancer (EOC) defective in homologous recombination (HR). The aim of this study was to evaluate fresh EOC tumor tissue in regard to PAR (Poly (ADP-ribose)) concentration as a surrogate marker for PARP activity and PARP protein expression in archival samples by immunohistochemistry (IHC). The prospective study cohort consisted of 57 fresh tumor samples derived from patients undergoing primary (n = 38) or interval debulking surgery (n = 19) for EOC and parallel archival paraffin-embedded tumor samples. PARP activity in fresh frozen tumor tissue was assessed by an enzymatic chemiluminescence assay and PARP protein expression in paraffin-embedded tumor tissue by IHC. No correlation was detected between PARP enzyme activity and PARP staining by IHC (p = 0.82). High PARP activity was associated with platinum sensitivity both in the entire study cohort (p = 0.022) and in the high-grade subgroup (p = 0.017). High PARP activity was also associated with improved progression-free survival (PFS) (32 vs 14 months, log-rank p = 0.009). However, PARP immunostaining pattern was not predictive of patient survival. In conclusion, we present a novel finding of high PARP activity associated with platinum sensitivity and improved PFS in EOC. There was no association between PARP IHC and pharmacodynamic assay, and the correlation of PARP IHC with clinico-pathological characteristics and patient survival was poor. Pharmacodynamic assay rather than IHC seems to reflect better biologically significant PARP.
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Ensayo de Inmunoadsorción Enzimática/métodos , Neoplasias Glandulares y Epiteliales/enzimología , Neoplasias Ováricas/enzimología , Poli(ADP-Ribosa) Polimerasa-1/análisis , Anciano , Carcinoma Epitelial de Ovario , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Estudios ProspectivosRESUMEN
OBJECTIVE: ERRs (estrogen-related receptors) regulate energy metabolism, the cell cycle and inflammatory processes in both normal and cancer cells. Chronic inflammation induced by lichen sclerosus (LS) or human papilloma virus (HPV) precedes vulvar squamous cell carcinoma (vulvar SCC). We investigated the expression of ERRα, ERRß and ERRγ in normal vulvar skin, LS as well as LS-dependent and LS-independent/HPV-related vulvar SCC. METHODS: A total of 203 samples were analyzed for ERRα, ERRß and ERRγ by using immunohistochemistry. These included 37 normal vulvar skin samples, 110 LS samples, 6 vulvar intraepithelial neoplasia (VIN) samples and 50 vulvar SCC samples. RESULTS: A substantial reduction in or disappearance of ERRα was detected in all vulvar SCC samples. A total of 79% of childhood-onset LS and 51% of adulthood-onset LS lesions showed decreases in ERRα staining. A gradual reduction in ERRα cytoplasmic staining was observed from healthy vulvar skin to precursor lesions and further to SCC. Nuclear ERRα staining was observed in 8/33 (24%) LS-dependent and 10/17 (59%) LS-independent SCC samples. CONCLUSIONS: ERRα, a key regulator of cell energy metabolism, may play a role in the pathogenesis of both LS and vulvar SCC.
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Carcinoma in Situ/química , Carcinoma de Células Escamosas/metabolismo , Receptores de Estrógenos/metabolismo , Liquen Escleroso Vulvar/metabolismo , Neoplasias de la Vulva/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma in Situ/etiología , Carcinoma de Células Escamosas/etiología , Niño , Preescolar , Femenino , Humanos , Persona de Mediana Edad , Piel/química , Vulva/química , Liquen Escleroso Vulvar/complicaciones , Neoplasias de la Vulva/etiología , Adulto Joven , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
PURPOSE: Clinical practice adherence to current guidelines that recommend primary prophylaxis (PP) with granulocyte colony-stimulating factors (G-CSFs) for patients at high (≥20 %) overall risk of febrile neutropenia (FN) was evaluated. METHODS: Adult patients with breast cancer, non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC), or ovarian cancer were enrolled if myelotoxic chemotherapy was planned, and they had an investigator-assessed overall FN risk ≥20 %. The primary outcome was FN incidence. RESULTS: In total, 1,347 patients were analysed (breast cancer, n = 829; NSCLC, n = 224; SCLC, n = 137; ovarian cancer, n = 157). Patients with breast cancer exhibited fewer individual FN risk factors than patients with other cancers and were far more likely to have received a high-FN-risk chemotherapy regimen. However, a substantial proportion of all patients (45-80 % across tumour types) did not receive G-CSF PP in alignment with investigator risk assessment and guideline recommendations. FN occurred in 127 patients overall (9 %, 95% confidence interval (CI) 8-11 %), and incidence was higher in SCLC (15 %) than other tumour types (8 % in ovarian and NSCLC, 9 % in breast cancer). A post hoc analysis of G-CSF use indicated that G-CSF prophylaxis was not given within the recommended timeframe after chemotherapy (within 1-3 days) or was not continued across all cycles in 39 % of patients. CONCLUSIONS: FN risk assessment was predominantly based on clinical judgement and individual risk factors, and guidelines regarding G-CSF PP for patients at high FN risk were not consistently followed. Improved education of physicians may enable more fully informed neutropenia management in patients with solid tumours.
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Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neutropenia Febril/tratamiento farmacológico , Neutropenia Febril/epidemiología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neutropenia Febril/inducido químicamente , Neutropenia Febril/prevención & control , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Medición de RiesgoRESUMEN
BACKGROUND: CA-125 as a tumour progression criterion in relapsing ovarian cancer (ROC) trials remains controversial. CALYPSO is a large randomised trial incorporating CA-125 (GCIG criteria) and symptomatic deterioration in addition to Response Evaluation Criteria in Solid Tumours (RECIST) criteria (radiological) to determine progression. METHODS: In all, 976 patients with platinum-sensitive ROC were randomised to carboplatin-paclitaxel (C-P) or carboplatin-pegylated liposomal doxorubicin (C-PLD). CT-scan and CA-125 were performed every 3 months until progression. RESULTS: In all, 832 patients (85%) progressed, with 60% experiencing a first radiological progression, 10% symptomatic progression, and 28% CA-125 progression without evidence of radiological or symptomatic progression. The benefit of C-PLD vs C-P in progression-free survival was not influenced by type of first progression (hazard ratio 0.85 (95% confidence interval (CI): 0.66-1.10) and 0.84 (95% CI: 0.72-0.98) for CA-125 and RECIST, respectively). In patients with CA-125 first progression who subsequently progressed radiologically, a delay of 2.3 months was observed between the two progression types. After CA-125 first progression, median time to new treatment was 2.0 months. In all, 81%of the patients with CA-125 or radiological first progression and 60% with symptomatic first progression received subsequent treatment. CONCLUSION: CA-125 and radiological tests performed similarly in determining progression with C-PLD or C-P. Additional follow-up with CA-125 measurements was not associated with overtreatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Ca-125/análisis , Neoplasias Ováricas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Femenino , Humanos , Neoplasias Ováricas/diagnóstico por imagen , Paclitaxel/administración & dosificación , Polietilenglicoles/efectos adversos , Recurrencia , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: Preoperative evaluation of the depth of myometrial invasion in endometrial carcinoma is challenging. The objective of this study was to evaluate the usefulness of three-dimensional power Doppler angiography (3D-PDA) in this setting. METHODS: Sonographic and histological data on 100 consecutive cases of endometrial carcinoma were analyzed. The endometrial and myometrial vascular indices VI (vascularization index), FI (flow index) and VFI (vascularization flow index) were calculated by 3D-PDA. The results were compared with a complete surgical staging. RESULTS: The mean ( ± SD) age of patients was 67.1 ± 8.8 (range, 33-87) years. Forty-six patients had deep (≥ 50%) myometrial invasion. Eight patients had metastases, seven of them with deep invasion. Three patients were found to have carcinomas of non-uterine origin on histology, and these were excluded from further statistical analysis. The median endometrial and myometrial vascular indices were higher in the group with deep invasion than in the group without. Following multivariable analysis of the indices only the endometrial FI was independently associated with deep invasion (OR, 1.061; 95% CI, 1.023-1.099; P = 0.001). However, a greater endometrial volume was also an independent predictor of deep invasion (OR, 1.109; 95% CI, 1.011-1.215; P = 0.028). CONCLUSION: Our study suggests that endometrial and, to a lesser degree, myometrial vascular indices and endometrial volume correlate with the depth of myometrial invasion in endometrial carcinoma.
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Angiografía/métodos , Neoplasias Endometriales/diagnóstico por imagen , Imagenología Tridimensional/métodos , Cuidados Preoperatorios/métodos , Adulto , Anciano , Anciano de 80 o más Años , Velocidad del Flujo Sanguíneo , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Cuidados Preoperatorios/instrumentación , Ultrasonografía , Resistencia VascularRESUMEN
BACKGROUND: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD). METHODS: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10(9) per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. RESULTS: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P=0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P=0.001), but not those experiencing leukopenia (aHR 0.93, P=0.54; interaction P=0.008).Of 949 patients, 32% (CP=62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P=0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P<0.0001), but not those with neuropathy (aHR 0.96, P=0.81; interaction P=0.15). CONCLUSION: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/efectos adversos , Doxorrubicina/administración & dosificación , Leucopenia/inducido químicamente , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/efectos adversos , Adulto , Anciano , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Pronóstico , RecurrenciaRESUMEN
To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers' attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfaction rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Toma de Decisiones , Neoplasias Endometriales/prevención & control , Histerectomía/psicología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Femenino , Finlandia , Pruebas Genéticas , Heterocigoto , Humanos , Histerectomía/estadística & datos numéricos , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Dolor Asociado a Procedimientos Médicos/psicología , Satisfacción del Paciente , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Toremifene, a selective estrogen receptor modulator, has been shown to be effective in alleviating premenstrual breast pain. However, the exact mechanism by which toremifene and related compounds work in premenstrual mastalgia is poorly understood. PURPOSE: To find out if the effect of toremifene on breast would be detectable with dynamic magnetic resonance imaging (MRI). MATERIAL AND METHODS: This randomized, double-blind crossover study was performed on women suffering from marked premenstrual mastalgia. Ten women were randomized to receive either toremifene (20 mg) or placebo from cycle day 15 until next menstruation for three menstrual cycles. After a washout period, the treatment was crossed over for three additional cycles. The MRI evaluations were performed premenstrually at the end of each treatment phase. Breast pain and quality-of-life scores were collected from one baseline cycle and from all the treatment cycles. RESULTS: Nine patients were evaluable for this analysis. Both the enhancement ratio and the maximum slope of enhancement tended to be smaller during the toremifene cycles as compared to placebo. On the left side, the difference in the maximum slope of enhancement between toremifene and placebo was statistically significant (median 5.150 [range 3.7-6.7] and 6.500 [range 4.9-9.5], respectively; P=0.047). T2 relaxation times as well as breast pain and quality-of-life scores were inconsistent. CONCLUSION: Use of toremifene is associated with measurable changes in dynamic breast MRI findings in women with cyclic breast pain.
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Enfermedades de la Mama/tratamiento farmacológico , Enfermedades de la Mama/patología , Imagen por Resonancia Magnética/métodos , Trastornos de la Menstruación/tratamiento farmacológico , Trastornos de la Menstruación/patología , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Toremifeno/uso terapéutico , Adulto , Medios de Contraste , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Meglumina , Persona de Mediana Edad , Compuestos Organometálicos , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Ovarian cancer has the highest mortality rate of all gynecologic malignancies. Identification of new biomarkers is highly needed due to its late diagnosis and high recurrence rate. The objective of this study was to identify mechanisms of therapy resistance and potential biomarkers by analyzing mRNA and protein expression from samples derived from patients with platinum-sensitive and -resistant ovarian cancer (total cohort nâ¯=â¯53). The data revealed new candidates for targeted therapies, such as GREB1 and ROR2. We showed that the development of platinum resistance correlated with upregulation of ROR2, whereas GREB1 was downregulated. Moreover, we demonstrated that high levels of ROR2 in platinum-resistant samples were associated with upregulation of Wnt5a, STAT3 and NF-kB levels, suggesting that a crosstalk between the non-canonical Wnt5a-ROR2 and STAT3/NF-kB signaling pathways. Upregulation of ROR2, Wnt5a, STAT3 and NF-kB was further detected in a platinum-resistant cell-line model. The results of the present study provided insight into molecular mechanisms associated with platinum resistance that could be further investigated to improve treatment strategies in this clinically challenging gynecological cancer.
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The effect of ionic strength, assay constituents, alpha-naphthoflavone (aNF), terfenadine and testosterone on human CYP3A mediated midazolam (MDZ) 1'-hydroxylation (MDZ 1'-OH) and 4-hydroxylation (MDZ 4-OH) in vitro was examined. Increasing concentration of Tris-HCl (Tris) and sodium phosphate (PO4) buffers differentially affected MDZ 1'-OH and MDZ 4-OH formation rates and had a different effect on MDZ metabolism mediated by microsomes containing CYP3A4 versus CYP3A4 and CYP3A5. MDZ metabolism was not affected by PO4 buffer concentration when cumene hydroperoxide (CUOOH) was used as the source of reactive oxygen. Interestingly, the ammonium ion present in the solution of glucose 6-phosphate dehydrogenase was found to inhibit MDZ metabolism. The addition of MgCl2 up to 50 mM and CaCl2 (5-30 mM) had no affect or inhibited MDZ metabolism, respectively. Formation of MDZ 1'-OH by microsomes from adult and fetal liver and expressed CYP3A4 was regioselectively stimulated by aNF (10 microM). In human hepatocytes, aNF stimulated MDZ 1'-OH formation (up to 100%). Terfenadine (20 microM) regioselectively stimulated MDZ 1'-OH formation in Tris (1-200 mM) and PO4 (1-10 mM) buffers by up to 159%. Surprisingly, with expressed CYP3A4, terfenadine (20 microM) inhibited MDZ 1'-OH formation. Terfenadine (20 microM) had little effect on MDZ 1'-OH formation by fetal liver microsomes. Testosterone (10 and 100 microM) regioselectively stimulated (up to 269%) MDZ 4-OH formation by adult liver microsomes and expressed CYP3A4. Testosterone (100 microM) inhibited (> 40%) MDZ 1'-OH and MDZ 4-OH formation by fetal liver microsomes. With adult liver microsomes, aNF and terfenadine had little effect on the Km for MDZ 1'-OH formation. However, the Km for MDZ 4-OH formation was decreased (up to 94%) by 100 microM testosterone. In the presence of CUOOH, no stimulation of MDZ metabolism was observed by aNF, terfenadine or testosterone in adult liver microsomes. These studies indicate that because assay conditions can substantially alter the catalytic activity of CYP3A, caution should be exerted when extrapolating results between in vitro and in vivo, and when results from different laboratories are compared. Further, these results suggest that the stimulation of CYP3A4 may also occur in vivo and, consequently, may have clinical importance.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Benzoflavonas/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Midazolam/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Terfenadina/farmacología , Testosterona/farmacología , Adulto , Derivados del Benceno/farmacología , Tampones (Química) , Cloruro de Calcio/farmacología , Citocromo P-450 CYP3A , Humanos , Cloruro de Magnesio/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , NADP/biosíntesisRESUMEN
BACKGROUND: Tangeretin is a flavonoid that stimulates the catalytic activity of cytochrome P450 3A4 (CYP3A4) and is found in high levels in tangerine juice. METHODS: The effect of tangeretin on hydroxylation of midazolam, a CYP3A4 probe, was examined in vitro with human liver microsomes and recombinant CYP3A4. In addition, the effect of tangerine juice on the pharmacokinetics and pharmacodynamics of orally administered midazolam (15 mg) and its active 1'-hydroxymetabolite was studied in a randomized crossover study in eight healthy volunteers. RESULTS: In microsomes from three human livers, tangeretin (1 to 100 micromol/L) increased 1'-hydroxymidazolam formation (12.5 micromol/L midazolam) by up to 212%. In complementary deoxyribonucleic acid-expressed CYP3A4, a 52% stimulation of midazolam 1'-hydroxylation was reached at 50 micromol/L tangeretin with no effect on midazolam 4-hydroxylation. In the pharmacokinetic-pharmacodynamic study, 200 mL tangerine juice reduced the area under the concentration versus time curve to 1.5 hours [AUC(O-1.5h)] of midazolam and 1'-hydroxymidazolam by 39% and 46%, respectively, and prolonged the time to reach peak concentration (P < .05) without affecting the total AUC values, elimination half-life values, or AUC ratios (1'-hydroxymidazolam/midazolam). These findings are consistent with a small delay in the absorption of midazolam and lack of effect on midazolam 1'-hydroxylation. Accordingly, tangerine juice slightly postponed the maximum pharmacodynamic effects of midazolam (P < .05). CONCLUSION: Tangeretin is a potent regioselective stimulator of midazolam 1'-hydroxylation by human liver microsomes and complementary deoxyribonucleic acid-expressed CYP3A4. However, tangerine juice is unlikely to have any appreciable effect on CYP3A4 in humans. Further studies are required to assess whether in vitro stimulators of CYP3A4 can influence drug metabolism in vivo.
Asunto(s)
Ansiolíticos/metabolismo , Antineoplásicos/farmacología , Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/metabolismo , Flavonas , Flavonoides/farmacología , Microsomas Hepáticos/efectos de los fármacos , Midazolam/metabolismo , Oxidorreductasas N-Desmetilantes/metabolismo , Adulto , Análisis de Varianza , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Femenino , Frutas , Semivida , Humanos , Hidroxilación/efectos de los fármacos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Midazolam/farmacocinética , Midazolam/farmacologíaRESUMEN
Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Toremifeno/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias Endometriales/inducido químicamente , Femenino , Humanos , Recurrencia Local de Neoplasia/prevención & controlRESUMEN
The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.
Asunto(s)
Neoplasias de la Mama/patología , Células Madre Neoplásicas/efectos de los fármacos , Tamoxifeno/farmacología , Animales , Neoplasias de la Mama/química , División Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/análisis , Trasplante de Neoplasias , Receptores de Estrógenos/análisis , Factores de Tiempo , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
Methoxsalen (8-methoxypsoralen) is a very potent inhibitor of human cytochrome P450 2A6 (CYP2A6) and mouse Cyp2a-5-mediated coumarin 7-hydroxylation in vitro. To determine the effect of methoxsalen on coumarin 7-hydroxylation in humans in vivo, five subjects were given 45 mg of methoxsalen and 5 mg of coumarin. Methoxsalen inhibited in vivo coumarin metabolism by 47 +/- 9.2% (mean +/- SEM). Methoxsalen was metabolized in human liver microsomes at the rate of 50-100 pmol/mg protein/min (approx. 30% of the activity in mouse liver microsomes). Metabolism was not inhibited by the anti-Cyp2a-5 antibody in human liver microsomes. NIH 3T3 cells stably expressing catalytically active CYP2A6 enzyme did not metabolize methoxsalen, indicating that CYP2A6 does not accept methoxsalen as a substrate. In pyrazole-induced mouse liver microsomes, methoxsalen metabolism was inhibited by the anti-Cyp2a-5 antibody. Cyp2a-5 protein expressed in the yeast Saccharomyces cerevisiae was capable of metabolizing methoxsalen, indicating that methoxsalen is a substrate of Cyp2a-5. Although kinetic studies indicated that the inhibition of coumarin 7-hydroxylation by methoxsalen is competitive in human liver microsomes, methoxsalen does not appear to be a substrate for CYP2A6. Methoxsalen and coumarin have the potential of strong metabolic interactions in man.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Cumarinas/metabolismo , Metoxaleno/metabolismo , Animales , Cumarinas/farmacocinética , Citocromo P-450 CYP2A6 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/orina , Interacciones Farmacológicas , Humanos , Cinética , Masculino , Ratones , Ratones Endogámicos DBA , Microsomas Hepáticos/metabolismo , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/orinaRESUMEN
We have studied coumarin 7-hydroxylase (COH) and testosterone 15 alpha-hydroxylase (15 alpha OH) activities in human liver microsomes and compared them with corresponding activities catalysed by members of the P450IIA sub-family in DBA/2N mouse liver microsomes. Human liver contained low levels of 15 alpha OH (about 5-30 pmol/min/mg protein) when compared with control mouse liver microsomes (about 200 pmol/min/mg protein). The anti-P450Coh antibody efficiently inhibited mouse liver 15 alpha OH, also 7 alpha OH (which is a member of the P450IIA sub-family), but it did not inhibit human 15 alpha OH or other testosterone hydroxylases. In mouse liver microsomes, metyrapone preferentially inhibited 15 alpha OH, but in human liver microsomes it inhibited all testosterone hydroxylations measured, including 15 alpha OH (IC50 = 2.0-5.0 microM). Metyrapone clearly inhibited COH in mouse liver microsomes, but interestingly it had no effect on COH activity in human liver microsomes, although these two isozymes have earlier been shown to be immunologically similar. On the basis of available evidence human and mouse P450Coh isozymes seem to be orthologous enzymes whereas the present results indicate that the human 15 alpha OH is different from the mouse P45015 alpha.