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1.
BMC Cancer ; 23(1): 613, 2023 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-37400764

RESUMEN

BACKGROUND: Ovarian clear cell carcinomas (OCCCs) are rare, aggressive and chemoresistant tumors. Geographical and ethnic differences in the incidence of OCCC have been reported with a higher incidence in Asiatic countries. There is a paucity of information regarding OCCC in Latin America (LA) and other countries. METHODS: Here, we characterized two cohorts of 33 patients with OCCC from LA (24 from Brazil and 9 from Costa Rica) and a cohort of 27 patients from Spain. Genomic analysis was performed for 26 OCCC using the OncoScan platform. Tumors were classified according to their genomic landscapes into subgroups. Clinical parameters were related to the frequency of genomic aberrations. RESULTS: The median overall survival (OS) was not significantly different between the cohorts. Genomic landscapes were characterized by different homologous recombination deficiency (HRD) levels. No difference in the distribution of genomic landscapes profiles was detected between patients from the different cohorts. OCCCs with MYC-amplified tumors harboring a concomitant loss of a region in chromosome 13q12-q13 that includes the BRCA2 gene had the longest OS. In contrast, patients carrying a high number (> 30) of total copy number (CN) aberrations with no concomitant alterations in MYC and BRCA2 genes presented the shortest OS. Furthermore, amplification of the ASH1L gene was also associated with a shorter OS. Initial-stage OCCCs with early progression were characterized by gains in the JNK1 and MKL1 genes. CONCLUSIONS: Our results provide new data from understudied OCCC populations and reveal new potential markers for OCCCs.


Asunto(s)
Adenocarcinoma de Células Claras , Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/patología , Genómica , Brasil , Adenocarcinoma de Células Claras/patología
2.
Int J Mol Sci ; 24(13)2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37446361

RESUMEN

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.


Asunto(s)
Linfocitos Infiltrantes de Tumor , Neoplasias Ováricas , Humanos , Femenino , Pronóstico , Estudios Retrospectivos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Ováricas/patología , Mutación
3.
Lancet Oncol ; 23(8): e374-e384, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35901833

RESUMEN

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.


Asunto(s)
Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Consenso , Femenino , Predicción , Humanos , Neoplasias Ováricas/terapia
4.
Acta Haematol ; 145(1): 72-77, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34352748

RESUMEN

Acquired thrombocytopenic thrombotic purpura (aTTP) is an autoantibody-mediated disease against the enzyme A Disintegrin and Metalloprotease domain with ThromboSpondin-1 type motif 13, which until now has been treated with plasma exchange (PEX) and corticosteroids. A 29-year-old female patient, who presented with aTTP in the context of pregnancy, has developed multiple relapses after treatment with PEX, corticosteroids, and rituximab. Recently, caplacizumab, a nanobody against von Willebrand factor, has been approved for the treatment of aTTP. In our patient, caplacizumab achieved better disease control, with a lower platelet count restoration time, days of PEX and hospitalization duration, as compared to standard therapy, reproducing the results of clinical trials. Caplacizumab represents a significant advance in the treatment of aTTP, especially in cases of recurrent relapses.


Asunto(s)
Intercambio Plasmático , Complicaciones Hematológicas del Embarazo/terapia , Púrpura Trombocitopénica Trombótica/terapia , Anticuerpos de Dominio Único/administración & dosificación , Adulto , Femenino , Humanos , Embarazo , Complicaciones Hematológicas del Embarazo/sangre , Púrpura Trombocitopénica Trombótica/sangre
5.
J Oncol Pharm Pract ; 28(7): 1583-1593, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34565241

RESUMEN

The presence of contamination in the healthcare work environment by one of the types of hazardous drugs, cytostatics, has been found in multiple international studies. Recent studies and guidelines recommend surface monitoring for risk assessment of healthcare professionals' exposure. The availability of detection techniques is critical to successfully carry out this type of monitoring. The use of new semi-quantitative techniques allows quicker results. The main objective of this study was to determine the existence of hazardous drugs on the working surfaces in different locations of a tertiary hospital using the BD HD Check® semi-quantitative device. The presence of methotrexate, doxorubicin and cyclophosphamide was analysed at 80, 89 and 82 locations in 10, 13 and 11 clinical units, respectively. A total of 251 samples were analysed. The monitoring results were positive for 13.1% of the analysed samples, with 36.3% of the methotrexate samples, 0% of the doxorubicin samples and 4.9% of the cyclophosphamide samples. Mapping the presence of HD in our hospital has allowed us to evaluate the effectiveness of controls established in the hospital to minimise the exposure of healthcare professionals to hazardous drugs. The speed in obtaining results has enabled immediate corrective actions in cases where contaminated surfaces were detected.


Asunto(s)
Antineoplásicos , Exposición Profesional , Antineoplásicos/efectos adversos , Antineoplásicos/análisis , Ciclofosfamida/análisis , Doxorrubicina , Monitoreo del Ambiente/métodos , Contaminación de Equipos , Humanos , Metotrexato/efectos adversos , Metotrexato/análisis , Exposición Profesional/análisis , Centros de Atención Terciaria
6.
J Clin Pharm Ther ; 47(10): 1570-1575, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35641241

RESUMEN

WHAT IS KNOWN AND OBJECTIVE: The technique of highlighted capital letters, Tall Man lettering, is a tool that allows differentiating the names of similar drugs in a way that contributes to reduce medication errors related to the drug identification. The objective was to implement and monitor the application protocol of the Tall Man lettering tool in drug information systems in the healthcare environment to improve the quality of care and patient safety in the pharmacy service and the medical institution. METHODS: Scope: Tertiary general hospital with 1000 beds in which a Tall Man lettering application protocol was approved in the pharmacy service information systems. DESIGN: Retrospective observational study. PERIOD: 2019-2021. POPULATION: Information systems and databases used in the pharmacy service. Working group: Made up of people in charge of information areas and systems. IMPLEMENTATION: Five phases were defined: organization of the working group, selection of drug names and information systems, establishment of actions, their execution, and results monitoring. VARIABLES: Number of pharmaceutical specialties, names of active ingredient and brands incorporated in the information systems. RESULTS AND DISCUSSION: The application of Tall Man lettering was authorized in 13/13 information systems, six have been fully implemented and seven are in the database update phase. Of the implanted systems, a total of 210 drug names have been modified (168/210 active ingredient and 42/210 brand names), corresponding to 659 pharmaceutical specialties. WHAT IS NEW AND CONCLUSION: The application of Tall Man lettering in hospital information systems is a tool for improving the quality of the pharmacy service and guarantees the safety of medicines in the hospital.


Asunto(s)
Etiquetado de Medicamentos , Errores de Medicación , Bases de Datos Factuales , Hospitales , Humanos , Masculino , Errores de Medicación/prevención & control , Preparaciones Farmacéuticas
7.
Int J Technol Assess Health Care ; 38(1): e64, 2022 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-35912833

RESUMEN

OBJECTIVES: Our aim was to assess the value of nintedanib for non-idiopathic progressive fibrosing interstitial lung disease (non-IPF PF-ILD) and systemic sclerosis-associated ILD (SSc-ILD) in the Spanish context, using a multi-criteria decision analysis (MCDA). METHODS: Following an adaptation of the Evidence and Value: Impact on DEcision Making (EVIDEM) MCDA methodology, the estimated value of nintedanib was obtained by means of an additive linear model that combined individual weights (100-points distribution) of criteria with the individual scoring of nintedanib in each criterion for every indication, assigned by a multidisciplinary committee of twelve clinicians, patients, pharmacists, and decision-makers. To assess the reproducibility, an alternative weighting method was applied, as well as a re-test of weights and scores at a different moment of time. RESULTS: The experts committee recognized nintedanib as an intervention with a positive value contribution in comparison to placebo for the treatment of non-IPF PF-ILD (0.50 ± 0.16, on a scale from -1 to 1) and SSc-ILD (0.40 ± 0.12), diseases which were considered as very severe and with high unmet needs. The drug was perceived as a treatment that provides an added therapeutic benefit for patients (0.06-0.07), given its proven clinical efficacy (0.05-0.06), slight improvements in patient-reported outcomes (0.01-0.02), and similar safety profile than placebo (-0.04-0.00), which will likely be positioned as a recommended therapy in the next clinical practice guidelines updates. CONCLUSIONS: Under this increasingly used methodology, nintedanib has shown to provide a positive value estimate for non-IPF PF-ILD and SSc-ILD when compared to placebo in Spain.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Técnicas de Apoyo para la Decisión , Progresión de la Enfermedad , Humanos , Indoles/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Reproducibilidad de los Resultados
8.
Lancet Oncol ; 22(5): 620-631, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33743851

RESUMEN

BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.


Asunto(s)
Genes BRCA1 , Genes BRCA2 , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Comprimidos , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Ftalazinas/efectos adversos , Piperazinas/efectos adversos
9.
J Oncol Pharm Pract ; 27(2): 268-278, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32279599

RESUMEN

PURPOSE: Intraperitoneal with intravenous chemotherapy (IP/IV) is the recommended option for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials and showing important improvements in overall survival and progression free survival. However, its application has not been largely adopted due to its difficult administration that requires a trained nurse staff. The aim of this work was to study the completion and the toxicity of an IP outpatient chemotherapy regimen in optimally debulked stage III ovarian cancer patients. METHODS: A single-center, retrospective observational study in women with stage III ovarian cancer following optimal cytoreductive surgery (<1 cm) followed by IP/IV chemotherapy from 2009 to 2017. The IP/IV regimen was as it follows: IV paclitaxel 175 mg/m2 in 3 h, day 1; IP cisplatin (100 mg/m2-until December 2013-or 75 mg/m2), day 2; IP paclitaxel 60 mg/m2, day 8, each 21 days for six cycles. RESULTS: A total of 60 patients received IP/IV regimen. Of these, 41 patients (68.3%) completed the six IP chemotherapy cycles and 51 (84.9%) completed four or more cycles. Most of the adverse events reported were non-hematological and G1-2. There was no difference neither in adherence nor in the frequency of adverse events between both cisplatin groups. Despite a high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Epitelial de Ovario/terapia , Neoplasias Ováricas/terapia , Cooperación del Paciente , Neoplasias Peritoneales/terapia , Adulto , Carcinoma Epitelial de Ovario/secundario , Cisplatino/administración & dosificación , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Infusiones Parenterales , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Neoplasias Peritoneales/secundario , Estudios Retrospectivos
10.
Cancer ; 126(4): 894-907, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31714594

RESUMEN

BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors. METHODS: Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient-derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line. RESULTS: Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ-H2AX. Inhibition of autophagy also increased ROS and γ-H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy. CONCLUSIONS: PARP inhibitor-induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild-type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.


Asunto(s)
Autofagia/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cloroquina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Indazoles/farmacología , Ratones Desnudos , Ratones SCID , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Ftalazinas/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
11.
Gynecol Oncol ; 159(3): 721-731, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32988624

RESUMEN

OBJECTIVE: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Endometriales/terapia , Terapia Neoadyuvante/métodos , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Quimioterapia Adyuvante/métodos , Ciclina D1/análisis , Ciclina D1/genética , Proteínas de Unión al ADN/genética , Relación Dosis-Respuesta a Droga , Neoplasias Endometriales/sangre , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Endometrio/efectos de los fármacos , Endometrio/patología , Endometrio/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transportador de Glucosa de Tipo 1/antagonistas & inhibidores , Transportador de Glucosa de Tipo 1/sangre , Humanos , Histerectomía , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Estudios Prospectivos , Comprimidos , Factores de Tiempo , Factores de Transcripción/genética , Resultado del Tratamiento
12.
Dig Dis ; 37(2): 108-115, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30149385

RESUMEN

INTRODUCTION: The association between infliximab (IFX) and fecal calprotectin (FC) levels on one hand, and the clinical and endoscopic response of patients with inflammatory bowel disease on the other, is well established. OBJECTIVE AND METHODS: To investigate the association between inflammatory biochemical parameters and serum concentrations of IFX during induction treatment with a primary nonresponse in a prospective cohort of Crohn's disease (CD) patients. RESULTS: Of the 35 patients included, 8 (22.8%) had primary nonresponse at the end of induction. Induction IFX levels were lower among primary nonresponders at weeks 6 and 14 (week 6: median IFX level 7.3 vs. 11.2 µg/mL, respectively, p = 0.090; week 14: median IFX level 1.5 vs. 4.7 µg/mL, respectively, p = 0.020). FC levels were higher in patients with primary nonresponse versus primary response at weeks 0, 6, and 14 (week 0: median FC level 1,830 vs. 410 µg/g, -respectively, p = 0.030; week 6: median FC level 1,150 vs. 230 µg/g, respectively, p = 0.074; week 14: median FC level 1,210 vs. 208 µg/g, respectively, p = 0.060). For the multivariate analysis, the median IFX level at week 14 and median FC level at week 0 were independently associated with primary nonresponse. A significant inverse correlation was determined between FC level at week 0 and IFX level at week 14 (Spearman's rho correlation, 0.440; p < 0.05). CONCLUSIONS: IFX levels (at week 14) and baseline FC levels could predict primary nonresponse after induction IFX therapy in patients with CD. A high baseline inflammatory load might modify the pharmacokinetic processes of anti-tumor necrosis factor drugs. Drug level monitoring and measurement of baseline inflammatory parameters could improve the efficacy of IFX in the induction therapy of patients with active CD.


Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Heces/química , Infliximab/uso terapéutico , Complejo de Antígeno L1 de Leucocito/metabolismo , Adolescente , Adulto , Anciano , Femenino , Fármacos Gastrointestinales/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven
13.
Future Oncol ; 15(32): 3651-3663, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31553234

RESUMEN

The poly(ADP-ribose) polymerase inhibitor olaparib (Lynparza™) is approved for maintenance treatment of platinum-sensitive relapsed ovarian cancer. OPINION is a single-arm, open-label, multicenter, Phase IIIb study to assess the efficacy and safety of olaparib tablet maintenance therapy in women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer without a germline BRCA1 or BRCA2 mutation. Eligible patients should have received ≥2 prior lines of platinum-based chemotherapy and be in complete or partial response following their most recent course or have no evidence of disease. Patients will receive olaparib tablets (300 mg twice daily) until disease progression, unacceptable toxicity or another discontinuation criterion. The primary end point is investigator-assessed progression-free survival; secondary end points include progression-free survival according to tumor homologous recombination deficiency status. Clinical trial registration: NCT03402841.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Femenino , Mutación de Línea Germinal , Humanos , Quimioterapia de Mantención , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Platino (Metal)/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión
14.
J Clin Pharm Ther ; 44(4): 572-578, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30851209

RESUMEN

WHAT IS KNOWN AND OBJECTIVE: Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. METHODS: A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. RESULTS AND DISCUSSION: A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1-5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C-reactive protein >100 mg/dL was associated with supra-therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. WHAT IS NEW AND CONCLUSIONS: There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.


Asunto(s)
Antifúngicos/sangre , Antifúngicos/farmacocinética , Voriconazol/sangre , Voriconazol/farmacocinética , Bilirrubina/metabolismo , Enfermedad Crítica , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Plasma/metabolismo , Estudios Prospectivos
15.
Am J Transplant ; 18(2): 504-509, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29116676

RESUMEN

Scedosporium is an important pathogen in cystic fibrosis (CF) and post-transplantation, but it rarely causes invasive infection. Treatment remains challenging, particularly due to the inherent resistance to multiple antifungal agents. We present 3 complicated invasive tracheobronchial and lung Scedosporium apiospermum infections following lung transplantation. In 2 of 3 cases, the infection was clinically and radiologically cured with frequent cleansing bronchoscopies, combining triazole with terbinafine therapy and nebulized posaconazole. These cases highlight the importance of adjunctive nebulized therapy in addition to prolonged triazole treatment to manage complex invasive Scedosporium infections in immunosuppressed patients. Posaconazole (PSZ) was delivered during the bronchoscopy procedure through intrabronchial administration, whereas an eFlow rapid® device was used for nebulized therapy. Topical posaconazole was well tolerated in 2 patients, with only a slight cough during administrations; the third patient had local irritation with poor tolerance, which led to its withdrawal. This is the first report on compassionate use of topical PSZ as salvage therapy for resistant mold infections in lung transplant recipients. These 3 cases represent the entire experience using this approach; no additional patients have received this therapy due to there not having been any additional cases of Scedosporium tracheobronchitis presented.


Asunto(s)
Fibrosis Quística/cirugía , Enfisema/cirugía , Trasplante de Pulmón/efectos adversos , Micosis/tratamiento farmacológico , Terapia Recuperativa , Scedosporium/efectos de los fármacos , Triazoles/administración & dosificación , Administración Tópica , Adulto , Antifúngicos/administración & dosificación , Fibrosis Quística/patología , Enfisema/patología , Femenino , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Micosis/etiología , Micosis/patología , Complicaciones Posoperatorias , Pronóstico , Receptores de Trasplantes
16.
J Clin Pharm Ther ; 43(6): 822-828, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29906305

RESUMEN

WHAT IS KNOWN AND OBJECTIVES: Most of the clotting factor (CF) dispensations to haemophiliac patients are centralized in a few haemophilia treatment centres, necessitating frequent visits and long travel distances. The aim was to evaluate the home delivery programme developed by the Outpatient Pharmaceutical Care Unit (OPCU) through the association of patients (ASHECOVA). METHODS: A specific software programme was designed to communicate the individual CF requirements. Dispensations were prepared in advance, and an ASHECOVA member collected and delivered to patients' homes in optimal conditions. Data regarding the programme were analysed from December 2011 to December 2017. An electronic satisfaction survey with 34 questions was conducted, asking about organizational aspects, education and communication, use of apps and satisfaction level. RESULTS AND DISCUSSION: Forty-nine patients were included and 2464 home deliveries were made, without any reported incident related to dispensation errors, drug preservation, communication or confidentiality problems. This system avoids 11.4 annual dispensation visits per patient to OCPU, and a mean travel distance, time and cost of 1189.1 km, 945.3 minutes and 373.5 euros, respectively. Overall satisfaction with home delivery was 9.7, without any change suggested in the current system. Ninety-five per cent of individuals believed that the programme improves adherence and all patients would recommend it to other patients. The most common benefits reported were less frequent visits to hospital, reducing time and cost spent on transportation. WHAT IS NEW AND CONCLUSION: The home delivery programme guarantees a proper follow-up of treatments with full patient satisfaction. This programme allows OPCU to achieve better pharmaceutical care, traceability of the process and optimization of working times and CF stock management.


Asunto(s)
Factores de Coagulación Sanguínea/administración & dosificación , Hemofilia A/tratamiento farmacológico , Servicios de Atención de Salud a Domicilio/organización & administración , Servicios Farmacéuticos/organización & administración , Adolescente , Adulto , Atención Ambulatoria/organización & administración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Proyectos Piloto , Programas Informáticos , Encuestas y Cuestionarios , Adulto Joven
17.
Lancet Oncol ; 18(9): 1274-1284, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28754483

RESUMEN

BACKGROUND: Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. METHODS: This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0-1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6-12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. FINDINGS: Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3-25·7]) than with placebo (5·5 months [5·2-5·8]; hazard ratio [HR] 0·30 [95% CI 0·22-0·41], p<0·0001). The most common adverse events of grade 3 or worse severity were anaemia (38 [19%] of 195 patients in the olaparib group vs two [2%] of 99 patients in the placebo group), fatigue or asthenia (eight [4%] vs two [2%]), and neutropenia (ten [5%] vs four [4%]). Serious adverse events were experienced by 35 (18%) patients in the olaparib group and eight (8%) patients in the placebo group. The most common in the olaparib group were anaemia (seven [4%] patients), abdominal pain (three [2%] patients), and intestinal obstruction (three [2%] patients). The most common in the placebo group were constipation (two [2%] patients) and intestinal obstruction (two [2%] patients). One (1%) patient in the olaparib group had a treatment-related adverse event (acute myeloid leukaemia) with an outcome of death. INTERPRETATION: Olaparib tablet maintenance treatment provided a significant progression-free survival improvement with no detrimental effect on quality of life in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Apart from anaemia, toxicities with olaparib were low grade and manageable. FUNDING: AstraZeneca.


Asunto(s)
Antineoplásicos/uso terapéutico , Quimioterapia de Mantención , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Método Doble Ciego , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/patología , Comprimidos
18.
Future Oncol ; 13(23s): 11-16, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29020823

RESUMEN

Although platinum-based chemotherapy continues to be the first-line option for advanced ovarian cancer and for platinum recurrences beyond 6 months, platinum rechallenge is not the best approach for some patients, such as those with residual toxicities, platinum-related hypersensitivity reactions or limited platinum-sensitivity (i.e., a platinum treatment-free interval [TFIp] of 6-12 months). Results of the MITO-8 study called into question the role of single-agent nonplatinum-based regimens in this specific subset of ovarian cancer patients. The current article summarizes the results of the MITO-8 study highlighting key limitations, and discusses the role of the nonplatinum-based combination of trabectedin + pegylated liposomal doxorubicin in the management of ovarian cancer patients who relapse between 6 and 12 months after last platinum.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Platino (Metal)/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Neoplasias Ováricas/mortalidad , Platino (Metal)/administración & dosificación , Platino (Metal)/efectos adversos , Recurrencia , Resultado del Tratamiento
19.
Int J Gynecol Cancer ; 27(8): 1619-1627, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28692635

RESUMEN

OBJECTIVES: The Response Evaluation Criteria in Solid Tumors (RECIST) International Working Group developed criteria for tumor response and progression to standardize radiological assessment in patients receiving chemotherapy in phase 2 trials. However, it is unclear whether the defined percentage change in tumor size and volume reflects true clinical benefit for the patient. The RECIST criteria were designed to improve objectivity in trials, but not to replace clinical decision making. The aim of this study was to understand clinicians' opinions about RECIST in current oncology practice. METHODS: Using Web-based questionnaires, we investigated attitudes to the use of RECIST at a large comprehensive cancer center and in an international group of gynecologic cancer specialists through the Gynecologic Cancer InterGroup. The results reported here relate to the survey focusing on gynecologic cancer. RESULTS: Sixty medical professionals from 13 countries responded to the survey. The majority of respondents worked at a tertiary or specialist cancer center (51; 86%). Overall, 66% of respondents felt RECIST increased trial objectivity and was a good measure of response. The majority of respondents (81%) reported that they infrequently challenged RECIST evaluation. Overall, 60% felt more than 10% of patients came off trial for clinical rather than radiological progression. In the context of a new small lesion, only 35% felt that should always be considered disease progression. The importance of both clinician and radiologist input was highlighted with nontarget progression. Nontarget progression and target progression were recognized as equally important for clinical decision making (72%). CONCLUSIONS: RECIST is a key criterion for endpoint assessment in clinical trials with its value recognized by clinicians. However, this survey also highlights the practical limitations of RECIST. Disconnect can be seen between the radiological result and the clinical picture-learning from these patients is critical. Continued efforts to improve metrics assessing patient benefit in trials remains a priority.


Asunto(s)
Ensayos Clínicos Fase II como Asunto/métodos , Neoplasias de los Genitales Femeninos/diagnóstico por imagen , Neoplasias de los Genitales Femeninos/terapia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Actitud del Personal de Salud , Toma de Decisiones Clínicas , Femenino , Humanos , Internet , Encuestas y Cuestionarios
20.
Int J Gynecol Cancer ; 27(7): 1367-1372, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28704322

RESUMEN

OBJECTIVE: The aim of this study was to describe the clinical and oncological outcomes of women with malignant bowel obstruction (MBO) for relapsed ovarian cancer and peritoneal carcinomatosis. METHODS: A retrospective cohort study was performed in all consecutive patients admitted at Instituto Valenciano de Oncología, Valencia, Spain, between July 2013 and July 2016 with MBO for relapsed ovarian cancer and peritoneal carcinomatosis. All patients underwent the same protocol of conservative management. Surgical treatment was indicated only in selected cases. RESULTS: There were a total of 22 patients presenting 59 episodes of MBO; 17 (77.2%) of those patients presented more than 1 episode of MBO. All patients had serous epithelial ovarian cancer; 18 (81.8%) were high grade, and 4 (18.2%) low-grade tumors. The median (range) number of episodes per patient was 3 (range, 1-7) with a mean length of hospitalization of 13 (SD, 13.6) days. The median time interval between episodes of MBO (54 episodes in 17 patients) was 17 days (range, 1-727 days). Twenty of 22 patients died with a median overall survival time from the first episode of MBO of 95 days (95% confidence interval, 49-124 days). CONCLUSIONS: Patients with MBO due to relapsed epithelial ovarian cancer in the peritoneal carcinomatosis setting have a short life expectancy, presenting a median of 3 episodes of MBO until death, with a short time interval between episodes. These findings show that bowel obstruction can represent a constant status over time until death.


Asunto(s)
Obstrucción Intestinal/etiología , Neoplasias Glandulares y Epiteliales/complicaciones , Neoplasias Ováricas/complicaciones , Neoplasias Peritoneales/complicaciones , Adulto , Anciano , Carcinoma Epitelial de Ovario , Estudios de Cohortes , Femenino , Humanos , Obstrucción Intestinal/mortalidad , Obstrucción Intestinal/patología , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/mortalidad , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/patología , Estudios Retrospectivos , España/epidemiología
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