RESUMEN
BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
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Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios Retrospectivos , Acrilamidas/uso terapéutico , Acrilamidas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores ErbB/genética , Compuestos de Anilina/uso terapéutico , Compuestos de Anilina/farmacología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Indoles , PirimidinasRESUMEN
BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.
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COVID-19 , Vacunas contra el Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Vacunas contra el Cáncer/efectos adversos , Antígeno HLA-A2/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Calidad de Vida , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , COVID-19/etiología , InmunoterapiaRESUMEN
BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Adulto , Compuestos de Anilina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Pemetrexed/uso terapéutico , Platino (Metal)/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Benzamidas , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Imidazoles , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas c-met/genética , TriazinasRESUMEN
PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received. PATIENTS: We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions. RESULTS: After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9-11.2] and 11.1 months [CI 95% 9.2-13.8], respectively, while TTF were 10.2 [CI 95% 8.5-12.6] and 11.9 months [CI 95% 9.7-17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3-33.7] in PFS and 30.4 months [CI 95% 24.7-34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8-54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0-73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6-NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3-34.0)] (P < 0.0001). CONCLUSION: The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.
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Quinasa de Linfoma Anaplásico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/uso terapéutico , Femenino , Reordenamiento Génico , Humanos , Italia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Incompatibility between currently available fetoscopes and the anatomical constraints of the distended fetal bladder, with the resulting curvature around the bladder neck, account for most technical difficulties during fetal cystoscopy in lower urinary tract obstruction (LUTO). The aim of this anatomical study was to assess by magnetic resonance imaging (MRI) the variation in three bladder angles (bladder-neck angle (BNA), vesicourethral angle (VUA) and angle between bladder dome and posterior urethra (DUA)), according to gestational age (GA), bladder volume and the presence of LUTO. METHODS: From our fetal medicine database, we retrieved for review 46 MRI examinations of male fetuses between 2015 and 2019, including 17 with LUTO, examined at a mean GA of 28.1 (range, 17.3-35.0) weeks and 29 age-matched controls, examined at 29.9 (range, 21.9-35.0) weeks. We measured bladder volume, bladder-wall thickness and the three bladder angles, and used the Mann-Whitney U-test to compare values between groups. Variations according to GA and bladder volume were determined using analysis of variance (ANOVA). A reliability study was performed using the Bland-Altman method and Lin's correlation coefficient was calculated. RESULTS: Both bladder volume and bladder-wall thickness were significantly greater in the LUTO group (P < 0.01). BNA was significantly larger in LUTO compared with control fetuses: the mean (range) was 127.1° (101.6-161.6°) vs 111.2° (88.5-157.3°) (P < 0.01). DUA averaged 117° and showed no difference between the groups (P = 0.92). No statistical comparison was performed on VUA since this was not measurable in most control fetuses. ANOVA showed no variation of any angle with bladder volume in both LUTO fetuses and control fetuses. BNA in LUTO fetuses was the only angle to vary with GA, being larger after, compared with at or before, 25 weeks (P = 0.04). The reliability study showed an acceptable bias for both intra- and interobserver reproducibility for all three angles. CONCLUSION: The findings that BNA is increased by approximately 15° in fetuses with LUTO and DUA averages 117° could aid in development of a customized fetal cystoscope and help to overcome the current technical challenges of fetal cystoscopy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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Diagnóstico Prenatal , Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico por imagen , Adulto , Biometría , Estudios de Casos y Controles , Cistoscopía/métodos , Femenino , Edad Gestacional , Humanos , Imagen por Resonancia Magnética , Masculino , Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal , Obstrucción del Cuello de la Vejiga Urinaria/congénitoRESUMEN
PURPOSE: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. METHODS: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. RESULTS: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. CONCLUSIONS: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.
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Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Área Bajo la Curva , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Humanos , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
AIMS: Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. METHODS: Plasma concentration-time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1-3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. RESULTS: Clearance was estimated to be 0.15 l h(-1), with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration-time curve (AUC) and the percentage drop of neutrophils (r(2) = 0.51, P < 10(-4)) or thrombocytes (r(2) = 0.49, P < 10(-4)). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1-3 regimen. CONCLUSION: This is the first integrated population PK-PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently undergoing early clinical development. A distinct relationship was found between drug exposure and haematological toxicity, supporting flat-dosing once every 3 weeks as the most adequate dosing regimen.
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Camptotecina/análogos & derivados , Inhibidores de Topoisomerasa I/farmacocinética , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Área Bajo la Curva , Plaquetas/citología , Plaquetas/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/sangre , Camptotecina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/efectos adversos , Inhibidores de Topoisomerasa I/sangreRESUMEN
BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.
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Relación Dosis-Respuesta a Droga , Naftalenos/análisis , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/análisis , Adulto , Anciano , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Persona de Mediana Edad , Neoplasias/clasificación , Neoplasias/patología , Neovascularización Patológica/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
OBJECTIVE: In a previous study, we found that patients who were offered the possibility of participation in a clinical trial had unexpressed concerns and fears that prevented them from making free or fully knowledgeable choices about their trial participation. In a selected population of patients who were offered participation in a phase I trial, we prospectively investigated whether a face-to-face discussion about their unexpressed fears might lead to a more conscious decision about whether to accept/refuse participation in the trial. METHODS: After the presentation of the trial, a questionnaire was administered to assess the presence of specific fears. Before the patients decided whether to participate in the trial, they discussed any fears that they had; finally, the impact of the discussion on the patients' choice to participate was evaluated. RESULTS: The majority (86%) of the patients thought that physicians conduct clinical trials for scientific interest, 13% felt exploited as 'guinea pigs' and 20% believed they were offered participation because they had no further hope for improvement. These existing fears were not elicited during the trial interview because the patients were themselves unaware of having them (28%) and because of fear of the doctors (3%). The possibility of discussing these fears was felt as an opportunity and made patients feel more conscious (92%) and freer (97%) when making their choice. CONCLUSIONS: Recognising and discussing misconceptions and fears, often unexpressed, make patients freer and more aware when facing the choice of whether or not \to participate in a phase I clinical trial.
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Ensayos Clínicos Fase I como Asunto/psicología , Toma de Decisiones , Conocimientos, Actitudes y Práctica en Salud , Neoplasias/psicología , Participación del Paciente , Adulto , Anciano , Conducta de Elección , Comunicación , Miedo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Encuestas y CuestionariosRESUMEN
BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Doxorrubicina/administración & dosificación , Ifosfamida/administración & dosificación , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina/efectos adversos , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Ifosfamida/efectos adversos , Masculino , Persona de Mediana Edad , Sarcoma/patología , Sarcoma/secundario , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/secundarioRESUMEN
Multiple symmetrical lipomatosis, also known as Madelung disease, Launois-Bensaude syndrome, and benign symmetrical lipomatosis, is an uncommon disease that is characterized by the presence of multiple and symmetrical deposits of nonencapsulated adipose tissue in the neck, upper trunk, arms, and legs. It affects mainly men, with a higher incidence in the Mediterranean area, and is typically associated with high alcohol consumption and a high prevalence of peripheral neuropathy that usually appears long after the development of lipomatous masses. We report the case of a patient with involvement of the scrotum. We present clinical, ultrasound, and magnetic resonance appearances of these scrotal lipomatous masses for the first time.
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Enfermedades de los Genitales Masculinos/diagnóstico , Lipomatosis Simétrica Múltiple/diagnóstico , Escroto/patología , Adulto , Humanos , Imagen por Resonancia Magnética , Masculino , Escroto/diagnóstico por imagen , UltrasonografíaRESUMEN
Intrahepatic cysts are generally classified as congenital, traumatic, infectious or neoplastic. Non-parasitic hepatic cysts (NPHCs) include simple cysts and adult polycystic liver disease in which the liver is diffusely occupied by cysts. NPHCs usually reach a large size before causing symptoms, unless a complication such as rupture, bleeding, infection, obstructive jaundice or neoplastic transformation occurs. We report the case of a 67-year-old man with spontaneous rupture of simple liver cyst. The clinical pictures and the unusual ultrasound features of this rare condition are discussed.
Asunto(s)
Quistes/diagnóstico por imagen , Hepatopatías/diagnóstico por imagen , Anciano , Humanos , Masculino , Remisión Espontánea , Rotura Espontánea/diagnóstico por imagen , UltrasonografíaRESUMEN
Dysferlin, the gene product of the limb girdle muscular dystrophy (LGMD) 2B locus, encodes a membrane-associated protein with homology to Caenorhabditis elegans fer-1. Humans with mutations in dysferlin ( DYSF ) develop muscle weakness that affects both proximal and distal muscles. Strikingly, the phenotype in LGMD 2B patients is highly variable, but the type of mutation in DYSF cannot explain this phenotypic variability. Through electronic database searching, we identified a protein highly homologous to dysferlin that we have named myoferlin. Myoferlin mRNA was highly expressed in cardiac muscle and to a lesser degree in skeletal muscle. However, antibodies raised to myoferlin showed abundant expression of myoferlin in both cardiac and skeletal muscle. Within the cell, myoferlin was associated with the plasma membrane but, unlike dysferlin, myoferlin was also associated with the nuclear membrane. Ferlin family members contain C2 domains, and these domains play a role in calcium-mediated membrane fusion events. To investigate this, we studied the expression of myoferlin in the mdx mouse, which lacks dystrophin and whose muscles undergo repeated rounds of degeneration and regeneration. We found upregulation of myoferlin at the membrane in mdx skeletal muscle. Thus, myoferlin ( MYOF ) is a candidate gene for muscular dystrophy and cardiomyopathy, or possibly a modifier of the muscular dystrophy phenotype.
Asunto(s)
Proteínas de la Membrana/genética , Proteínas Musculares/genética , Distrofias Musculares/genética , Secuencia de Aminoácidos , Animales , Northern Blotting , Proteínas de Unión al Calcio , Membrana Celular/metabolismo , Disferlina , Humanos , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/aislamiento & purificación , Ratones , Ratones Endogámicos mdx , Datos de Secuencia Molecular , Proteínas Musculares/biosíntesis , Proteínas Musculares/aislamiento & purificación , Músculo Esquelético/metabolismo , Distrofias Musculares/metabolismo , Miocardio/metabolismo , Membrana Nuclear/metabolismo , ARN Mensajero/análisisRESUMEN
A combined experimental and theoretical investigation of the deuterium isotope effects on the bacterial luciferase reaction is described. The experimental studies focus on determining if the unusual aldehydic deuterium isotope effect of approximately 1.5 observed in these reactions is an intrinsic isotope effect resulting from a single rate-limiting step or is a composite of multiple rate-limiting steps. The isotope effect observed is not significantly affected by variation in the aldehyde chain length, changes in the pH over a range of 6-9, use of alphaC106A and alphaC106S site-directed mutants, or chloride substitution at the 8-position of the reduced flavin, though the isotope effect is decreased when the 8-methoxy-substituted flavin is used as a substrate. From these observations it is concluded that the aldehydic isotope effect arises from the change in rate of a single kinetic step. A stopped-flow kinetic analysis of the microscopic rate constants for the reactions of 1-[1H]decanal and 1-[2H]decanal in the bacterial luciferase reaction was carried out, and aldehyde hydration isotope effects were determined. From the results it is estimated that the aldehydic deuterium isotope effect is approximately 1.9 after formation of an intermediate flavin C4a-hydroperoxy hemiacetal. Ab initio calculations were used to examine the transformation of the aldehyde into a carboxylic acid and to predict isotope effects for possible mechanisms. These calculations indicate that the mechanism involving rate-limiting electron transfer from the flavin C4a-hydroxide to an intermediate dioxirane is consistent with the enigmatic aldehydic isotope effect and that the intermediacy of a dioxirane is energetically plausible.
Asunto(s)
Deuterio/química , Luciferasas/química , Luciferasas/metabolismo , Aldehídos/química , Sitios de Unión/genética , Escherichia coli/genética , Mononucleótido de Flavina/química , Concentración de Iones de Hidrógeno , Cinética , Luciferasas/genética , Mediciones Luminiscentes , Mutagénesis Sitio-Dirigida , Recombinación Genética , Solventes , Espectrofotometría , Termodinámica , Vibrio/enzimología , Vibrio/genéticaRESUMEN
Ante la carencia de información sobre la residualidad biócida de atrazina en las diversas regiones del Sudoeste de la Pcia. de Buenos Sires, los autores presentan este trabajo proporcionando resultados de tres suelos de los partidos de Balcarce, González Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1, 2 y 4 kg. i.a.ha-1. El estudio se realizó mediante biotest con avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biócida de más de 223 días en el suelo de menor contenido orgánico(San Cayetano)
Asunto(s)
Argentina , Ingeniería Sanitaria , Herbicidas , CongresoRESUMEN
Ante la carencia de información sobre la residualidad biócida de atrazina en las diversas regiones del Sudoeste de la Pcia. de Buenos Sires, los autores presentan este trabajo proporcionando resultados de tres suelos de los partidos de Balcarce, González Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1, 2 y 4 kg. i.a.ha-1. El estudio se realizó mediante biotest con avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biócida de más de 223 días en el suelo de menor contenido orgánico(San Cayetano)
Asunto(s)
Ingeniería Sanitaria , Herbicidas , CongresoRESUMEN
Se carece de información sobre la residualidad biocida de atrazina en las diversas regiones del sudeste, de la Pcia. de Bs.As. El presente trabajo proporciona resultados de tres suelos de los partidos de Balcarce, Gonzáles Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1,2 y 4 kg.i.a.ha-1. El estudio se realizó mediante biotests con Avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biocida de más de 223 días en el suelo de menor contenido orgánico (San Cayetano)
Asunto(s)
Argentina , Ingeniería Sanitaria , Plaguicidas , Contaminación del Agua , CongresoRESUMEN
Se carece de información sobre la residualidad biocida de atrazina en las diversas regiones del sudeste, de la Pcia. de Bs.As. El presente trabajo proporciona resultados de tres suelos de los partidos de Balcarce, Gonzáles Chaves y San Cayetano, sobre los que se efectuaron aplicaciones de 1,2 y 4 kg.i.a.ha-1. El estudio se realizó mediante biotests con Avena sativa, en condiciones controladas, determinando el efecto del herbicida sobre la evolución del peso seco. Se determinó que la atrazina tuvo una persistencia biocida de más de 223 días en el suelo de menor contenido orgánico (San Cayetano)