Summary Background Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for ...stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer. Methods We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model. Findings We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months 95% CI 15–22) and a low-risk group (90 patients; median progression-free survival 38 months 24–not estimable; hazard ratio HR 1·85 1·29–2·64, p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33–4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11–1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03–2·13, p=0·036; OC263: adjusted HR 3·09 2·24–4·28, p<0·0001; and OC452: HR 1·41 1·11–1·79, p=0·0047). Interpretation MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay. Funding AIRC and CARIPLO Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Summary Background Carboplatin plus paclitaxel administered every 3 weeks is standard first-line chemotherapy for patients with advanced ovarian cancer. A weekly paclitaxel schedule combined with ...carboplatin every 3 weeks prolonged progression-free survival and overall survival in a Japanese phase 3 trial. The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more effective than the same drugs given every 3 weeks. Methods We did a multicentre, randomised, phase 3 study at 67 institutions in Italy and France. Women with FIGO stage IC–IV ovarian cancer, an ECOG performance status of 2 or lower, and who had never received chemotherapy were randomly allocated in a 1:1 ratio to receive either carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m2 ) every 3 weeks for six cycles or carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m2 ) every week for 18 weeks. Randomisation was done by computer-based minimisation, stratified by centre, residual disease after surgery, and ECOG performance status. The study was not blinded. Coprimary endpoints were progression-free survival and quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index FACT-O/TOI score), and analysis was by modified intention to treat. This report presents the final analysis. The study is registered with ClinicalTrials.gov , number NCT00660842. Findings 822 patients were enrolled into the study between Nov 20, 2008, and March 1, 2012; 12 withdrew their consent immediately after randomisation and were excluded, and 810 were eligible for analysis. 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule. After median follow-up of 22·3 months (IQR 16·2–30·9), 449 progression-free survival events were recorded. Median progression-free survival was 17·3 months (95% CI 15·2–20·2) in patients assigned to treatment every 3 weeks, versus 18·3 months (16·8–20·9) in women allocated to the weekly schedule (hazard ratio 0·96, 95% CI 0·80–1·16; p=0·66). FACT-O/TOI scores differed significantly between the two schedules (treatment-by-time interaction p<0·0001); with treatment every 3 weeks, FACT-O/TOI scores worsened at every cycle (weeks 1, 4, and 7), whereas for the weekly schedule, after transient worsening at week 1, FACT-O/TOI scores remained stable. Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3–4 neutropenia (167 42% of 399 patients vs 200 50% of 400 patients), febrile neutropenia (two 0·5% vs 11 3%), grade 3–4 thrombocytopenia (four 1% vs 27 7%), and grade 2 or worse neuropathy (24 6% vs 68 17%). Three deaths during the study were attributed to chemotherapy; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen. Interpretation A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer. Funding None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective To describe the feasibility and efficacy of multiple sequential rechallenges and analyze the predictive factors that may aid in selecting patients who are more likely to respond. Several ...studies have demonstrated the feasibility and activity of a single docetaxel rechallenge in patients with castration-resistant prostate cancer (CRPC), thus providing an additional opportunity for treatment in docetaxel-sensitive CRPC patients in clinical practice. Materials and Methods CRPC patients who completed first-line docetaxel therapy without disease progression have been offered a docetaxel rechallenge, and the responders have undergone further rechallenges until the appearance of docetaxel resistance. We assessed their clinical outcomes and evaluated all the variables potentially capable of predicting the response to rechallenge by means of uni- and multivariate analysis. Results Forty-six consecutive patients underwent 92 rechallenges. The overall biochemical response rate (prostate-specific antigen PSA reduction >50%) was 66%. Median overall survival was 32 months with a projected 2-year overall survival from the first docetaxel administration of 77.5%. Multivariate analysis showed that the time slope-log PSA, the time from the previous cycle, and the response to the previous cycle were predictive of the response to a rechallenge. Conclusion A docetaxel rechallenge may be safely repeated several times in CRPC patients and in selected patients could improve disease control. The predictive factors found in our analysis may help select the most appropriate strategy in the light of the availability of active second-line drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
El artículo presenta la experiencia de una narrativa transmedia en una escuela secundaria de Argentina con el objetivo de reflexionar sobre las implicaciones en el proceso educativo. La metodología ...de análisis es cualitativa, basada en observación participante y revisión bibliográfica. Los resultados vinculan las narrativas transmedia con las competencias de los estudiantes, el rol del docente y el diálogo con la comunidad. PALABRAS CLAVE: Educación, narrativas transmedia, filosofía, alfabetización digital. The article presents the experience of a transmedia narrative in a high school in Argentina with the aim of reflecting on the implications in the educational process. The analysis methodology is qualitative, based on participant observation and bibliographic review. The results link the transmedia narratives with the competences of the students, the role of the teacher and the dialogue with the community. KEYWORDS: Education, transmedia narrative, philosophy, digital literacy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Resumen En el artículo nos propusimos analizar la inclusión de la “Narrativas transmedia pedagógicas” y caracterizarlas a partir del estudio de dos experiencias en escuelas secundarias en Argentina ...en 2017 y 2018. Para el análisis adoptamos una metodología de investigación de tipo cualitativa, basada en técnicas de recolección y producción de datos: entrevistas, observación de las prácticas áulicas, análisis de documentos y revisión de bibliografía. El hallazgo principal del trabajo fue partir de las experiencias en las escuelas para abordar tres contextos (institucional, áulico y de la comunidad), y las dimensiones principales en las que debería reflexionar un docente para implementar la narrativa transmedia como estrategia de enseñanza y aprendizaje. En las conclusiones problematizamos el propósito de crear narrativas transmedia, poniendo en discusión la idea de que la inclusión de las Tecnologías de la Información y la Comunicación (TIC) implica necesariamente una mejora en el proceso educativo, sin reflexionar en profundidad sobre el potencial que tienen estas narrativas para favorecer: el aprendizaje significativo; el desarrollo de habilidades de la cultura digital y el alfabetismo transmedia; y el recupero de aprendizajes informales de los estudiantes y las intervenciones en la comunidad, a partir de la formulación de problemas de la realidad y la afirmación del rol político de la educación.
Purpose Platinum-based chemotherapy (PBC) for patients with progressing ovarian cancer (OC) is more effective with a longer time interval from previous platinum treatment (platinum-free interval ...PFI). In 1999, it was hypothesized that prolonging PFI with single-agent non-PBC (NPBC) may offer a strategy to improve overall outcome. MITO-8 aimed to verify this hypothesis commonly used in clinical practice although it has not been prospectively tested. Methods MITO-8 is an open-label, prospective, randomized, superiority trial. Patients with OC who experienced disease progression 6 to 12 months after their last platinum treatment were randomly assigned 1:1 to the experimental sequence of NPBC followed by PBC at subsequent relapse or the standard reverse treatment sequence. Overall survival (OS) was the primary end point. Results Two hundred fifteen patients were enrolled (standard arm n = 108; experimental arm n = 107). The trial ended before planned because of slow enrollment. PFI was prolonged in the experimental arm (median, 7.8 v 0.01 months). There was no OS benefit in the experimental arm (median, 21.8 v 24.5 months; hazard ratio, 1.38; 95% CI, 0.99 to 1.94; P = .06). Progression-free survival after the sequence was significantly shorter in the experimental arm (median, 12.8 v 16.4 months; hazard ratio, 1.41; 95% CI, 1.04 to 1.92; P = .025). Global quality-of-life change after three cycles was worse in the experimental arm. Slight differences were observed in the incidence of adverse effects. Conclusion MITO-8 supports the recommendation that PBC not be delayed in favor of an NPBC in patients with partially platinum-sensitive OC. PBC should be used as a control arm in future trials of new drugs in this setting.
Abstract Brain metastases from Non-Small Cell Lung Cancer are usually associated with poor prognosis and up to now chemotherapy has shown a modest activity upon cerebral localizations. We ...investigated the role of Pemetrexed, a new, well tolerated multi-target antifolate, on brain metastases. Patients and methods We collected 39 patients with evidence of cerebral nervous system (CNS) localizations from Non-Small Cell Lung Cancer (NSCLC) before starting treatment with Pemetrexed as second-line or further-line therapy. Results We confirmed the good tolerability of Pemetrexed even in that setting of patients and we reported a progressive disease (PD) in 12 patients (30.8%), a stable disease (SD) and partial response (PR) in 12 (30.8%) and 15 (38.4%) patients respectively, with an overall clinical benefit obtained in 69% of patients. The cerebral response to Pemetrexed was interesting with a cerebral radiological benefit obtained in 32 patients (82%), while 7 patients only showed brain progressive disease. Overall median survival was 10 months. All irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed, overall 22 patients, were included in one group, in order to avoid overlapping effects between brain radiotherapy and Pemetrexed over CNS localizations. Within that setting, we demonstrated an overall clinical benefit (SD + PR) and cerebral benefit in 63% and 68%, of patients respectively. Distribution of patients by overall response to Pemetrexed and CNS response was highly suggestive of activity of Pemetrexed on brain metastases. Conclusion We demonstrated the good tolerability of Pemetrexed even in patients with advanced NSCLC and brain metastases, and we found a very good overall response rate with evidence of activity on brain localizations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
It has not been well established whether the oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant ...systems. To further investigate this question, we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. We also investigated serum levels of proinflammatory cytokines and IL-2. All of these parameters were studied in relation to the most important clinical index of disease progression--namely, the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity and the reduction of serum levels of IL-6 and TNF-alpha.
We carried out an open nonrandomized study on 28 advanced stage cancer patients (stage III, 10.7% and stage IV, 89.3%) with tumors at different sites. The patients were divided into 5 groups, and a different antioxidant treatment was administered to each group. The antioxidants were alpha lipoic acid 200 mg/day orally; N-acetylcysteine 1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally; amifostine 375 mg/day i.v.; reduced glutathione 600 mg/day i.v.; and a combination of vitamin A 30,000 IU/day orally, vitamin E 70 mg/day orally, and vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days.
We found that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels, and two of them (cysteine-containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the antioxidant treatment was found to have an effect on both reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced the serum levels of IL-6 and TNF-alpha. Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.
Introduction:
Non-small-cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers, and one of the leading causes of cancer-related mortality. As most newly diagnosed patients present ...distant metastases, chemotherapy is the treatment of choice. Chemotherapy also plays a central role in postoperative and radical treatment in addition to radiotherapy.
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This paper reviews the role of vinorelbine, both alone and in combination with platinum-derivates, in the treatment of NSCLC. The authors review its efficacy at different stages of disease and under different conditions. Specifically, the authors evaluate its pharmacokinetic and toxicity profile and provide insight into its future as an NSCLC therapeutic.
Expert opinion:
In the first-line treatment of advanced NSCLC, the use of vinorelbine-based regimens may be less efficacious in controlling disease than other combinations. However, since their activity is not related to histology, vinorelbine still has potential as a first-line treatment for NSCLC patients in whom histology has failed to distinguish non-squamous from squamous histotypes. The use of an oral formulation may furthermore improve tolerability and patient compliance. Vinorelbine should be the drug of choice in the adjuvant setting as the vinorelbine/cisplatin doublet is the only regimen so far that has led to a survival gain in two Phase III trials. In patients aged > 70 years, vinorelbine (together with gemcitabine) should furthermore be the reference drug for first- and second-line therapy when single-agent chemotherapy is the treatment of choice. However, new efforts still need to be made to develop oral schedules for NSCLC.
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