Recommendations on screen time, sleep and physical activity: associations with academic achievement in Swiss adolescents.

OBJECTIVES: This study aimed to investigate how meeting international recommendations for screen time (<2 h/day), moderate-to-vigorous physical activity (MVPA; at least 60 min/day) and sleep (8-10 h/night), as well as media multitasking (MMI) as a form of screen time, impact academic achievement in early adolescence. STUDY DESIGN: A prospective design was used, where self-report measures were collected during the spring semester and academic achievement at the end of the school year. METHODS: A total of 1208 grade 3 middle school students (Mage = 13.55 years, SDage = 0.60) in 37 Swiss schools filled out a paper-and-pencil questionnaire including measures of screen time (covering watching television, playing video games, Internet use, smartphone use and social media use), MMI, sleep time and time for MVPA. To evaluate academic achievement, end-term grades were provided by the collaborating education administration for Italian, Maths, Science, History, Geography, Music and Visual arts. RESULTS: After adjustment for covariates, such as gender, socio-economic status, body mass index and stressful life events, multivariate linear mixed-effect models, nesting participants in schools, showed that meeting recommendations for screen time (B = 0.12, ß = 0.105, P < 0.001) and MVPA (B = 0.09, ß = 0.09, P = 0.001), but not sleep (B = 0.05, P = 0.087), were associated with higher academic achievement. Considering the number of recommendations met, meeting all three recommendations improved academic achievement the most (B = 0.24, ß = 0.21, P < 0.001), followed by meeting the guidelines for screen time + MVPA (B = 0.20, ß = 0.15, P < 0.001) and for screen time + sleep (B = 0.21, ß = 0.13, P < 0.001). In the fully adjusted model, multitasking with two or more media was related to a worse academic achievement. CONCLUSIONS: Screen time (including MMI), sleep and MVPA impact academic achievement in adolescence; hence, governmental organisations and schools should raise awareness about the positive and negative effects of following or not recommendations for MVPA, sleep and screen time among adolescents and their parents. In addition, support should be provided to promote sufficient sleep and MVPA while limiting overall screen time and parallel device use.

Metronomic oral vinorelbine in previously untreated advanced non-small-cell lung cancer patients unfit for platinum-based chemotherapy: results of the randomized phase II Tempo Lung trial.

BACKGROUND: To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy. PATIENTS AND METHODS: This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL). RESULTS: A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms. CONCLUSIONS: Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population.

Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis.

PURPOSE: Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance. METHODS: We retrospectively collected data on 270 patients [median age 76 (range 48-92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously. RESULTS: Patients received an overall median of 6 (range 1-25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1-21) months [T1 7 (1-21), T2 5.5 (1-19) and T3 4 (1-19) months] and median overall survival 9 (range 1-36) months [T1 10 (1-31), T2 8 (1-36) and T3 6.5 (2-29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7-36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine. CONCLUSION: We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy.

Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy.

OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS: All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS: We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION: Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.

Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.

Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: a multicenter study.

BACKGROUND: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). RESULTS: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. CONCLUSIONS: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

First-line chemotherapy with planned sequential administration of cisplatin/gemcitabine followed by docetaxel in elderly 'unfrail' patients with advanced non-small-cell lung cancer: a multicenter phase II study.

PURPOSE: The role of cisplatin in the first-line treatment for elderly advanced non-small-cell lung cancer is not completely defined. We previously reported in this subset of patients an interesting efficacy and tolerability of a sequential schedule of gemcitabine followed by docetaxel. METHODS: Patients aged ≥70 years and with Eastern Cooperative Oncology Group performance status 0 or 1 received cisplatin 60 mg/m(2) on Day 1 and gemcitabine 1,000 mg/m(2) on Day 1 and 8 every 3 weeks for 3 courses followed by 3 courses of docetaxel 37.5 mg/m(2) on Day 1 and 8 every 3 weeks, provided there was no evidence of disease progression. Patients were excluded if considered 'frail' according to the Multidimensional Geriatric Assessment. The main objective of the study was the 4-month progression-free survival rate. Simon's two-stage minimax design was applied to calculate the sample size. RESULTS: After 30 patients were enroled into the study, the 4-month progression-free survival rate was 53.3 % and the study was closed at the first stage for futility; the overall response rate was 16.7 %; the median time to progression and median duration of survival were 5.1 and 8.6 months, respectively; the 1-year survival rate was 30 %. CONCLUSION: The incorporation of cisplatin in a sequential schedule of gemcitabine followed by docetaxel is feasible but did not yield a substantial advantage to deserve further investigations.

Phase II trial of single-agent oral vinorelbine in elderly (> or =70 years) patients with advanced non-small-cell lung cancer and poor performance status.

BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) with poor performance status (PS) are a special population requiring particular attention. Single-agent oral vinorelbine could be an attractive option. PATIENTS AND METHODS: A total of 43 patients with stage IIIB-IV NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of two or more with good functional status were prospectively recruited. Oral vinorelbine was administered at the dose of 60 mg/m(2) on days 1-8 every 3 weeks. Primary end points were response rate and safety. RESULTS: Overall response rate was 18.6% with 8 partial responses; 18 of 43 (41.8%) experienced stable disease lasting >12 weeks and 17 of 43 (39.6%) disease progression for an overall clinical benefit of 60.4%. Median time to progression was 4.0 (range 2-22) months and median overall survival 8.0 (range 3-35) months. Treatment was well tolerated. Of 187 cycles, we did not observe any grade 3/4 toxicity with the exception of a single not-febrile G3 neutropenia. Regardless of severity, main toxic effects observed were nausea in 48.1% and vomiting in 22.9% of patients, anemia in 43.2%, fatigue in 32.6% and leukopenia in 23.2%. CONCLUSION: Single-agent oral vinorelbine is extremely safe in elderly patients with advanced NSCLC and ECOG PS of two or more and may represent a valid option in this very special population.

Analysis of dystroglycan regulation and functions in mouse mammary epithelial cells and implications for mammary tumorigenesis.

Abnormalities in the interactions of cells with the extracellular matrix (ECM) play an important role in the development and progression of many types of cancer and are a hallmark of malignant transformation. The dystroglycan (DG) complex is a transmembrane glycoprotein that forms a continuous link from the ECM to the actin cytoskeleton, providing structural integrity and perhaps transducing signal, in a manner similar to integrins. Deregulated expression of DG has been reported in a variety of human malignancies and related to tumor differentiation and aggressiveness. In breast cancer, reduced DG expression has been associated with patient survival and with loss of differentiation of tumor cells. Limited data are available on DG physiology in epithelial cells. In this study, we used the HC11 spontaneously immortalized murine mammary epithelial cells to study DG function(s) and regulation in normal cells. We found that expression of DG protein and mRNA is cell-cycle and cell-density regulated in these cells. Moreover, expression of both DG subunits increased upon lactogenic differentiation of the HC11 cells. The turnover of cell-surface-expressed DG was evaluated in the same cells and half-life of DG subunits was evaluated to be about 12 h. DG-specific small inhibitory RNAs were used to analyze the effects of a reduced expression of DG in these cells. Cells in which DG expression was suppressed were growth inhibited, accumulated in the S-phase of the cell cycle, failed to undergo lactogenic differentiation, and displayed an increase in the percentage of apoptotic cells. Moreover, changes were observed in the expression and/or activity of several molecules involved in cell growth control. These results demonstrate that DG expression is tightly regulated in normal mammary epithelial cells and support the hypothesis that DG is involved in several functions other than structural integrity in these cells. This finding provides new insight into the roles played by DG in epithelial cell physiology and will contribute to our understanding of its involvement in the process of epithelial cell transformation.

Increased expression of cyclin E is associated with an increased resistance to doxorubicin in rat fibroblasts.

Cell cycle progression in eukaryotic cells is regulated by a family of cyclin-dependent kinases (CDKs). Cyclin E is a regulatory subunit of CDK2 and drives cells from G1 to S phase. Increased expression of cyclin E is a frequent event in human malignancies and has been associated with poor prognosis in various cancers. In this study, we evaluated the effects of cyclin E-overexpression on the sensitivity of rat fibroblasts to anticancer drugs. Cyclin E-overexpressing cells were less sensitive to doxorubicin-induced inhibition of cell growth but not to other antineoplastic drugs, such as paclitaxel, vincristine, etoposide and methotrexate. Cyclin E-overexpressing fibroblasts also displayed a reduction in ROS levels and a significantly lower increase following doxorubicin treatment compared with vector control cells. The expression of manganese superoxide dismutase (MnSOD) and its activity were increased (about 1.3-fold) in cyclin E-overexpressing derivatives compared with control cells. These results suggest that cyclin E overexpression might reduce tumour cells sensitivity to doxorubicin by affecting the expression of MnSOD and that determination of cyclin E expression levels might help to select patients to be treated with an anthracycline-based antineoplastic therapy.

[Use of digitalis in chronic heart failure: an unresolved problem?]. / Utilizzo della digitale nello scompenso cardiaco cronico: una questione irrisolvibile?

The role of digitalis in the treatment of patients with heart failure is still being debated. The DIG study, a trial which enrolled about 6800 patients with the aim at overcoming the doubts on efficiency and safety of digoxin, showed a neutral effect on mortality but there was a statistically significant decreased risk of hospitalization due to worsening heart failure in the digoxin group compared to the placebo group. The trial disclosed several problems about patient selection (many patients were on digitalis before the start of the trial), digoxin dosage, which seemed to be high, and about the true reported beneficial effects of this therapy. Finally the data available do not permit any evaluation on the use of beta-blockers and the association between digitalis and beta-blockers considering the properties of these drugs in suppressing orthosympathetic activation.

Panoramic coronary angiography.

OBJECTIVES: We describe a new imaging technique for coronary angiography. BACKGROUND: The conventional approach to coronary angiography exploits static perspective imaging over multiple cardiac cycles, using a limited number of empirically selected views. This approach entails both lack and redundancy of information and may result in suboptimal visualization of the individual lesion, contributing to diagnostic inaccuracy. METHODS: We developed a new imaging technique exploiting dynamic perspective, obtained by transverse 180 degree rotation of the C arm of a conventional angiographic unit during standard selective coronary opacification and filming. This technique yields a picture of the coronary tree isocentrically rotating around the longitudinal axis and conveying complete three-dimensional information. RESULTS: A complete diagnostic run for both coronary arteries, including two 25 degree cranial and two 25 degree caudal scans is accomplished with a total cine time of 16 s and 45 ml of contrast medium, about half of that required by conventional angiography. In a series of 129 consecutive patients studied by both the conventional and the new technique with quantitative measurements of the severity of the stenoses, the final diagnosis was identical in 65. In no case was a stenosis detected only by the conventional approach. However, in 31 patients the new technique permitted identification of 34 critical stenoses (79+/-8% [mean +/- SD]) either underestimated (61+/-3% n = 24, p < 0.001) or undetected (21+/-22%, n = 10, p < 0.001) in the standard projections. In a further 28 cases, 33 subcritical lesions (60+/-5%) were visualized in the rotational images but were insignificant (24+/-22% p < 0.001) in the standard projections. In five additional patients, distinct laminar plaques were clearly visualized only by the panoramic approach. CONCLUSIONS: This new technique can be easily implemented on conventional angiographic equipment at no additional cost. It provides complete, operator-independent exploitation of the angiographic information, resulting in enhanced diagnostic accuracy.

[The prognostic stratification of the risk of sudden death and sustained ventricular tachycardia after an acute myocardial infarct: which patients should undergo programmed ventricular stimulation?]. / Stratificazione prognostica del rischio di morte improvvisa e tachicardia ventricolare sostenuta dopo infarto miocardico acuto: quali pazienti dovrebbero essere sottoposti a stimolazione ventricolare programmata?

BACKGROUND: Programmed ventricular stimulation performed early after acute myocardial infarction allows to identify patients at risk of sudden death and sustained ventricular tachycardia with high degree of predictive accuracy. This procedure, however, because of its invasive nature, is not desirable as a screening test for large numbers of patients. Therefore, it should be performed on a smaller group of postinfarction patients preselected on the basis of noninvasive testing. The aim of the present study was to identify, early after acute myocardial infarction, any procedure among noninvasive testing, able to selected with the highest sensitivity patients at risk of sudden death and sustained ventricular tachycardia to submit to programmed ventricular stimulation. METHODS: Two hundred and sixty four consecutive patients with recent myocardial infarction were evaluated and followed during a period of 12 months. In each patient 48 epidemiological, clinical and laboratory variables were evaluated. Laboratory variables were acquired between the 7th and the 12th day after the acute event. RESULTS: Multiple linear regression analysis showed that only Killip class, the number of ventricular premature depolarizations per hour and the presence of ventricular late potentials were significantly and independently related to the occurrence of sudden death and sustained ventricular tachycardia (F = 18.7; p < 0.00001). Combinations of these variables, determined at cut off levels best discriminating two subgroups of patients at different risk of the end-point events, proved to be able to accurately predict the outcome of our patients. The presence of at least one of the following conditions: Killip class > or = 2, ventricular premature depolarizations > or = 30 per hour, ventricular late potentials allowed to identify a first subgroup of patients at risk with a sensitivity of 100% (p = 0.00007), whereas the presence, at the same time, of all the above mentioned parameters allowed to identify a second subgroup of patients at risk with a 44% of positive predictive value (p = 0.00007). CONCLUSIONS: Our findings suggest that the first subgroup of postinfarction patients selected on the basis of noninvasive testing should undergo programmed ventricular stimulation, the second might be treated by adequate antiarrhythmic therapy without undergo any further investigation, whereas the remaining patients (without late potentials, in Killip class 1 and with ventricular premature depolarizations < 30 per hour) might be discharged without any antiarrhythmic therapy.

Predicting severe ischemic events after uncomplicated myocardial infarction by exercise testing and rest and exercise radionuclide ventriculography.

BACKGROUND: In 183 patients with uncomplicated myocardial infarction, exercise-induced angina, ST segment depression, decrease in ejection fraction, or inadequate increase in systolic blood pressure and low exercise tolerance were significantly associated with 4-year incidence of hard ischemic events. METHODS AND RESULTS: Only the onset of both ST segment depression and a decrease in left ventricular ejection fraction with exercise was an independent predictor. ST segment depression and decrease in left ventricular ejection fraction had low sensitivity (61% and 70%) and specificity (56% and 51%) for hard ischemic events, but specificity increased to 78% when both were present. During medical therapy, 22 of 53 patients with both ST segment depression and a decrease in left ventricular ejection fraction with exercise had an ischemic event (i.e., 48.1% 4-year probability on Kaplan-Meier analysis vs 19.2% in the remaining 130 patients [p < 0.0005]). CONCLUSIONS: Even if no single variable, derived from exercise testing, is a highly sensitive and specific predictor, specificity increases to a clinically relevant level by combining ST segment depression and a decrease in left ventricular ejection fraction with exercise, and in this way patients with recent infarction may be selected for coronary arteriography.

Predicting cardiac mortality after uncomplicated myocardial infarction by exercise radionuclide ventriculography and exercise-induced ST segment elevation.

In 183 consecutive patients with recent, uncomplicated myocardial infarction, the following variables were associated with 4-year cardiac death: haemodynamic decompensation with exercise (P = 0.01), left ventricular ejection fraction at rest (P = 0.004) and at peak exercise (P = 0.003), persistent ST segment elevation at rest in the area of infarction = (P = 0.004), exercise-induced ST segment elevation (P = 0.02), and late aneurysmal evolution (P = 0.01). Exercise left ventricular ejection fraction was the sole variable selected by Cox regression analysis as an independent predictor of cardiac death. In 40 patients with ST segment elevation at rest, left ventricular ejection fraction was 42 +/- 17% at rest and 40 +/- 18% at peak exercise, versus 52 +/- 12% and 52 +/- 14% in the remaining patients (both P less than 0.01). Among these 40, 16 (all with anterior infarction) also had exercise-induced ST segment elevation; their ejection fraction was 32 +/- 13% at rest, 30 +/- 13% during exercise, versus 53 +/- 15% and 53 +/- 15% in 129 patients with no ST segment elevation either at rest, or during exercise (both P less than 0.01). The 4-year risk of death was 20% in the former 40 patients, 36% in the latter 16, while in the complete absence of ST segment elevation, such risk was 3%. All 14 patients with ST segment elevation only during exercise were alive after 4 years: their left ventricular ejection fraction was 47 +/- 12% at rest, 45 +/- 13% with exercise. ST segment elevation was associated with late aneurysmal evolution but not with exercise-induced ischaemia.(ABSTRACT TRUNCATED AT 250 WORDS)