Summary Background The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase ( ALK )-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and ...safety of ceritinib versus platinum-based chemotherapy in these patients. Methods This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK -rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m2 every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT01828099. Findings Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 95% CI 0·42–0·73; p<0·00001). The most common adverse events were diarrhoea (in 160 85% of 189 patients), nausea (130 69%), vomiting (125 66%), and an increase in alanine aminotransferase (114 60%) in the ceritinib group and nausea (in 97 55% of 175 patients), vomiting (63 36%), and anaemia (62 35%) in the chemotherapy group. Interpretation First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK -rearranged NSCLC. Funding Novartis Pharmaceuticals Corporation.
The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common ...EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.
Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).
Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval CI: 2.6–5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).
Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
The fall risk assessment tool (FRAT-up) is a tool for predicting falls in community-dwelling older people based on a meta-analysis of fall risk factors. Based on the fall risk factor profile, this ...tool calculates the individual risk of falling over the next year. The objective of this study is to evaluate the performance of FRAT-up in predicting future falls in multiple cohorts.
Information about fall risk factors in 4 European cohorts of older people Activity and Function in the Elderly (ActiFE), Germany; English Longitudinal Study of Aging (ELSA), England; Invecchiare nel Chianti (InCHIANTI), Italy; Irish Longitudinal Study on Aging (TILDA), Ireland was used to calculate the FRAT-up risk score in individual participants. Information about falls that occurred after the assessment of the risk factors was collected from subsequent longitudinal follow-ups. We compared the performance of FRAT-up against those of other prediction models specifically fitted in each cohort by calculation of the area under the receiver operating characteristic curve (AUC).
The AUC attained by FRAT-up is 0.562 95% confidence interval (CI) 0.530–0.594 for ActiFE, 0.699 (95% CI 0.680–0.718) for ELSA, 0.636 (95% CI 0.594–0.681) for InCHIANTI, and 0.685 (95% CI 0.660–0.709) for TILDA. Mean FRAT-up AUC as estimated from meta-analysis is 0.646 (95% CI 0.584–0.708), with substantial heterogeneity between studies. In each cohort, FRAT-up discriminant ability is surpassed, at most, by the cohort-specific risk model fitted on that same cohort.
We conclude that FRAT-up is a valid approach to estimate risk of falls in populations of community-dwelling older people. However, further studies should be performed to better understand the reasons for the observed heterogeneity across studies and to refine a tool that performs homogeneously with higher accuracy measures across different populations.
Degeneration of a surgically implanted valve bioprosthesis may occur in elderly, frail patients with an extremely high risk to undergo redo cardiac surgery. Transapical or fully percutaneous ...transseptal approaches have been described in order to treat degenerated aortic and mitral bioprosthesis. We performed the first-in-man successful mitral transcatheter valve delivery with a valve-in-valve technique through an innovative route; ie, a video-assisted endoscopic direct access to the left atrium, in an 82-year-old patient who previously underwent surgical replacement of the mitral valve and with a prohibitive surgical risk.
Acute leaflet rupture occurred in a Freedom Solo (Sorin Group, Milan, Italy) pericardial stentless aortic bioprosthesis after chest blunt trauma 8 years after valve replacement. Intraoperative ...findings revealed an acute tear of the right cusp at the level of the structural suture line. Pericardial leaflets were not degenerated at histologic analysis. Reoperation was easy, with simple removal of the prosthetic cusps, and a sutureless Perceval (Sorin Group) bioprosthesis was successfully implanted. This is the first reported case of an acute rupture of a stentless aortic bioprosthesis after a chest blunt trauma and the first histologic analysis of an 8-year-old Freedom Solo.
The platypnea-orthodeoxia syndrome is a rare clinical manifestation. Platypnea is defined as shortness of breath that worsens in the upright position, and orthodeoxia represents hypoxemia that ...aggravates in the upright position. We report a case of a patient with platypnea-orthodeoxia syndrome associated with pulmonary embolism and patent foramen ovale.
Behçet's disease (BD) is a multisystemic, chronic, inflammatory disease of unknown origin characterized by alternation of exacerbation and quiescence phases. Cardiac involvement in BD is infrequent. ...We report a case of a young man with BD with right ventricular thrombus and pulmonary thromboembolism. A 20-year-old man was admitted to our hospital with a 6-month history of dyspnea at rest, asthenia, and fever. Transthoracic echocardiography showed right wall thickened and presence of floating masses in the right outflow tract. Transesophageal echocardiography confirmed the presence of diffuse thrombosis in the right ventricle, with mobile ramifications in its outflow tract. Cardiovascular magnetic resonance and computed tomography of heart confirmed the presence of thrombi, the increased thickness of endocardiac tissue, and altered cardiac wall signal transmission. Computed tomography scan showed multiple pulmonary thrombi. Myocardial biopsy specimen showed diffused subendocardial thrombosis with damage of cardiac myocytes and presence of granulocytes. Six months after discharge, no cardiac masses were detected by transthoracic echocardiography. However, a few weeks after this last echocardiogram, the patient was again hospitalized for a new episode of acute pulmonary embolism. The patient was discharged with increasing dose of oral anticoagulant, with no evidence of cardiac masses at transthoracic echocardiography and thrombosis at computed tomography. The patient is still healthy on anticoagulant, immunosuppressive, and steroid therapy. This case provides a rare example of BD, in which we found-at the same time-heart and pulmonary manifestations, with the presence of right ventricular thrombus and pulmonary thrombi in situ.
In today's clinical practice, the size of lymph nodes is assessed by measuring the long and the short axis in the axial plane. This study compares this approach with three-dimensional (3D) ...assessment.
For a representative set of 49 lymph nodes, the axes in the axial plane have been measured and a 3D model has been created manually. Based on the 3D model, the real axial long and short axis as well as the three 3D axes and the volume have been computed and compared to the measured axial axes.
The inter-observer variability is around 10% for all measured lengths and almost 16% for the computed volume. The average relative error of the measured long (short) axial axis is 9.73% (24.57%) to the computed axial axis and 25.05% (19.97%) to the computed 3D axis, respectively. The product of the axial long axis and the square of the axial short axis provides best correlation to the volume.
This study confirms Response Evaluation Criteria In Solid Tumours 1.1 that measuring the short axis is more robust than measuring the long axis because of less impact of the node's spatial orientation. Nonetheless it is shown that considering both axes is a better prognostic factor for the volume than measuring the short axis only.
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