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Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAFV600E-mutant or BRAFV600K-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma. We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAFV600E-mutant or BRAFV600K-mutant metastatic melanoma who received the approved dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily. Data were pooled from patients in the BRF113220 (part C; March 26, 2010, to Jan 15, 2015), COMBI-d (May 4, 2012, to Jan 12, 2015), and COMBI-v (June 4, 2012, to March 13, 2015) randomised trials. Patients with untreated brain metastases were not permitted to enrol in these trials. Baseline factors, identified a priori based on known melanoma clinical or prognostic characteristics, were analysed for association with progression-free survival and overall survival using univariate and multivariate analyses and assessed for hierarchical effect on outcomes using regression tree analyses. We also analysed factors identified after baseline, on treatment, and at progression, for associations with survival after progression. The trials included in this analysis are registered with ClinicalTrials.gov: BRF113220, number NCT01072175; COMBI-d, number NCT01584648; COMBI-v, number NCT01597908. 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0−48·0, IQR 10·1−24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months [95% CI 9·7−12·9]), median overall survival (25·6 months [23·1−34·3]), 1-year progression-free survival (48% [44–52]) and overall survival (74% [71–78]), and 2-year progression-free survival (30% [26–34]) and overall survival (53% [49–57]) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% [95% CI 62–74]) and overall survival (90% [87–94]) and 2-year progression-free survival (46% [40–54]) and overall survival (75% [70–81]), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% [3–19]) and overall survival (40% [29–55]) and 2-year progression-free survival (2% [0–13]) and overall survival (7% [3–19]). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months [95% CI 7·9−12·0]) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months [3·5−4·9]). Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets. Novartis.

Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific, slow, biologically perturbing, or a combination thereof. Here, we show that single-cell micro-Raman spectroscopy averts these shortcomings and can be used to discriminate between unfixed normal human lymphocytes and transformed Jurkat and Raji lymphocyte cell lines based on their biomolecular Raman signatures. We demonstrate that single-cell Raman spectra provide a highly reproducible biomolecular fingerprint of each cell type. Characteristic peaks, mostly due to different DNA and protein concentrations, allow for discerning normal lymphocytes from transformed lymphocytes with high confidence ( p ≪ 0.05). Spectra are also compared and analyzed by principal component analysis to demonstrate that normal and transformed cells form distinct clusters that can be defined using just two principal components. The method is shown to have a sensitivity of 98.3% for cancer detection, with 97.2% of the cells being correctly classified as belonging to the normal or transformed type. These results demonstrate the potential application of confocal micro-Raman spectroscopy as a clinical tool for single cancer cell detection based on intrinsic biomolecular signatures, therefore eliminating the need for exogenous fluorescent labeling.

In this paper we report the development of two attachments to a commercial cell phone that transform the phone's integrated lens and image sensor into a 350x microscope and visible-light spectrometer. The microscope is capable of transmission and polarized microscopy modes and is shown to have 1.5 micron resolution and a usable field-of-view of 150 x 50 with no image processing, and approximately 350 x 350 when post-processing is applied. The spectrometer has a 300 nm bandwidth with a limiting spectral resolution of close to 5 nm. We show applications of the devices to medically relevant problems. In the case of the microscope, we image both stained and unstained blood-smears showing the ability to acquire images of similar quality to commercial microscope platforms, thus allowing diagnosis of clinical pathologies. With the spectrometer we demonstrate acquisition of a white-light transmission spectrum through diffuse tissue as well as the acquisition of a fluorescence spectrum. We also envision the devices to have immediate relevance in the educational field.

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9–68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.

Critical illness may be associated with increased bone turnover and loss of bone mineral density (BMD). Prospective evidence describing long-term changes in BMD after critical illness is needed to further define this relationship. To measure the change in BMD and bone turnover markers (BTMs) in subjects 1 year after critical illness compared with population-based control subjects. We studied adult patients admitted to a tertiary intensive care unit (ICU) who required mechanical ventilation for at least 24 hours. We measured clinical characteristics, BTMs, and BMD during admission and 1 year after ICU discharge. We compared change in BMD to age- and sex-matched control subjects from the Geelong Osteoporosis Study. Sixty-six patients completed BMD testing. BMD decreased significantly in the year after critical illness at both femoral neck and anterior-posterior spine sites. The annual decrease was significantly greater in the ICU cohort compared with matched control subjects (anterior-posterior spine, -1.59%; 95% confidence interval, -2.18 to -1.01; P < 0.001; femoral neck, -1.20%; 95% confidence interval, -1.69 to -0.70; P < 0.001). There was a significant increase in 10-year fracture risk for major fractures (4.85 ± 5.25 vs. 5.50 ± 5.52; P < 0.001) and hip fractures (1.57 ± 2.40 vs. 1.79 ± 2.69; P = 0.001). The pattern of bone resorption markers was consistent with accelerated bone turnover. Critically ill individuals experience a significantly greater decrease in BMD in the year after admission compared with population-based control subjects. Their bone turnover biomarker pattern is consistent with an increased rate of bone loss.

The current (March 2008 to February 2009) summit eruptive activity at Kilauea Volcano is characterized by explosive degassing bursts accompanied by very long period (VLP) seismic signals. We model the source mechanisms of VLP signals in the 10–50 s band using data recorded for 15 bursts with a 10‐station broadband network deployed in the summit caldera. To determine the source centroid location and source mechanism, we minimize the residual error between data and synthetics calculated by the finite difference method for a point source embedded in a homogeneous medium that takes topography into account. The VLP signals associated with the bursts originate in a source region ∼1 km below the eastern perimeter of Halemaumau pit crater. The observed waveforms are well explained by the combination of a volumetric component and a vertical single force component. For the volumetric component, several source geometries are obtained which equally explain the observed waveforms. These geometries include (1) a pipe dipping 64° to the northeast; (2) two intersecting cracks including an east striking crack (dike) dipping 80° to the north, intersecting a north striking crack (another dike) dipping 65° to the east; (3) a pipe dipping 58° to the northeast, intersecting a crack dipping 48° to the west–southwest; and (4) a pipe dipping 57° to the northeast, intersecting a pipe dipping 58° to the west–southwest. Using the dual‐crack model as reference, the largest volume change obtained among the 15 bursts is ∼24,400 m3, and the maximum amplitude (peak to peak) of the force is ∼20 GN. Each burst is marked by a similar sequence of deflation and inflation, trailed by decaying oscillations of the volumetric source. The vertical force is initially upward, synchronous with source deflation, then downward, synchronous with source reinflation, followed by oscillations with polarity opposite to the volumetric oscillations. This combination of force and volume change is attributed to pressure and momentum changes induced during a fluid dynamic source mechanism involving the ascent, expansion, and burst of a large slug of gas within the upper ∼150 m of the magma conduit. As the slug expands upon approach to the surface and more liquid becomes wall supported by viscous shear forces, the pressure below the slug decreases, inducing conduit deflation and an upward force on the Earth. The final rapid slug expansion and burst stimulate VLP and LP oscillations of the conduit system, which slowly decay due to viscous dissipation and elastic radiation. Consideration of the fluid dynamic arguments leads us to prefer the dual‐crack VLP source model as it is the only candidate model capable of producing plausible values of length scales and pressure changes. The magnitudes of the vertical forces observed in the 15 bursts appear consistent with slug masses of 104 to 106 kg.

To compare patient-reported outcomes (PROs) and satisfaction results after multifocal intraocular lens (IOL) implantation in three groups: two receiving bilateral implantation of the same IOL and another undergoing blended vision with two different multifocal IOLs. A questionnaire was administered to patients who had undergone uncomplicated cataract surgery and 2 months of follow-up: the first group underwent bilateral implantation with Alcon's AcrySof ReSTOR 3.0 lens (\"3.0/3.0,\" n=78); the second group underwent implantation with the ReSTOR ActiveFocus 2.5 or the ReSTOR ActiveFocus 2.5 toric lens (\"2.5 mini-monovision,\" n=102); and the third group underwent implantation with the ReSTOR 2.5 lens in the dominant eye and the ReSTOR 3.0 lens in the non-dominant eye (\"2.5/3.0,\" n=89). Overall PROs and satisfaction was similar among the groups. Refractive outcomes and accuracy were similar among the groups, but the 2.5 mini-monovision group reported better intermediate vision. Refractive outcome differences were not meaningful among the groups and were not a differentiating factor in PROs. Substantially fewer patients in the 2.5 mini-monovision group noticed glare and halo compared with the 3.0/3.0 group ( <0.0001, chi-square test). No new safety concerns were reported. The 2.5 mini-monovision results in a higher percentage of patients being satisfied with intermediate vision than bilateral ReSTOR 3.0 or blended vision with ReSTOR 2.5/3.0 implants, but overall PRO differences were not statistically significant.

Background Dual bronchodilation combining a long-acting β 2 -agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 μg and LAMA, glycopyrronium 50 μg (IND/GLY 110/50 μg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. Methods The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 μg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. Results The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV 1 ; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV 1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. Conclusions IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. Trial registration ClinicalTrials.gov number: NCT01985334 .

To reduce the burden of fracture, not only does bone fragility need to be addressed, but also injury prevention. Thus, fracture epidemiology irrespective of degree of trauma is informative. We aimed to determine age-and-sex-specific fracture incidence rates for the Barwon Statistical Division, Australia, 2006–2007. Using radiology reports, incident fractures were identified for 5342 males and 4512 females, with incidence of 210.4 (95 % CI 204.8, 216.2) and 160.0 (155.3, 164.7)/10,000/year, respectively. In females, spine (clinical vertebral), hip (proximal femoral) and distal forearm fractures demonstrated a pattern of stable incidence through early adult life, with an exponential increase beginning in postmenopausal years for fractures of the forearm followed by spine and hip. A similar pattern was observed for the pelvis, humerus, femur and patella. Distal forearm, humerus, other forearm and ankle fractures showed incidence peaks during childhood and adolescence. For males, age-related changes mimicked the female pattern for fractures of the spine, hip, ribs, pelvis and humerus. Incidence at these sites was generally lower for males, particularly among the elderly. A similar childhood-adolescent peak was seen for the distal forearm and humerus. For ankle fractures, there was an increase during childhood and adolescence but this extended into early adult life; in contrast to females, there were no further age-related increases. An adolescent-young adult peak incidence was observed for fractures of the face, clavicle, carpal bones, hand, fingers, foot and toe, without further age-related increases. Examining patterns of fracture provides the evidence base for monitoring temporal changes in fracture burden, and for identifying high-incidence groups to which fracture prevention strategies could be directed.

Chronic obstructive pulmonary disease (COPD) negatively impacts clinical health outcomes, resulting in frequent exacerbations, increased hospitalizations, reduced physical activity, deteriorated quality of life, and diminished self-efficacy. Previous studies demonstrated that a self-management program tailored for adults with COPD improves self-management decisions, resulting in a positive effect on clinical health outcomes. Limitations of these studies include issues regarding heterogeneity among interventions used, patient population characteristics, outcome measures, and longitudinal studies. Limited studies focused on the use of a comprehensive self-management program using a smartphone app for adults with COPD over 12 months. This study aimed to explore the effectiveness of a smartphone app self-management program and monthly phone calls compared with standard respiratory outpatient care on clinical health outcomes in adults with COPD. This was a 3-arm parallel pilot randomized controlled trial (RCT) that included 92 participants. Participants were randomized into intervention arm 1, which included a self-management smartphone app and monthly phone calls (n=31); intervention arm 2, which included a self-management smartphone app (n=31); and arm 3, which was standard respiratory outpatient care (n=30). All arms received standard respiratory outpatient care. The primary outcome was a binary indicator equal to 1 if participants reported attendance to a general practitioner (GP) and or a hospital setting as a result of an exacerbation and 0 otherwise. This indicator was recorded at 6 months and 12 months from the baseline. Secondary outcomes included engagement, breathlessness, physical activity, health-related quality of life, and self-efficacy. There was a statistically significant difference (P=.03), indicating fewer exacerbations in the intervention arm 2 compared with the control arm at 6 months in the hospital setting. The intervention arms had a statistically significant difference indicating a lower risk of developing an exacerbation at 6 months in both the GP (P=.01) and hospital setting (P=.006) compared to the control arm. Furthermore, intervention arm 1 demonstrated a statistically significant difference in exercise capacity at 6 and 12 months (P=.02 and P=.03). The intervention arm 2 illustrated a statistically significant difference in step count (P=.009) compared to the control arm. The majority of participants (60%, 33/55) used the app over the 12-month period. This study demonstrated that a smartphone app self-management program had a positive effect on clinical health outcomes for participants with COPD in comparison to standard respiratory outpatient care. This study illustrated benefits such as reduced exacerbations resulting in fewer hospitalizations, improved exercise capacity, and physical activity among the intervention arms. This was a single-center study, which was limited in power to demonstrate significant effects on all measured outcomes but paves the way for a larger, fully powered multicenter trial exploring the effect of a smartphone app self-management program on clinical health outcomes in adults with COPD. ClinicalTrials.gov NCT05061810; https://clinicaltrials.gov/study/NCT05061810.