Optical characteristics of thin film-based InGaN micro-LED arrays: a study on size effect and far field behavior.

Micro-light emitting diodes (µ-LEDs) are considered the key enabler for various high-resolution micro-display applications such as augmented reality, smartphones or head-up displays. Within this study we fabricated nitride-based µ-LED arrays in a thin film chip architecture with lateral pixel sizes down to 1 µm. A metal mirror on the p-side enhances the light outcoupling via the n-side after removal of the epitaxial growth substrate. Mounted devices with pixel sizes ranging from 1×1 to 8×8 µm2 were electro-optically characterized within an integrating sphere and in a goniometer system. We measure increased external quantum efficiencies on smaller devices due to a higher light extraction efficiency (LEE) as predicted by wave optical simulations. Besides this size dependence of the LEE, also the far field properties show a substantial change with pixel size. In addition, we compared µ-LEDs with 40 nm and 80 nm thick aluminium oxide around the pixel mesa. Considerably different far field patterns were observed which indicate the sensitivity of optical properties to any design changes for tiny µ-LEDs. The experimentally obtained radiation behavior could be reasonably predicted by finite-difference time-domain simulations. This clearly reveals the importance of understanding and modeling wave optical effects inside µ-LED devices and the resulting impact on their optical performance.

A Phase I Study of the Pan-Notch Inhibitor CB-103 for Patients with Advanced Adenoid Cystic Carcinoma and Other Tumors.

PURPOSE: CB-103 selectively inhibits the CSL-NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity. EXPERIMENTAL DESIGN: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression. RESULTS: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3-4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5-3.7] and median overall survival was 18.4 months (95% CI, 6.3-not reached). CONCLUSIONS: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study. SIGNIFICANCE: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL-NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs.

Role of pixel design and emission wavelength on the light extraction of nitride-based micro-LEDs.

Micro-light emitting diodes (µ-LEDs) suffer from a drastic drop in internal quantum efficiency that emerges with the miniaturization of pixels down to the single micrometer size regime. In addition, the light extraction efficiency (LEE) and far field characteristics change significantly as the pixel size approaches the wavelength of the emitted light. In this work, we systematically investigate the fundamental optical properties of nitride-based µ-LEDs with the focus on pixel sizes from 1 µm to 5 µm and various pixel sidewall angles from 0∘ to 60∘ using finite-difference time-domain simulations. We find that the LEE strictly increases with decreasing pixel size, resulting in a LEE improvement of up to 45% for a 1 µm pixel compared to a 20 µm pixel. The ideal pixel sidewall angle varies between 35∘ and 40∘, leading to a factor of 1.4 enhancement with respect to vertical pixel sidewalls. For pixel sizes in the order of 2 µm and smaller, a substantial transition of far field properties can be observed. Here, the far field shape depends severely on the pixel sidewall angle and affects the LEE within a solid angle of ±15∘. Moreover, we investigate the impact of emission wavelength and observe major differences in optical characteristics for blue, green and red emitting pixels, which is relevant for real-world applications. Finally, we discuss the implications of the assumptions we made and their significance for the design of µ-LEDs.

A deep-learning approach for automatically detecting gait-events based on foot-marker kinematics in children with cerebral palsy-Which markers work best for which gait patterns?

Neuromotor pathologies often cause motor deficits and deviations from typical locomotion, reducing the quality of life. Clinical gait analysis is used to effectively classify these motor deficits to gain deeper insights into resulting walking behaviours. To allow the ensemble averaging of spatio-temporal metrics across individuals during walking, gait events, such as initial contact (IC) or toe-off (TO), are extracted through either manual annotation based on video data, or through force thresholds using force plates. This study developed a deep-learning long short-term memory (LSTM) approach to detect IC and TO automatically based on foot-marker kinematics of 363 cerebral palsy subjects (age: 11.8 ± 3.2). These foot-marker kinematics, including 3D positions and velocities of the markers located on the hallux (HLX), calcaneus (HEE), distal second metatarsal (TOE), and proximal fifth metatarsal (PMT5), were extracted retrospectively from standard barefoot gait analysis sessions. Different input combinations of these four foot-markers were evaluated across three gait subgroups (IC with the heel, midfoot, or forefoot). For the overall group, our approach detected 89.7% of ICs within 16ms of the true event with a 18.5% false alarm rate. For TOs, only 71.6% of events were detected with a 33.8% false alarm rate. While the TOE|HEE marker combination performed well across all subgroups for IC detection, optimal performance for TO detection required different input markers per subgroup with performance differences of 5-10%. Thus, deep-learning LSTM based detection of IC events using the TOE|HEE markers offers an automated alternative to avoid operator-dependent and laborious manual annotation, as well as the limited step coverage and inability to measure assisted walking for force plate-based detection of IC events.

CB-103: A novel CSL-NICD inhibitor for the treatment of NOTCH-driven T-cell acute lymphoblastic leukemia: A case report of complete clinical response in a patient with relapsed and refractory T-ALL.

Relapsed T cell acute lymphoblastic leukaemia (T-ALL) has a very poor prognosis. A 24-year-old patient with relapsed high-risk T-ALL (PTEN gene deletion; NOTCH1 mutation), was treated with the NOTCH inhibitor CB-103. Within 1 week of starting CB-103, the bone marrow was free of T-ALL blast infiltration (MRD+) and successfully underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Sequential samples of ctDNA to monitor the disease after allo-HSCT showed a decrease of circulating Notch1 and PTEN alterations. This is the first T-ALL patient treated with CB-103. The observed clinical response encourages further exploration of CB-103 in ALL.

Personalised pose estimation from single-plane moving fluoroscope images using deep convolutional neural networks.

Measuring joint kinematics is a key requirement for a plethora of biomechanical research and applications. While x-ray based systems avoid the soft-tissue artefacts arising in skin-based measurement systems, extracting the object's pose (translation and rotation) from the x-ray images is a time-consuming and expensive task. Based on about 106'000 annotated images of knee implants, collected over the last decade with our moving fluoroscope during activities of daily living, we trained a deep-learning model to automatically estimate the 6D poses for the femoral and tibial implant components. By pretraining a single stage of our architecture using renderings of the implant geometries, our approach offers personalised predictions of the implant poses, even for unseen subjects. Our approach predicted the pose of both implant components better than about 0.75 mm (in-plane translation), 25 mm (out-of-plane translation), and 2° (all Euler-angle rotations) over 50% of the test samples. When evaluating over 90% of test samples, which included heavy occlusions and low contrast images, translation performance was better than 1.5 mm (in-plane) and 30 mm (out-of-plane), while rotations were predicted better than 3-4°. Importantly, this approach now allows for pose estimation in a fully automated manner.

Occult Pathologic Findings in Reduction Mammaplasty in 5781 Patients-An International Multicenter Study.

Breast cancer is among the most commonly diagnosed cancers in the world, affecting one in eight women in their lifetimes. The disease places a substantial burden on healthcare systems in developed countries and often requires surgical correction. In spite of this, much of the breast cancer pathophysiology remains unknown, allowing for the cancer to develop to later stages prior to detection. Many women undergo reduction mammaplasties (RM) to adjust breast size, with over 500,000 operations being performed annually. Tissue samples from such procedures have drawn interest recently, with studies attempting to garner a better understanding of breast cancer's development. A number of samples have revealed nascent cancer developments that were previously undetected and unexpected. Investigating these so-called "occult" findings of cancer in otherwise healthy patients may provide further insight regarding risk factors and countermeasures. Here, we detail occult findings of cancer in reduction mammaplasty samples provided from a cohort of over 5000 patients from 16 different institutions in Europe. Although the majority of our resected breast tissue specimens were benign, our findings indicate that there is a continued need for histopathological examination. As a result, our study suggests that preoperative imaging should be routinely performed in patients scheduled for RM, especially those with risk factors of breast cancer, to identify and enable a primary oncologic approach.

Differentiation between mechanically loose and fixed press-fit implants using quantitative acoustics and load self-referencing: A phantom study on shoulder prostheses in polyurethane foam.

This study proposes to use cross-interface quantitative acoustics (ci-qA) and load self-referencing (LSR) to assess implant stability in a radiation-free, inexpensive, rapid, and quantitative manner. Eight bone analog specimens, made from polyurethane foam, were implanted with a cementless stemless shoulder implant-first in a fixed and later in a loose configuration-and measured using ci-qA under two load conditions. The loose implants exhibited higher micromotion and lower pull-out strength than their stable counterparts, with all values falling within the range of reported reference values. All acoustic characteristics differentiated between loose and fixed implants (maximum area-under-curve AUC = 1.0 for mean total signal energy, AUC = 1.0 for mean total signal energy ratio, AUC = 0.8 for harmonic ratio, and AUC = 0.92 for load self-referencing coefficient). While these results on bone substitute material will need to be confirmed on real bone specimen, ci-qA could ultimately facilitate the assessment of primary stability during implantation surgery and avoid unnecessary revision through quantitative evaluation of secondary stability during follow-up.

Sensitivity of low-frequency axial transmission acoustics to axially and azimuthally varying cortical thickness: A phantom-based study.

PURPOSE: Cortical thickness (cTh) is one of the main factors determining a bone's mechanical properties, and its quantification is therefore critical for understanding and monitoring bone pathologies such as osteoporosis. Axial quantitative acoustics (ax-QA) offers a non-radiative, non-invasive method to measure cTh. Even though previous works have ascertained ax-QA's ability to measure azimuthally varying cTh, the effect of axially varying cTh remains unclear. Furthermore, previous experiments and theoretical predictions indicate that measurement of the fundamental flexural mode at low frequencies in the kHz range could increase sensitivity to cTh. However, due to the associated long wavelengths, the approximation of bone geometry as a tube could break down at such frequencies. The presented study therefore investigates a) the sensitivity of ax-QA measurements to cTh in the kHz-regime, b) the applicability of tube theory in this regime, and c) the effect of varying cTh along the long axis on the bone. MATERIALS AND METHODS: Axial-transmission acoustic measurements were performed at 3kHz on 14 bone phantoms with a femur-like cross-section and a) axially varying cortical thickness or b) axially and azimuthally varying cortical thickness (cTh-range: 1.5mm-7.5mm). Experimental results were compared to theoretical predictions based on an exact elastic tube theory. RESULTS AND DISCUSSION: Phase velocity measurements using low-frequency ax-QA exhibited a high sensitivity to local cTh less than 4mm, albeit with a complex, not yet understood pattern. Tube theory failed to predict the wave's behavior in the kHz range, indicating that due to the corresponding long wavelengths the bone can no longer be approximated by a tube, thus requiring more faithful modelling of the bone geometry. The fact that results from both types of phantoms were similar (Pearson correlation coefficient: 0.94) further indicates that the slowly varying cTh along the bone's long axis did not strongly affect wave propagation as measured by ax-QA measurements.

A method to concatenate multiple short time series for evaluating dynamic behaviour during walking.

Gait variability is a sensitive metric for assessing functional deficits in individuals with mobility impairments. To correctly represent the temporal evolution of gait kinematics, nonlinear measures require extended and uninterrupted time series. In this study, we present and validate a novel algorithm for concatenating multiple time-series in order to allow the nonlinear analysis of gait data from standard and unrestricted overground walking protocols. The full-body gait patterns of twenty healthy subjects were captured during five walking trials (at least 5 minutes) on a treadmill under different weight perturbation conditions. The collected time series were cut into multiple shorter time series of varying lengths and subsequently concatenated using a novel algorithm that identifies similar poses in successive time series in order to determine an optimal concatenation time point. After alignment of the datasets, the approach then concatenated the data to provide a smooth transition. Nonlinear measures to assess stability (Largest Lyapunov Exponent, LyE) and regularity (Sample Entropy, SE) were calculated in order to quantify the efficacy of the concatenation approach using intra-class correlation coefficients, standard error of measurement and paired effect sizes. Our results indicate overall good agreement between the full uninterrupted and the concatenated time series for LyE. However, SE was more sensitive to the proposed concatenation algorithm and might lead to false interpretation of physiological gait signals. This approach opens perspectives for analysis of dynamic stability of gait data from physiological overground walking protocols, but also the re-processing and estimation of nonlinear metrics from previously collected datasets.

A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB).

PURPOSE: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

Can low-frequency guided waves at the tibia paired with machine learning differentiate between healthy and osteopenic/osteoporotic subjects? A pilot study.

PURPOSE: Axial transmission quantitative acoustics (ax-QA) has shown to be a promising tool for assessing bone health and properties in a safe, inexpensive, and portable manner. This study investigated the efficacy of low-frequency ax-QA measured at the tibia, paired with a support vector machine (SVM) approach for combining multiple acoustic indicators, to diagnose osteoporosis as defined by bone mineral density. METHODS: This pilot study measured 41 female subjects using ax-QA (flexural mode, 3 kHz) at the tibia and using dual X-ray absorptiometry (DXA) at the lumbar spine, femoral neck, and distal radius. For each location, a threshold classifier and SVM were trained to differentiate between healthy and non-healthy subjects based on the phase velocity at different frequencies. Receiver Operating Characteristics and area under curve values (AUC) were used to assess the classifiers' performances for various thresholds and class-weights. RESULTS: The SVM outperformed the threshold classifier for all three bone locations at low false positive rates. While differentiation between healthy and non-healthy bone states was poor for the spine (AUC: 0.56 ±â€¯0.04), good to moderate performances were observed for the radius (AUC: 0.83 ±â€¯0.03) and hip (AUC: 0.71 ±â€¯0.04). CONCLUSIONS: Low-frequency ax-QA has demonstrated potential for complementing DXA in screening for osteoporosis at the radius and hip. Through further addition of acoustic indicators ax-QA could provide a diagnostic alternative in third-world countries, and bring bone health screening and monitoring into the hands of clinicians and general health practitioners everywhere.

A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors.

Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.

Towards assessing cortical bone porosity using low-frequency quantitative acoustics: A phantom-based study.

PURPOSE: Cortical porosity is a key characteristic governing the structural properties and mechanical behaviour of bone, and its quantification is therefore critical for understanding and monitoring the development of various bone pathologies such as osteoporosis. Axial transmission quantitative acoustics has shown to be a promising technique for assessing bone health in a fast, non-invasive, and radiation-free manner. One major hurdle in bringing this approach to clinical application is the entanglement of the effects of individual characteristics (e.g. geometry, porosity, anisotropy etc.) on the measured wave propagation. In order to address this entanglement problem, we therefore propose a systematic bottom-up approach, in which only one bone property is varied, before addressing interaction effects. This work therefore investigated the sensitivity of low-frequency quantitative acoustics to changes in porosity as well as individual pore characteristics using specifically designed cortical bone phantoms. MATERIALS AND METHODS: 14 bone phantoms were designed with varying pore size, axial-, and radial pore number, resulting in porosities (bone volume fraction) between 0% and 15%, similar to porosity values found in human cortical bone. All phantoms were manufactured using laser sintering, measured using axial-transmission acoustics and analysed using a full-wave approach. Experimental results were compared to theoretical predictions based on a modified Timoshenko theory. RESULTS: A clear dependence of phase velocity on frequency and porosity produced by increasing pore size or radial pore number was demonstrated, with the velocity decreasing by between 2-5 m/s per percent of additional porosity, which corresponds to -0.5% to -1.0% of wave speed. While the change in phase velocity due to axial pore number was consistent with the results due to pore size and radial pore number, the relative uncertainties for the estimates were too high to draw any conclusions for this parameter. CONCLUSIONS: This work has shown the capability of low-frequency quantitative acoustics to reflect changes in porosity and individual pore characteristics and demonstrated that additive manufacturing is an appropriate method that allows the influence of individual bone properties on the wave propagation to be systematically assessed. The results of this work opens perspectives for the efficient development of a multi-frequency, multi-mode approach to screen, diagnose, and monitor bone pathologies in individuals.

A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia.

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML . Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.

PURPOSE: The study objective was to evaluate chemotherapy treatment patterns and incidence, cost, and resource utilization of febrile neutropenia-related hospitalization (FNH) in patients with breast cancer, lung cancer, and non-Hodgkin's lymphoma (NHL) from Kaiser Permanente Southern California (KPSC), a large integrated delivery system. METHODS: Adults ≥18 years with any stage breast cancer, lung cancer, or NHL who initiated myelosuppressive chemotherapy from 01/01/2006 to 12/31/2009 were included. Chemotherapy dose delays ≥7 days, relative dose intensity (RDI), regimen switching, FNH and all-cause mortality, granulocyte colony-stimulating factor (G-CSF) and antibiotic use, and healthcare utilization/cost were evaluated by cancer type, regimen, and/or cycle. RESULTS: Among 3314 breast cancer patients, 25.3% received an RDI ≤85%, 13.9% experienced FNH with an all-cause mortality rate of 2.0%, and 20.2% received primary prophylaxis with G-CSF. Among those with FNH, mean hospital length of stay (LOS) was 4.1 days, and mean total costs were $20,462. Among 1443 lung cancer patients, 17.9% had an RDI ≤85%, 8.0% experienced FNH with an all-cause mortality rate of 25.2%, and 4.5% received primary prophylaxis with G-CSF. Among those with FNH, mean LOS was 6.8 days, and mean total costs were $32,964. Among 581 NHL patients, 27.9% had an RDI ≤85% and 22.4% experienced FNH with an all-cause mortality rate of 13%. Among those with FNH, mean LOS was 7.9 days, and mean total costs were $37,555. CONCLUSIONS: Marked variability was observed among different cancer types and chemotherapy regimens. Given the variability, detailed insight into incidence, management, and burden of FN can help inform clinical decision making.

ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer.

AIMS: Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. METHODS: Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. RESULTS: Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2-9.0) in the trebananib arm and 7.2 months (95% CI, 4.8-8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68-1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78-6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7-7.6]; placebo, 3.9 months [95% CI, 2.3-6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). CONCLUSIONS: Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01281254.

Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): Long-term survival, impact of ascites, and progression-free survival-2.

PURPOSE: Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). PATIENTS AND METHODS: Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. RESULTS: Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3months; HR, 0.72; 95% CI, 0.55-0.93; P=0.011) in patients with ascites at baseline (n=295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9months; HR, 0.85; 95% CI, 0.74-0.98; P=0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected. CONCLUSIONS: OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy.

Reliability of Phase Velocity Measurements of Flexural Acoustic Waves in the Human Tibia In-Vivo.

PURPOSE: Axial-transmission acoustics have shown to be a promising technique to measure individual bone properties and detect bone pathologies. With the ultimate goal being the in-vivo application of such systems, quantification of the key aspects governing the reliability is crucial to bring this method towards clinical use. MATERIALS AND METHODS: This work presents a systematic reliability study quantifying the sources of variability and their magnitudes of in-vivo measurements using axial-transmission acoustics. 42 healthy subjects were measured by an experienced operator twice per week, over a four-month period, resulting in over 150000 wave measurements. In a complementary study to assess the influence of different operators performing the measurements, 10 novice operators were trained, and each measured 5 subjects on a single occasion, using the same measurement protocol as in the first part of the study. RESULTS: The estimated standard error for the measurement protocol used to collect the study data was ∼ 17 m/s (∼ 4% of the grand mean) and the index of dependability, as a measure of reliability, was Φ = 0.81. It was shown that the method is suitable for multi-operator use and that the reliability can be improved efficiently by additional measurements with device repositioning, while additional measurements without repositioning cannot improve the reliability substantially. Phase velocity values were found to be significantly higher in males than in females (p < 10-5) and an intra-class correlation coefficient of r = 0.70 was found between the legs of each subject. CONCLUSIONS: The high reliability of this non-invasive approach and its intrinsic sensitivity to mechanical properties opens perspectives for the rapid and inexpensive clinical assessment of bone pathologies, as well as for monitoring programmes without any radiation exposure for the patient.