Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with ...recurrent glioblastoma with PI3K pathway activation.
This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2.
Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKT
immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6
and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 10.8%), fatigue (n = 4 6.2%), hyperglycemia (n = 3 4.6%), and elevated ALT (n = 3 4.6%).
Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
Structure-from-Motion Multi-View Stereo (SfM-MVS) photogrammetry is a viable method to digitize underground spaces for inspection, documentation, or remote mapping. However, the conventional image ...acquisition process can be laborious and time-consuming. Previous studies confirmed that the acquisition time can be reduced when using a 360-degree camera to capture the images. This paper demonstrates a method for rapid photogrammetric reconstruction of tunnels using a 360-degree camera. The method is demonstrated in a field test executed in a tunnel section of the Underground Research Laboratory of Aalto University in Espoo, Finland. A 10 m-long tunnel section with exposed rock was photographed using the 360-degree camera from 27 locations and a 3D model was reconstructed using SfM-MVS photogrammetry. The resulting model was then compared with a reference laser scan and a more conventional digital single-lens reflex (DSLR) camera-based model. Image acquisition with a 360-degree camera was 3× faster than with a conventional DSLR camera and the workflow was easier and less prone to errors. The 360-degree camera-based model achieved a 0.0046 m distance accuracy error compared to the reference laser scan. In addition, the orientation of discontinuities was measured remotely from the 3D model and the digitally obtained values matched the manual compass measurements of the sub-vertical fracture sets, with an average error of 2–5°.
Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations ...underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.
Stope design is a core discipline within mining engineering. This study analyzes the current state-of-the-art of stope design through a survey addressed to mining industry professionals. In stope ...design research the dominance of empirical methods has slowly shifted towards numerical methods. Recent advancements have mostly focused on the development of stope optimization algorithms. The survey consisted of 19 questions and was distributed to stope design experts via email, LinkedIn messages, and the Mining Industry Professionals network forum. In total, 36 responses of satisfying quality from 20 countries were received and analyzed. No dominance of a single stope design method was recognized. Empirical methods and personal expertise are still used widely. However, a readiness for change in stope design practice was indicated in 87% of responses. The current needs of the stoping-based underground mining sector are to increase the amount of geotechnical data, automate stope design and implement related software, and integrate these into general mine planning. According to 70% of the participants, acquired geotechnical data should be available within three days to be employed in design practice. The industry is ready to implement more efficient stope design methods if they offer results proven in case studies.
Rock discontinuities play an important role in the behavior of rock masses and have a high impact on their mechanical and hydrological properties, such as strength and permeability. The surfaces ...roughness and physical aperture of rock joints are vital characteristics in joint shear strength and fluid flow properties. This study presents a method to digitally measure the physical aperture of a rock fracture digitized using photogrammetry. A 50 cm × 50 cm rock sample of Kuru grey granite with a thoroughgoing fracture was digitized. The data was collected using a high-resolution digital camera and four low-cost cameras. The aperture and surface roughness were measured, and the influence of the camera type and 3D model rasterization on the measurement results was quantified. The results showed that low-cost cameras and smartphones can be used for generating 3D models for accurate measurement of physical aperture and roughness of rock fractures. However, the selection of appropriate rasterization grid interval plays a key role in accurate estimations. For measuring the physical aperture from the photogrammetric 3D models, reducing rasterization grid interval results in less scattered measurement results and a small rasterization grid interval of 0.1 mm is recommended. For roughness measurements, increasing the grid interval results in smaller measurement errors, and therefore a larger rasterization grid interval of 0.5 mm is recommended for high-resolution smartphones and 1 mm for other low-cost cameras.
Summary
Bing‐Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In ...this retrospective multi‐centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3‐year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi‐institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.
HYDROCK method aims to store thermal energy in the rock mass using hydraulically propagated fracture planes. The hydraulic fractures can interact with the pre-existing natural fractures resulting in ...a complex fracture network, which can influence the storage performance. This study investigates the interactions between hydraulic and natural fractures using a fracture mechanics approach. The new functionality of the fracture mechanics modelling code FRACOD that enables crossing of hydraulically driven fracture by a pre-existing fracture is presented. A series of two-dimensional numerical models is prepared to simulate the interaction at different approach angles in granitic rock of low permeability. It is demonstrated that multiple interaction mechanisms can be simulated using the fracture mechanics approach. The numerical results are in agreement with the modified Renshaw and Pollard analytical criterion for fracture crossing. The results show that for large approach angles, the hydraulic fracture crosses the natural fracture, whereas for small approach angles, the hydraulic fracture activates the natural fracture and the wing-shaped tensile fractures are propagated from its tips. Thus, the presence of fractures with low dip angles can lead to the growth of more complex fracture network that could impair the thermal performance of the HYDROCK method.
PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation ...study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD),
n
= 7; 300 mg QD,
n
= 6). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.
Trial registration
: clinicaltrials.gov: (NCT02160951).
Photogrammetry, reconstructing three-dimensional (3D) models from overlapping two-dimensional (2D) photos, finds application in rock mechanics and rock engineering to extract geometrical details of ...reconstructed objects, for example rock fractures. Fracture properties are important for determining the mechanical stability, permeability, strength, and shear behavior of the rock mass. Photogrammetry can be used to reconstruct detailed 3D models of two separated rock fracture surfaces to characterize fracture roughness and physical aperture, which controls the fluid flow, hydromechanical and shear behavior of the rock mass. This research aimed to determine the optimal number of scale bars required to produce high-precision 3D models of a fracture surface. A workflow has been developed to define the physical aperture of a fracture using photogrammetry. Three blocks of Kuru granite (25 cm × 25 cm × 10 cm) with an artificially induced fracture, were investigated. For scaling 3D models, 321 markers were used as ground control points (GCPs) with predefined distances on each block. When the samples were well-matched in their original positions, the entire block was photographed. Coordinate data of the GCPs were extracted from the 3D model of the blocks. Each half was surveyed separately and georeferenced by GCPs and merged into the same coordinate system. Two fracture surfaces were extracted from the 3D models and the vertical distance between the two surfaces was digitally calculated as physical aperture. Accuracy assessment of the photogrammetric reconstruction showed a 20–30 μm digital control distance accuracy when compared to known distances defined between markers. To attain this accuracy, the study found that at least 200 scale bars were required. Furthermore, photogrammetry was employed to measure changes in aperture under normal stresses. The results obtained from this approach were found to be in good agreement with those obtained using linear variable displacement transducers (LVDTs), with differences ranging from 1 μm to 8 μm.
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