Molecular Subtypes and Personalized Therapy in Metastatic Colorectal Cancer

Development of colorectal cancer occurs via a number of key pathways, with the clinicopathological features of specific subgroups being driven by underlying molecular changes. Mutations in key genes within the network of signalling pathways have been identified; however, therapeutic strategies to target these aberrations remain limited. As understanding of the biology of colorectal cancer has improved, this has led to a move toward broader genomic testing, collaborative research and innovative, adaptive clinical trial design. Recent developments in therapy include the routine adoption of wider mutational spectrum testing prior to use of targeted therapies and the first promise of effective immunotherapy for colorectal cancer patients. This review details current biomarkers in colorectal cancer for molecular stratification and for treatment allocation purposes, including open and planned precision medicine trials. Advances in our understanding, therapeutic strategy and technology will also be outlined

Downward continued multichannel seismic refraction analysis of Atlantis Massif oceanic core complex, 30°N, Mid-Atlantic Ridge

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 13 (2012): Q0AG07, doi:10.1029/2012GC004059.Detailed seismic refraction results show striking lateral and vertical variability of velocity structure within the Atlantis Massif oceanic core complex (OCC), contrasting notably with its conjugate ridge flank. Multichannel seismic (MCS) data are downward continued using the Synthetic On Bottom Experiment (SOBE) method, providing unprecedented detail in tomographic models of the P-wave velocity structure to subseafloor depths of up to 1.5 km. Velocities can vary up to 3 km/s over several hundred meters and unusually high velocities (~5 km/s) are found immediately beneath the seafloor in key regions. Correlation with in situ and dredged rock samples, video and records from submersible dives, and a 1.415 km drill core, allow us to infer dominant lithologies. A high velocity body(ies) found to shoal near to the seafloor in multiple locations is interpreted as gabbro and is displaced along isochrons within the OCC, indicating a propagating magmatic source as the origin for this pluton(s). The western two-thirds of the Southern Ridge is capped in serpentinite that may extend nearly to the base of our ray coverage. The distribution of inferred serpentinite indicates that the gabbroic pluton(s) was emplaced into a dominantly peridotitic host rock. Presumably the mantle host rock was later altered via seawater penetration along the detachment zone, which controlled development of the OCC. The asymmetric distribution of seismic velocities and morphology of Atlantis Massif are consistent with a detachment fault with a component of dip to the southeast. The lowest velocities observed atop the eastern Central Dome and conjugate crust are most likely volcanics. Here, an updated model of the magmatic and extensional faulting processes at Atlantis Massif is deduced from the seismic results, contributing more generally to understanding the processes controlling the formation of heterogeneous lithosphere at slow-rate spreading centers.NSF support was provided via grant OCE-0927442.2012-11-1

Reduced rates of primary joint replacement for osteoarthritis in Italian and Greek migrants to Australia: the Melbourne Collaborative Cohort Study

Introduction Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals. Methods Eligible participants (n = 39,023) aged 27 to 75 years, born in Italy, Greece, Australia and the United Kingdom, were recruited for the Melbourne Collaborative Cohort Study between 1990 and 1994. Primary hip and knee replacement for osteoarthritis between 2001 and 2005 was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Results Participants born in Italy and Greece had a lower rate of primary joint replacement compared with those born in Australia (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.26 to 0.39, P < 0.001), independent of age, gender, body mass index, education level, and physical functioning. This lower rate was observed for joint replacements performed in private hospitals (HR 0.17, 95% CI 0.13 to 0.23), but not for joint replacements performed in public hospitals (HR 0.96, 95% CI 0.72 to 1.29). Conclusions People born in Italy and Greece had a lower rate of primary joint replacement for osteoarthritis in this cohort study compared with Australian-born people, which could not simply be explained by factors such as education level, physical functioning, and weight. Although differential access to health care found in the population may explain the different rates of joint replacement, it may be that social factors and preferences regarding treatment or different rates of progression to end-stage osteoarthritis in this population are important to ethnic disparity.Yuanyuan Wang, Julie A Simpson, Anita E Wluka, Donna M Urquhart, Dallas R English, Graham G Giles, Stephen Graves and Flavia M Cicuttin

Vastus medialis cross-sectional area is positively associated with patella cartilage and bone volumes in a pain-free community-based population

INTRODUCTION: Although vastus medialis and lateralis are important determinants of patellofemoral joint function, their relationship with patellofemoral joint structure is unknown. The aim of this study was to examine potential determinants of vastus medialis and lateralis cross-sectional areas and the relationship between the cross-sectional area and patella cartilage and bone volumes. METHODS: Two hundred ninety-seven healthy adult subjects had magnetic resonance imaging of their dominant knee. Vastus medialis and lateralis cross-sectional areas were measured 37.5 mm superior to the quadriceps tendon insertion at the proximal pole of the patella. Patella cartilage and bone volumes were measured from these images. Demographic data and participation in vigorous physical activity were assessed by questionnaire. RESULTS: The determinants of increased vastus medialis and lateralis cross-sectional areas were older age (P <or= 0.002), male gender (P < 0.001), and greater body mass index (P <or= 0.07). Participation in vigorous physical activity was positively associated with vastus medialis cross-sectional area (regression coefficient [beta] 90.0; 95% confidence interval [CI] 38.2, 141.7) (P < 0.001) but not with vastus lateralis cross-sectional area (beta 10.1; 95% CI -18.1, 38.3) (P = 0.48). The cross-sectional area of vastus medialis only was positively associated with patella cartilage volume (beta 0.6; 95% CI 0.23, 0.94) (P = 0.001) and bone volume (beta 3.0; 95% CI 1.40, 4.68) (P < 0.001) after adjustment for potential confounders. CONCLUSIONS: Our results in a pain-free community-based population suggest that increased cross-sectional area of vastus medialis, which is associated with vigorous physical activity, and increased patella cartilage and bone volumes may benefit patellofemoral joint health and reduce the long-term risk of patellofemoral pathology

Standards for heart valve surgery in a ‘heart valve centre of excellence’

Surgical centres of excellence should include multidisciplinary teams with specialist expertise in imaging, clinical assessment and surgery for patients with heart valve disease. There should be structured training programmes for the staff involved in the periprocedural care of the patient and these should be overseen by national or international professional societies. Good results are usually associated with high individual and centre volumes, but this relationship is complex. Results of surgery should be published by centre and should include rates of residual regurgitation for mitral repairs and reoperation rates matched to the preoperative pathology and risk

Expressions 1987

https://openspace.dmacc.edu/expressions/1030/thumbnail.jp

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors:The phase I/II first-in-human MATINS trial

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer