Predictive preventive personalized medicine Liver cancer is the fifth most common form of cancer worldwide [1], with an incidence rate almost equals the mortality rate and ranks 3 rd among causes of cancer related death [2]. The coexistence of two life threatening conditions, cancer and liver cirrhosis makes the staging challenging. However, there are some staging systems, e.g. the Barcelona staging system for Hepatocellular carcinoma (HCC) [3], that suggest treatment options and management. Whereas diagnosis in early stages gives hope for a curative outcome, the treatment regime for around 80 % [2] of the patients classified as severe stages only gears towards palliation [4]. An intra-arterial radiation approach, radioembolisation (RE) is ubiquitously applied as one of palliative approaches. Although, in general RE shows promising results in intermediate and advanced stage HCC [5], individual treatment outcomes are currently unpredictable. Corresponding stratification criteria are still unclear. We hypothesised that individual radioresistance/radiosensitivity may play a crucial role in treatment response towards RE strongly influencing individual outcomes. Further, HCC represents a highly heterogeneous group of patients which requires patient stratification according to clear criteria for treatment algorithms to be applied individually. Multilevel diagnostic approach (MLDA) is considered helpful to set-up optimal predictive and prognostic biomarker panel for individualised application of radioembolisation. Besides comprehensive medical imaging, our MLDA includes non-invasive multi-omics and sub-cellular imaging. Individual patient profiles are expected to give a clue to targeting shifted molecular pathways, individual RE susceptibility, treatment response. Hence, a dysregulation of the detoxification pathway (SOD2/Catalase) might indicate possible adverse effects of RE, and highly increased systemic activities of matrix metalloproteinases indicate an enhanced tumour aggressiveness and provide insights into molecular mechanisms/targets. Consequently, an optimal set-up of predictive and prognostic biomarker panels may lead to the changed treatment paradigm from untargeted "treat and wait" to the cost-effective predictive, preventive and personalised approach, improving the life quality and life expectancy of HCC patients. Keywords: Market access, Value, Strategy, Companion diagnostics, Cost-effectiveness, Reimbursement, Health technology assessment, Economic models, Predictive preventive personalized medicine Achieving and sustaining seamless "drug -companion diagnostic" market access requires a sound strategy throughout a product life cycle, which enables timely creation, substantiation and communication of value to key stakeholders [1, 2]. The study aims at understanding the root-cause of market access inefficiencies of companies by gazing at the "Rx-CDx" co-development process through the prism of "value", and developing a perfect co-development scenario based on the literature review and discussions with the ...

Aim: The study sought to evaluate the influence of anesthesia on chronic pain after total knee arthroplasty (TKA). Methods: This was a single-center, randomized controlled study, with patients receiving a spinal anesthetic (SP) alone or a general anesthetic (GA) with femoral block, with follow-up at 3 and at 6 months. The primary outcome was the WOMAC® score at 6 months. Results: 199 patients were enrolled. Group SP had better function (WOMAC: GA: 16.9 vs SP: 14.4, p = 0.015) and less pain (WOMAC pain: GA: 3.04 vs SP: 2.69, p = 0.02) at 3 months, but not at 6 months. Overall, 11% of patients had chronic postsurgical pain (CPSP), with Group GA having a higher incidence of CPSP at 6 months. Neuropathic pain increased during the follow-up and was more common in patients with CPSP. Conclusion: An SP reduces pain and incidence of CPSP after TKA. Clinical Trial Registration: NCT04206046 ( ClinicalTrials.gov )

Protein expression, activation and stability are regulated through inter-connected signal transduction pathways resulting in specific cellular states. This study sought to differentiate between the complex mechanisms of intrinsic and acquired trastuzumab resistance, by quantifying changes in expression and activity of proteins (phospho-protein profile) in key signal transduction pathways, in breast cancer cellular models of trastuzumab resistance. To this effect, we utilized a multiplex, bead-based protein assay, DigiWest®, to measure around 100 proteins and protein modifications using specific antibodies. The main advantage of this methodology is the quantification of multiple analytes in one sample, utilising input volumes of a normal western blot. The intrinsically trastuzumab-resistant cell line JIMT-1 showed the largest number of concurrent resistance mechanisms, including PI3K/Akt and RAS/RAF/MEK/ERK activation, β catenin stabilization by inhibitory phosphorylation of GSK3β, cell cycle progression by Rb suppression, and CREB-mediated cell survival. MAPK (ERK) pathway activation was common to both intrinsic and acquired resistance cellular models. The overexpression of upstream RAS/RAF, however, was confined to JIMT 1; meanwhile, in a cellular model of acquired trastuzumab resistance generated in this study (T15), entry into the ERK pathway seemed to be mostly mediated by PKCα activation. This is a novel observation and merits further investigation that can lead to new therapeutic combinations in HER2-positive breast cancer with acquired therapeutic resistance.

Protein phosphatase 2A (PP2A) is a ubiquitously expressed intracellular serine/threonine phosphatase. Deregulation of PP2A is a common event associated with adenocarcinomas of the colon and rectum. We have previously shown that breast cancer cell lines are sensitive to the PP2A activator FTY720, and that sensitivity is predicted by high Aurora kinase A (AURKA) mRNA expression. In this study, we hypothesized that high relative AURKA expression could predict sensitivity to FTY720-induced apoptosis in colorectal cancer (CRC). The CRC cell lines NCI H716, COLO320DM, DLD-1, SW480, and HT-29 show a high relative AURKA expression as compared to LS411N, T84, HCT116, SW48, and LOVO. Following viability assays, LS411N, T84, HCT116, and SW480 were shown to be sensitive to FTY720, whereas DLD-1 and HT-29 were non-sensitive. Hence, AURKA mRNA expression does not predict sensitivity to FTY720 in CRC cell lines. Differentially expressed genes (DEGs) were obtained by comparing the sensitive CRC cell lines (LS411N and HCT116) against the non-sensitive (HT-29 and DLD-1). We found that 253 genes were significantly altered in expression, and upregulation of CERS4, PPP2R2C, GNAZ, PRKCG, BCL2, MAPK12, and MAPK11 suggests the involvement of the sphingolipid signaling pathway, known to be activated by phosphorylated-FTY720. In conclusion, although AURKA expression did not predict sensitivity to FTY720, it is evident that specific CRC cell lines are sensitive to 5 µM FTY720, potentially because of the differential expression of genes involved in the sphingolipid pathway.

1092 The chemical heterogeneity of fetal hemoglobin (Hb F) due to variable ratios of the Gγ and Aγ globin subunits reflects genetic complexity because of common dimorphisms such as Hb F Sardegna (or Aγ75(E19) Ile>Thr; also known as AγT) in Caucasians, and common variants such the Gγ globin variant, Hb F Malta I (or Gγ117(G19) His>Arg) that is in tight linkage disequilibrium with the β globin variant Hb Valletta (or β87(F3) Thr>Pro) and is found in 1.8% of neonates from Malta. Comprehensive and integrated maternal and neonatal testing has led to the finding of triple compound heterozygotes with Hb F Malta I in association with Hb F Sardegna and Hb Valletta in whom all globin genes that are functional in the transition from fetal to adult Hemoglobin profiles are genetically tagged, and quantifiable with High Performance Liquid Chromatography in the neonate or mRNA in the adult in the context of diverse XMNI −158 C>T Gγ globin and (AT)XTY −540 β globin haplotypes. The interaction between XMNI and (AT)XTY revealed “conditional” cis-trans interplay that appeared to be under developmental control. A family with members carrying Hb F Malta I in association with a rare form of the Hereditary Persistence of Fetal Hemoglobin has also been found. The genetic cause has been traced to haplo-insufficiency of the putative erythroid master regulator KLF1, and, as confirmed by functional assays in vitro. However, levels of Hb F expression varied considerably (3.3% – 19.5%) while a second family from Malta with the same KLF1 mutation (p.K288X) had normal Hb F indicating interplay of KLF1 with modifying genes. These data, together with comparative expression profiling of human erythroid progenitors, indicated a small set of additional gene products that may interact positively (friends) or negatively (foes) at the level of commitment or expression in globin gene switching with significant effects on the Mean Corpuscular - Hb F. Whole genome sequencing on critically informative family members currently in progress may further uncover the complex genetic interactions in developmental globin gene control. Disclosures: No relevant conflicts of interest to declare.