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Lung cancer and mesothelioma
Published in Peter Hoskin, Peter Ostler, Clinical Oncology, 2020
Molecular phenotyping has developed significantly over the last few years and now makes an impact on treatment decision. Tumours are routinely tested for EGFR (∼15% of cancers) and EML4-ALK or ROS1 (5% of cancers), and for PDL1 expression. Testing for several more molecular pathways are being researched and may also be useful in guiding potential therapy options.
Predictive Markers for Targeted Breast Cancer Treatment
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Hans Christian B. Pedersen, John M. S. Bartlett
As our understanding of cancer as a disease progresses and the tools to investigate cancer biology develops, the complexity of the disease is unraveling. Breast cancers are now being classified not only on the basis of traditional pathology traits but also according to molecular phenotype and, more recently, gene expression profiles. New molecular targeted therapeutics will lead to more predictive markers being introduced, and these markers must be prospectively validated, internally and externally quality assured, and rigorously quantitative to allow correct decisions for treatment. Therefore, an evolution of the pathology laboratory is likely to take place in the near future, leading to a switch to fluorescent-based techniques, digital imaging of slides, and computerized scoring of predictive markers. On a longer time horizon, new technologies being developed and applied are likely to change cancer diagnostics so that molecular phenotyping of patients will take center stage in patient management. In the not too distant future, there is the possibility that pathologists will type and stage tumors and simultaneously identify key areas of tissue for automated microdissection and processing. The subsequent process of molecular phenotyping, which may include kinomic, proteomic, and transcriptomic assays performed simultaneously could be carried out in specialised laboratories using robotics and microfluidics on high-density protein and gene arrays to determine optimal treatment regimens for tumors with specific molecular profiles linked to drug response. Such a future vision may represent the more radical view of what could be accomplished by linking of current concepts and technologies to maximize patient benefit from therapeutic options. However, we must dream of such futures if we are to maximize progress in the area of molecular pathology for the benefit of the most important people, our patients.
Personalizing treatments for patients based on cardiovascular phenotyping
Published in Expert Review of Precision Medicine and Drug Development, 2022
For true precision cardiovascular phenotyping to become mainstream, several factors that must be considered. The first is to identify the types of data that are required to construct the cardiovascular phenome. This typically includes data from the history and physical, laboratory tests, and imaging, but should be expanded to include a detailed history of exposures, social determinants of health, diet, and sleep as well as objective exercise data from wearable activity trackers [7]. These latter measures impact cardiovascular health and well-being yet are often not incorporated into the clinical record or assessed over time. The next decision is whether to perform molecular phenotyping using a singular or multiomics platform, if the tests will be performed as part of a cross-sectional or longitudinal evaluation, and whether analyses should focus on the population, the individual or both. Many of the studies published to date only partially address these important factors and this had likely contributed to the heterogeneous and often disparate published results.
Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic
Published in Expert Opinion on Investigational Drugs, 2021
Massimiliano Cadamuro, Alberto Lasagni, Angela Lamarca, Laura Fouassier, Maria Guido, Samantha Sarcognato, Enrico Gringeri, Umberto Cillo, Mario Strazzabosco, Jose JG Marin, Jesus M Banales, Luca Fabris
Currently, there are 256 ongoing clinical trials including patients with eCCA, aimed at 131 different compounds belonging to the molecular targeted class (Supplemental Table 1) [77]. These studies are mainly designed as basket trials and the most specific ones include not only eCCA, but also gallbladder or iCCA. Targeted DNA-sequencing and whole-genome expression-based studies have pinpointed KRAS, TP53, ARID1A and SMAD4 as the most frequent genetic alterations in eCCA [39]. As aforementioned, in about a quarter of eCCAs, these mutations result in at least a putative actionable driver (BRCA1-2, EGFR, ERBB2, CDK4, IDH1-2, BRAF, NRAS, PI3K, MDM2). Nevertheless, the only currently approved (Level 1) targeted therapy for use in eCCA is the PD-1 monoclonal antibody pembrolizumab, which show an improved outcome in tissue-agnostic DNA MMR deficient tumors including CCA [78], whereas it showed only a 7–13% objective response rate in BTCs [79]. Compared with iCCA, actionable molecular aberrations, with proven clinical benefit in different tumor types, are expressed in a minority of eCCA, such as BRCA1/2 (3%), EGFR (1%), IDH2 mutations (3%), ERBB2 overexpression (5%), CDK4 amplifications (1%), BRAF mutant (2%) [39]. However, the deep molecular phenotyping may open up interesting perspective on new targets amenable of intervention, with a certain specificity for each class (Supplemental Table 2).
Can we use the dynamic and complex interplay between pain and sleep to quantify neuromodulation responsiveness for chronic pain?
Published in Expert Review of Neurotherapeutics, 2021
Thomas Kinfe, Michael Buchfelder, Andreas Stadlbauer
Although a small number of mostly uncontrolled human neurostimulation-pain trials have assessed possible associations between circulating mediators of neuroinflammation and neurostimulation responsiveness, neuroinflammatory phenotyping may become a useful and easily accessible tool to reveal the molecular mechanisms of pain, sleep and mood alterations [14,15]. For example, cervical noninvasive vagus nerve stimulation has been found to significantly decrease the levels of pro-inflammatory IL-1β in refractory migraines in a randomized sham-controlled human trial. Whether such concentration changes are responsible for the observed vagus nerve stimulation effects and/or might reflect disease state progression warrants further reexamination [14]. In a large systematic review, Irwin et al. have analyzed 72 studies examining the possible associations between inflammation and sleep alterations in more than 50,000 participants [15]. Circulating C-reactive protein and pro-inflammatory interleukin 6 were found to be associated with sleep disturbance, whereas sleep duration changes (either short or long sleep subtype) were associated with only a C-reactive protein increase, thus indicating an effect of neuroinflammation in the pathophysiology of sleep architecture. For instance, pro-inflammatory IL-1β evokes distinct chronic pain and mood disorders [16,17]. Under such circumstances, molecular phenotyping may be biased by a considerable number of confounders such as age, race, sex, medication, lifestyle and environmental factors [14,15].