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High-grade Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Donald C. Macarthur, Christof M. Kramm, Matthias A. Karajannis
Although a number of “actionable” genetic alterations, including oncogene mutations and amplifications, can be found in both adult and pediatric HGG,5 the treatment of unselected HGG patients with single-agent, molecular targeted therapies has not resulted in improved outcome.109,110 While the selection of “target-enriched” populations is a rational next step, and is being incorporated into recent and future trials,111 this approach will face known challenges including intratumor heterogeneity with molecular pathway redundancy19,112 and clonal evolution during therapy,113 as well as issues with drug delivery such as poor blood–brain barrier penetration of many molecular targeted agents.114
Looking ahead Opportunities and challenges in radiomics and radiogenomics
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Ruijiang Li, Yan Wu, Michael Gensheimer, Masoud Badiei Khuzani, Lei Xing
It has been widely recognized that tumors often do not consist of spatially well mixed cell populations, but demonstrate regional variations in genotypes and phenotypes due to clonal evolution.21,22 Some parts of the tumor may be more biologically aggressive and treatment-resistant than others. Image-based tumor partitioning could reveal aggressive subregions that are more important for determining prognosis and treatment response.23 To address this issue, Gatenby and colleagues proposed to cascade T1 post-gadolinium MRI with T2-weighted fluid-attenuated inversion recovery sequences to divide the whole tumor into multiple regional habitats with distinct contrast enhancement and edema/cellularity.24 A preliminary study of 32 the cancer genome atlas (TCGA) glioblastoma multiforme patients showed that the distribution of MRI-based habitats was significantly correlated with survival. Cao and colleagues proposed a clustering-based algorithm to identify the significant subvolumes for primary tumors from dynamic contrast-enhanced (DCE) MRI in head and neck cancer.25 They showed that large poorly perfused subvolumes of primary tumor at baseline and persisting during the early course of chemoradiotherapy might be used to predict local or regional failure, which could potentially stratify patients for local dose intensification.
Classifications and Risk Factors
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Haematological malignancies encompass cancers which involve blood cells and reflect the architectural complexity of haematopoiesis, its inherent genetic heterogeneity and the intricacies associated with the bone marrow niches. These niches can be defined as a specialized ‘local’ bone marrow tissue microenvironment that directly maintains and regulates the haematopoietic stem cell (HSC), which in turn, generates all the lineages of blood and immune cells. Myeloid malignancies arise from a clonal evolution from within the HSC, and in some cases, a maturing progenitor cell from the myeloid lineage, which has turned into a cancer-initiating cell. Lymphoid neoplasms are derived from the lymphoid lineage encompassing B-, T- and NK (natural killer)-cells; rarely they may arise from a histiocytic cell (a macrophage; previously known as a clasmatocyte). Unlike myeloid malignancies, mature lymphoid malignancies do not appear to result from transformation of normal stem cells or progenitors; rather, they evolve from mature lymphoid cells, but may still harbour cancer stem cell compartments. Clearly, the existence of a stem cell compartment in malignancies impacts on the definition, classification and treatment. Conventional leukaemogenesis models suggest clonal evolution as a ‘step-wise’ process, whereby driver mutations are serially acquired, and the impact of the cellular eco-system, which includes the tumour microenvironment and the immune system, is poorly understood at present.
The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies
Published in Cancer Investigation, 2023
Xuezheng Sun, Page Abrahamson, Nicholas Ballew, Linda Kalilani, Kelesitse Phiri, Kelly F. Bell, Alexander Slowley, Magdalena Zajac, Erin Hofstatter, Alexander Stojadinovic, Angela Silvestro, Zebin Wang, Amine Aziez, Solange Peters
Clonal evolution, or the acquisition of new mutations in response to selective pressures, is increasingly recognized to explain tumor heterogeneity and therapeutic resistance (134). Longitudinal profiling of ctDNA in serial monitoring provides an attractive, cost-effective, noninvasive monitoring technique to describe tumor genomic clonal evolution in response to treatment in a real-time manner, and consequently contribute to understanding the mechanisms of acquired drug resistance. Several studies have evaluated the prognostic effect of newly acquired mutations during TKI treatment, with EGFR T790M most frequently evaluated. Additional studies evaluated small samples of patients during treatment for several different ctDNA-based genetic changes. These ctDNA-based genetic changes included the acquisition of new mutations during TKI treatment (122,135) or chemotherapy (36), increases in gene copy numbers or losses of tumor suppressor genes during ICI therapy (136), and the frequency of C > G and C > A substitutions during chemotherapy (77).
Emerging drugs for the treatment of paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Emerging Drugs, 2022
Camilla Frieri, Régis Peffault de Latour, Flore Sicre De Fontbrune
AA and PNH can be considered two sides of the same coin; about 30–40% of PNH patients may present AA during their disease course [50]. However, the presence of a PNH clone in the context of severe AA (SAA) does not change the therapeutic approach of SAA: the first option for patients younger than 40 years with a matched related donor should be bone marrow transplantation, whereas, for patients older than 40 years or lacking a matched related donor, immunosuppression (horse anti-thymocyte globulin and cyclosporine) remains the first-line treatment [51,52]. The onset of non-hemolytic anemia, neutropenia, and/or thrombocytopenia should require bone marrow aspiration and a cytological examination in order to find out not only AA, but also a clonal evolution to myelodysplastic syndrome or acute myeloid leukemia. Although rare, the risk of clonal evolution is approximately 1–5% [50].
Bone marrow morphological features and therapy in patients with Philadelphia-negative neoplasms
Published in Expert Review of Hematology, 2021
Achille Pich, Eloise Beggiato, Laura Godio, Ludovica Riera, Paola Francia di Celle, Giuseppe Lanzarone, Giulia Benevolo
Most data from the literature show that HU (Table 1) can reduce BM cellularity, especially of the erythroid and MK lineage but has little influence on fibrotic evolution. There is general agreement on its dysplastic effects. INF therapy (Table 2) can reduce or normalize BM cellularity, improve erythropoiesis, and reduce the number and atypia of MKs. Most data describe reduction or complete resolution of marrow fibrosis, although a few studies report no change. Dysplastic effects and AML/MDS have not been reported. ANA (Table 3) may induce an increase in the number of BM MKs, especially immature MKs or precursors, worsen marrow fibrosis and, in some cases, increase the transformation of ET to secondary myelofibrosis. Dysplastic effects or AML/MDS are not (or only occasionally) reported. Concerning RUX (Table 4), most studies agree on improvement or stabilization of BM fibrosis, especially in PMF, and on reduction of the frequency and dense clustering of MKs. JAK inhibitors have demonstrated a limited impact on disease modification. However, there are concerns regarding the impact on the clonal landscape: a clonal evolution has been observed, and transformation to acute leukemia can still occur. Therefore, despite the benefits, there is limited impact in inducing complete hematological remission with normalization of blood counts, reduction of the mutant allelic burden, or reversal of BM fibrosis [55].