Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.
Cognitive impairment is reported frequently by cancer survivors. There are no proven treatments. We evaluated a cognitive rehabilitation program (Insight) and compared it with standard care in cancer survivors self-reporting cognitive symptoms.
Patients and MethodsWe recruited adult cancer survivors with a primary malignancy (excluding central nervous system malignancies) who had completed three or more cycles of adjuvant chemotherapy in the previous 6 to 60 months and reported persistent cognitive symptoms. All participants received a 30-minute telephone consultation and were then randomly assigned to the 15-week, home-based intervention or to standard care. Primary outcome was self-reported cognitive function (Functional Assessment of Cancer Therapy Cognitive Function [FACT-COG] perceived cognitive impairment [PCI] subscale): difference between groups after intervention (T2) and 6 months later (T3).
ResultsA total of 242 participants were randomly assigned: median age, 53 years; 95% female. The primary outcome of difference in FACT-COG PCI was significant, with less PCI in the intervention group at T2 (P , .001). This difference was sustained at T3 (P , .001). At T2, there was a significant difference in all FACT-COG subscales, favoring the intervention. Neuropsychological results were not significantly different between the groups at T2 or T3. There were significantly lower levels of anxiety/ depression and fatigue in the intervention group at T2. There were significant improvements in stress in the intervention group at both time points. There was no significant difference in quality of life between the groups at T2, but the intervention group had better quality of life at T3.
ConclusionThe intervention, Insight, led to improvements in cognitive symptoms compared with standard care. To our knowledge, this is the first large randomized controlled trial showing an improvement in selfreported cognitive function in cancer survivors, indicating that this intervention is a feasible treatment.
Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.
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