Individualized dynamic frailty-tailored therapy (DynaFiT) in elderly patients with newly diagnosed multiple myeloma: a prospective study.

It remains a substantial challenge to balance treatment efficacy and toxicity in geriatric patients with multiple myeloma (MM), primarily due to the dynamic nature of frailty. Here, we conducted a prospective study to evaluate the feasibility and benefits of dynamic frailty-tailored therapy (DynaFiT) in elderly patients. Patients with newly diagnosed MM (aged ≥ 65 years) received eight induction cycles of bortezomib, lenalidomide, and dexamethasone (daratumumab was recommended for frail patients), with treatment intensity adjusted according to longitudinal changes in the frailty category (IMWG-FI) at each cycle. Of 90 patients, 33 (37%), 16 (18%), and 41 (45%) were fit, intermediate fit, and frail at baseline, respectively. Of 75 patients who had geriatric assessment at least twice, 28 (37%) experienced frailty category changes at least once. At analysis, 15/26 (58%) frail patients improved (27% became fit and 31% became intermediate fit), 4/15 (27%) intermediate fit patients either improved or deteriorated (two for each), and 6/30 (20%) fit patients deteriorated. During induction, 34/90 (38%) patients discontinued treatment, including 10/33 (30%) fit, 4/16 (25%) intermediate fit, and 20/41 (49%) frail; 14/40 (35%) frail patients discontinued treatment within the first two cycles, mainly because of non-hematologic toxicity (mostly infections). For fit, intermediate-fit, and frail patients, the overall response rate was 100%, 93%, and 73%, respectively; one-year overall survival was 90%, 75%, and 54%, respectively. Therefore, the individualized DynaFiT is feasible and promising for heterogeneous elderly patients.

Research on the pathological mechanism of rectal adenocarcinoma based on DNA methylation.

Colorectal cancer is one of the 3 most common cancers worldwide. In this study, a weighted network-based analysis method was proposed to explore the pathological mechanisms and prognostic targets of rectal adenocarcinoma (READ) at the deoxyribonucleic acid (DNA) methylation level. In this study, we downloaded clinical information and DNA methylation data from The Cancer Genome Atlas database. Differentially methylated gene analysis was used to identify the differential methylated genes in READ. Canonical correlation analysis was used to construct the weighted gene regulatory network for READ. Multilevel analysis and association analyses between gene modules and clinical information were used to mine key modules related to tumor metastasis evaluation. Genetic significance analysis was used to identify methylation sites in key modules. Finally, the importance of these methylation sites was confirmed using survival analysis. DNA methylation datasets from 90 cancer tissue samples and 6 paracancerous tissue samples were selected. A weighted gene regulatory network was constructed, and a multilevel algorithm was used to divide the gene co-expression network into 20 modules. From gene ontology enrichment analysis, characteristic M was related to biological processes such as the chemotaxis of fibroblast growth factors and the activation and regulation of immune cells etc and characteristic N was associated with the regulation of cytoskeleton formation, mainly microtubules and flagella, regulation of synapses, and regulation of cell mitosis. Based on the results of survival analysis, 7 key methylation sites were found closely correlated to the survival rate of READ, such as cg04441191 (microtubule-associated protein 4 [MAP4]), cg05658717 (KSR2), cg09622330 (GRIN2A), cg10698404 (YWHAG), cg17047993 (SPAG9), cg24504843 (CEP135), and cg24531267 (CEP250). Mutational and transcriptomic level studies revealed significant differences in DNA methylation, single nucleotide polymorphism, and transcript levels between YWHAG and MAP4 in normal tissues compared to tumor tissues, and differential expression of the 2 proteins in immunohistochemistry. Therefore, potential targeting drugs were screened for these 2 proteins for molecular docking, and artenimol was found to bind to MAP4 protein and 27-hydroxycholesterol to YWHAG. Our study found that key methylation sites played an important role in tumor metastasis and were associated with the prognosis of READ. Mutations and methylation may jointly regulate the transcription and translation of related genes, which in turn affect cancer progression. This may provide some new potential therapeutic targets and thoughts for the prognosis of READ.

Proposed risk-scoring model for estimating the prognostic impact of 1q gain in patients with newly diagnosed multiple myeloma.

1q gain (+1q) is the most common high-risk cytogenetic abnormality (HRCA) in patients with multiple myeloma (MM). However, its prognostic value remains unclear in the era of novel agents. Here, we retrospectively analyzed the impact of +1q on the outcomes of 934 patients newly diagnosed with MM. +1q was identified in 53.1% of patients and verified as an independent variate for inferior overall survival (OS) (hazard ratio, 1.400; 95% confidence interval, 1.097-1.787; p = .007). Concurrence of other HRCAs (particularly t(14;16) and del(17p)) further exacerbated the outcomes of patients with +1q, suggesting prognostic heterogeneity. Thus, a risk-scoring algorithm based on four risk variates (t(14;16), hypercalcemia, ISS III, and high LDH) was developed to estimate the outcomes of patients with +1q. Of the patients, 376 evaluable patients with +1q were re-stratified into low (31.6%), intermediate (61.7%), and high risk (6.7%) groups, with significantly different progression-free survival and OS (p < .0001), in association with early relapse of the disease. The prognostic value of this model was validated in the CoMMpass cohort. While attaining undetectable MRD largely circumvented the adverse impact of +1q, it scarcely ameliorated the outcome of the patients with high risk, who likely represent a subset of patients with extremely poor survival. Hence, patients with +1q are a heterogeneous group of high-risk patients, therefore underlining the necessity for their re-stratification. The proposed simple risk-scoring model can estimate the outcomes of patients with +1q, which may help guide risk-adapted treatment for such patients.

Prognostic targets recognition of rectal adenocarcinoma based on transcriptomics.

ABSTRACT: Colorectal cancer is currently the third most common cancer around the world. In this study, we chose a bioinformatics analysis method based on network analysis to dig out the pathological mechanism and key prognostic targets of rectal adenocarcinoma (READ).In this study, we downloaded the clinical information data and transcriptome data from the Cancer Genome Atlas database. Differentially expressed genes analysis was used to identify the differential expressed genes in READ. Community discovery algorithm analysis and Correlation analysis between gene modules and clinical data were performed to mine the key modules related to tumor proliferation, metastasis, and invasion. Genetic significance (GS) analysis and PageRank algorithm analysis were applied for find key genes in the key module. Finally, the importance of these genes was confirmed by survival analysis.Transcriptome datasets of 165 cancer tissue samples and 9 paracancerous tissue samples were selected. Gene coexpression networks were constructed, multilevel algorithm was used to divide the gene coexpression network into 11 modules. From GO enrichment analysis, module 11 significantly associated with clinical characteristic N, T, and event, mainly involved in 2 types of biological processes which were highly related to tumor metastasis, invasion, and tumor microenvironment regulation: cell development and differentiation; the development of vascular and nervous systems. Based on the results of survival analysis, 7 key genes were found negatively correlated to the survival rate of READ, such as MMP14, SDC2, LAMC1, ELN, ACTA2, ZNF532, and CYBRD1.Our study found that these key genes were predicted playing an important role in tumor invasion and metastasis, and being associated with the prognosis of READ. This may provide some new potential therapeutic targets and thoughts for the prognosis of READ.