Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation

PURPOSE To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment. MATERIALS AND METHODS Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial. RESULTS In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms). CONCLUSION Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study in Southeast Scotland

Background: MGMT methylation in glioblastoma predicts response to temozolomide but dichotomising methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. Methods: We included consecutive glioblastoma patients diagnosed (April 2012-May 2020) at a neuro-oncology centre. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumours were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, post-operative Karnofsky performance score, extent of resection, temozolomide regimen and radiotherapy. Findings: There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%) and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46-0.79, p=0.005) and low (HR 0.67, 95%CI 0.50-0.89, p<0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation p=0.097; high methylation p=0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms p<0.001). Interpretation: Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.

Preoperative Lymphocyte-to-Monocyte Ratio in the Prognostication of Advanced Resectable Colon Cancer: a Retrospective Observational Study

Lymphocyte-to-monocyte ratio (LMR) has been reported as a biomarker for predicting the prognosis of colorectal cancer. However, the clinical usefulness of LMR requires detailed research, which can contribute to better therapeutic strategies. A cohort of 554 patients with resectable advanced colon cancer in our institution was analyzed retrospectively. An analysis of stages II and III resectable advanced colon cancer was performed. LMR was useful for predicting overall survival (OS) and relapse-free survival (RFS). The ROC curve revealed an LMR value of 2.77 as a cutoff for OS. A high LMR was an independent prognostic factor and was associated with a high hazard ratio (HR) in all cases for OS (HR = 0.530, 95% confidence interval (CI) = 0.334–0.842, p = 0.007). A high LMR was not an independent prognostic factor in stage II cases but was a predictor with the strongest association with prognosis in patients with stage III cases for OS (HR = 0.383, 95% CI = 0.160–0.915, p = 0.031). LMR is a strong predictor of prognosis in patients with stage III colon cancer and may be useful in postoperative treatment options.

Comparison all-cause mortality between individuals with COVID-19 and propensity-score-matched individuals without COVID-19 in South Korea

Background We compared all-cause mortality between individuals in South Korea with and without coronavirus disease (COVID-19), using propensity score (PS)-matching. Methods This population-based cohort study used data from the National Health Insurance Service COVID-19 cohort database. In the database, we included individuals (COVID-19 patients, control population, and test-negative individuals) aged 20 years or older, regardless of hospitalization. The primary endpoint was all-cause mortality between January 1, 2020 and August 27, 2020. Results A total of 328,374 adults were included in the study: 7,713 and 320,660 in the COVID-19 group and the control group, respectively. After PS-matching, a total of 15,426 individuals (7,713 per group) were included in the analysis. All-cause mortality 3.2% (248/7,713) and 1.6% (126/7,713) in the COVID-19 group and the control group, respectively. In Cox regression analysis after PS-matching, the risk of death in the COVID-19 group was twice as high (hazard ratio: 2.00; 95% confidence interval: 1.61 to 2.48; P&lt;0.001) than that in the control group. Among patients aged ≥60 years, the COVID-19 group had a 2.32-fold higher all-cause mortality compared with the control group, while statistically statistical differences were not observed in the age groups 20–39 years (P=0.339) and 40–59 years (P=0.562). Conclusions In South Korea, all-cause mortality was twice as high among individuals with COVID-19 than among those with similar underlying risks, primarily because of the elevated COVID-19-associated mortality in those aged ≥60 years. Our results highlight the need for prevention of COVID-19 with respect to mortality as a public health outcome.

Extent of MGMT promoter methylation modifies the effect of temozolomide on overall survival in patients with glioblastoma: a regional cohort study

Background MGMT methylation in glioblastoma predicts response to temozolomide but dichotomizing methylation status may mask the true prognostic value of quantitative MGMT methylation. This study evaluated whether extent of MGMT methylation interacts with the effect of temozolomide on overall survival. Methods We included consecutive glioblastoma patients aged ≥16 years diagnosed (April 2012–May 2020) at a neuro-oncology center. All patients had quantitative MGMT methylation measured using pyrosequencing. Those with MGMT methylated tumors were stratified into high and low methylation groups based on a cut-off using Youden index on 2-year survival. Our accelerated failure time survival models included extent of MGMT methylation, age, postoperative Karnofsky performance score, extent of resection, temozolomide regimen, and radiotherapy. Results There were 414 patients. Optimal cut-off point using Youden index was 25.9% MGMT methylation. The number of patients in the unmethylated, low and high methylation groups was 223 (53.9%), 81 (19.6%), and 110 (26.6%), respectively. In the adjusted model, high (hazard ratio [HR] 0.60, 95% confidence intervals [CI] 0.46–0.79, P = 0.005) and low (HR 0.67, 95% CI 0.50–0.89, P &lt; 0.001) methylation groups had better survival compared to unmethylated group. There was no evidence for interaction between MGMT methylation and completed temozolomide regimen (interaction term for low methylation P = 0.097; high methylation P = 0.071). This suggests no strong effect of MGMT status on survival in patients completing temozolomide regimen. In patients not completing the temozolomide regimen, higher MGMT methylation predicted better survival (interaction terms P &lt; 0.001). Conclusions Quantitative MGMT methylation may provide additional prognostic value. This is important when assessing clinical and research therapies.

Problems of Lymph Node Dissection in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Study Using Inverse Probability of Treatment Weighting.

Background Lymph node dissection (LND) is considered to improve the prognosis of patients with intrahepatic cholangiocarcinoma (ICC). Although the National Comprehensive Cancer Network (NCCN) guidelines recommend routine LND in ICC, the role of LND remains controversial. This study aimed to explore the effect of LND on the prognosis of patients with ICC from two Chinese centers.MethodsPatients were identified in two Chinese academic centers. Inverse probability of treatment weighting (IPTW) was used to reduce bias. Kaplan–Meier curves and Cox proportional hazards models were used to compare overall survival (OS) and disease-free survival (DFS).ResultsOf 251 patients, 189 (75.2%) underwent LND, and 72 (38%) had metastatic lymph nodes. A minimum of 6 lymph nodes were dissected in 67 patients (35.5%). Lymph node metastasis (LNM) was a risk factor with a high hazard ratio. There was no association between LND and OS after IPTW; however, LND may affect the DFS. Tumors in the LNM group were more malignant, and surgical trauma was greater in the LNM group.ConclusionsOnly a few LNDs meet the NCCN guidelines’ requirements. LND did not improve prognosis, with higher surgical trauma. The best approach for LND requires further discussion.

Characterization and validation of long noncoding RNAs as new candidates in prostate cancer

Background Long noncoding RNAs (lncRNAs) have been proved to be an important regulator in gene expression. In almost all kinds of cancers, lncRNAs participated in the process of pathogenesis, invasion, and metastasis. Meanwhile, compared with the large amounts of patients, there is rare knowledge about the role of lncRNAs in prostate cancer (PCa). Material/Method In this study, lncRNA expression profiles of prostate cancer were detected by Agilent microarray chip, 5 pairs of case and control specimens were involved in. Differentially expressed lncRNAs were screened out by volcano plot for constructing lncRNA-miRNA-mRNA central network. Then, the top ten up-regulated and down-regulated lncRNAs were validated by qRT-PCR in another 5 tumor specimens and 7 para-cancerous/benign contrasts. Furthermore, we searched for the survival curve of the top 10 upregulated and downregulated lncRNAs. Results A total of 817 differentially expressed lncRNAs were filtered out by the criteria of fold change (FC) and t-test p < 0.05. Among them, 422 were upregulated, whereas 395 were downregulated in PCa tissues. Gene ontology and KEGG pathway analyses showed that many lncRNAs were implicated in carcinogenesis. lnc-MYL2-4:1 (FC = 0.00141, p = 0.01909) and NR_125857 (FC = 59.27658, p = 0.00128) had the highest magnitude of change. The subsequent qPCR confirmed the expression of NR_125857 was in accordance with the clinical samples. High expression of PCA3, PCAT14 and AP001610.9 led to high hazard ratio while low expression of RP11-279F6.2 led to high hazard ratio. Conclusions Our study detected a relatively novel complicated map of lncRNAs in PCa, which may have the potential to investigate for diagnosis, treatment and follow-up in PCa. Our study revealed the expression of NR_125857 in human PCa tissues was most up-regulated. Further studies are needed to investigate to figure out the mechanisms in PCa.

Characterization and validation of long noncoding RNAs as new candidates in prostate cancer

Background: Long noncoding RNAs (lncRNAs) have been proved to be an important regulator in gene expression. In almost all kinds of cancers, lncRNAs participated in the process of pathogenesis, invasion, and metastasis. Meanwhile, compared with the large amounts of patients, there is rare knowledge about the role of lncRNAs in prostate cancer (PCa). Material/Method: In this study, lncRNA expression profiles of prostate cancer were detected by Agilent microarray chip, 5 pairs of case and control specimens were involved in. Differentially expressed lncRNAs were screened out by volcano plot for constructing lncRNA-miRNA-mRNA central network. Then, the top ten up-regulated and down-regulated lncRNAs were validated by qRT-PCR in another 5 tumor specimens and 7 para-cancerous/benign contrasts. Furthermore, we searched for the survival curve of the top 10 upregulated and downregulated lncRNAs. Results: A total of 817 differentially expressed lncRNAs were filtered out by the criteria of fold change (FC) and t-test p < 0.05. Among them, 422 were upregulated, whereas 395 were downregulated in PCa tissues. Gene ontology and KEGG pathway analyses showed that many lncRNAs were implicated in carcinogenesis. lnc-MYL2-4:1 (FC = 0.00141, p = 0.01909) and NR_125857 (FC = 59.27658, p = 0.00128) had the highest magnitude of change. The subsequent qPCR confirmed the expression of NR_125857 was in accordance with the clinical samples. High expression of PCA3, PCAT14 and AP001610.9 led to high hazard ratio while low expression of RP11-279F6.2 led to high hazard ratio. Conclusions: Our study detected a relatively novel complicated map of lncRNAs in PCa, which may have the potential to investigate for diagnosis, treatment and follow-up in PCa. Our study revealed the expression of NR_125857 in human PCa tissues was most up-regulated. Further studies are needed to investigate to figure out the mechanisms in PCa.

A novel analysis of the differentiated expression of long noncoding RNAs profiles in human prostate cancer

Background: Long noncoding RNAs (lncRNAs) have been proved to be an important regulator in gene expression. In almost all kinds of cancers, lncRNAs participated in the process of pathogenesis, invasion, and metastasis. Meanwhile, compared with the large amounts of patients, there is rare knowledge about the role of lncRNAs in prostate cancer (PCa).Material/Method: In this study, lncRNA expression profiles of prostate cancer were detected by Agilent microarray chip, 5 pairs of case and control specimens were involved in. Differentially expressed lncRNAs were screened out by volcano plot for constructing lncRNA-miRNA-mRNA central network. Then, the top ten up-regulated and down-regulated lncRNAs were validated by qRT-PCR in another 5 tumor specimens and 7 para-cancerous/benign contrasts. Furthermore, we searched for the survival curve of the top 10 upregulated and downregulated lncRNAs.Results: A total of 817 differentially expressed lncRNAs were filtered out by the criteria of fold change (FC) and t-test p < 0.05. Among them, 422 were upregulated, whereas 395 were downregulated in PCa tissues. Gene ontology and KEGG pathway analyses showed that many lncRNAs were implicated in carcinogenesis. lnc-MYL2-4:1 (FC = 0.00141, p = 0.01909) and NR_125857 (FC = 59.27658, p = 0.00128) had the highest magnitude of change. The subsequent qPCR confirmed the expression of NR_125857 was in accordance with the clinical samples. High expression of PCA3, PCAT14 and AP001610.9 led to high hazard ratio while low expression of RP11-279F6.2 led to high hazard ratio.Conclusions: Our study detected a relatively novel complicated map of lncRNAs in PCa, which may have the potential to investigate for diagnosis, treatment and follow-up in PCa. Our study revealed the expression of NR_125857 in human PCa tissues was most up-regulated. Further studies are needed to investigate to figure out the mechanisms in PCa.

Exosomal TUBB3 mRNA expression level to predict prognosis for abiraterone treatment in metastatic prostate patients.

244 Background: TUBB3 (Class III β-tubulin), a dynamic component of microtubules, is considered a prognostic biomarker of tumor aggressiveness and poor survival. Previous studies have researched into its indication of resistance to chemotherapeutic drugs. However, its association with abiraterone, a next-generation androgen-axis targeting drug in prostate cancer has not been studied yet. In this study, we aimed to find out if exosomal TUBB3 expression could predict the efficacy of abiraterone in metastatic prostate cancer patients. Methods: Blood samples of metastatic prostate cancer patients during different disease stages were collected. We isolated the exosomes and extracted the RNA for analysis of TUBB3 by ddPCR. Absolute target mRNA concentration was measured by ddPCR as copies per milliliter (copies/20ul). Clinical data were collected for all patients. Primary study endpoint was progression-free survival (PFS). Statistical analyses were performed with SPSS 25.0. Results: A total of 54 metastatic prostate cancer patients who have received abiraterone treatment were enrolled. Baseline characteristics are comparable between high (≥10 copies/20ul) and low (<10 copies/20ul) TUBB3 expression groups. Univariate analyses revealed that baseline hemoglobin≤120g/L, baseline sodium concentration >140 mmol/L, baseline potassium concentration >4.39 mmol/L and high exosomal TUBB3 expression were associated with shorter PFS, while only baseline sodium concentration and exosomal TUBB3 expression were independent prognosticators in multivariate analyses. In subsequently subgroup analyses, high exosomal TUBB3 expression demonstrates particularly high hazard ratio in multiple subgroups (patients younger than 70 years old, without neuroendocrine differentiation and immunohistochemical androgen-receptor splice variant 7 expression, with baseline PSA >100 ng/mL, and patients receiving abiraterone as first-line therapy). Conclusions: Exosomal TUBB3 expression has potential in making treatment plan and predict prognosis in metastatic prostate cancer patients. High exosomal TUBB3 expression indicates poor response to abiraterone, especially as first line therapy.