Univariate Cox Proportional Hazards Analyses Research Articles

Abstract P1-04-06: Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results

Abstract Background: HER2-positive versus HER2-negative ductal carcinoma in situ (DCIS) of the breast has been associated with an increased risk of local recurrence after breast-conserving surgery (BCS) and radiotherapy (RT). In recognition of this, the NASBP-B43 trial was designed to determine if two doses of trastuzumab would improve local control with BCS plus RT in HER2-positive DCIS. The trial demonstrated a non-statistically significant advantage with the addition of trastuzumab in reducing ipsilateral breast recurrence (IBR). The predictive 7-gene DCIS biosignature, DCISionRT with Residual Risk Subtype (PreludeDxTM, Laguna Hills, CA) has been shown to classify DCIS patients into two distinct groups of patients with substantially different rates of IBR following BCS plus RT. Based upon these differences in outcome, we assessed the IBR rate in patients with HER2(+) DCIS treated with BCS and RT who were or were not in the Residual Risk Subtype group defined using DCISionRT, while accounting for the varying clinicopathologic profile of the patients. Materials & Methods: DCISionRT was evaluated in a subset of 178 women with HER2(+) DCIS treated with BCS and RT as part of a multinational cohort of 926 patients from the United States, Sweden, and Australia, who were used in the validation studies for DCISionRT. Central pathology review and biosignature testing were performed at a CLIA-certified lab (Laguna Hills, CA). HER2(+) DCIS was defined as patients with a HER2(3+) immunohistochemistry >10% per ASCO/CAP guidelines. The IBR rate was calculated for the overall group of HER2(+) patients and those in the Residual Risk group. Individual patient outcome and biosignature results were analyzed using Kaplan Meier and Cox Proportional Hazard analyses. Results: The biosignature classified 113 of the 178 (63%) HER2(+) women into the Residual Risk group (DS>2.8 with RRt). Patients in the Residual Risk group had a significantly greater IBR (HR=8.3; 95%CI: 1.1,50, p=.012) over 10-years, with a corresponding 10-year total IBR rate of 16.2% (95%CI: 9.7%, 26.5%) versus 1.6% (95%CI: 0.2%, 10.9%) for all other HER2(+) patients. In univariate analysis, younger patients tended to have higher IBR rate after BCS plus RT, but only Residual Risk was significantly associated with IBR rate after BCS plus RT. Moreover, multivariable analysis demonstrated that the Residual Risk group was eight times more likely to recur after BCS and RT, while clinicopathologic factors (age, grade, tumor size) were not associated with higher IBR rates. Conclusion: The DCISionRT Residual Risk group was predictive for 10-year IBR risk after BCS plus RT in women with HER2(+) DCIS. Approximately 40% of patients with HER2(+) DCIS would be expected to achieve low rates of recurrence with BCS and RT, while about 60% of these women (classified in the Residual Risk group) would have higher recurrence rates and may benefit from further therapy, such as HER2-directed therapies. These findings suggest that if the results of the B43 trial were re-analyzed using the predictive 7-gene biosignature (DCISionRT with Residual Risk Subtype), better clarity could be gained on the true impact of trastuzumab on IBR rates in patients with HER2(+) DCIS and the patients most likely to benefit from this additional therapy. Table 1. Univariate and Multivariable Cox Proportional Hazards Analyses. Citation Format: Frank Vicini, Chirag Shah, Rachel Rabinovitch, Pat Whitworth, Julie A. Margenthaler, Brian J. Czerniecki, DAVID J. DABBS, Sheila Weinmann, Michael Leo, G Bruce Mann, Fredrik Wärnberg, jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-06.

Identification of Wnt/β-Catenin- and Autophagy-Related lncRNA Signature for Predicting Immune Efficacy in Pancreatic Adenocarcinoma

Pancreatic cancer is one of the tumors with a poor prognosis. Therefore, it is significant and urgent to explore effective biomarkers for risk stratification and prognosis prediction to promote individualized treatment and prolong the survival of patients with PAAD. In this study, we identified Wnt/β-catenin- and autophagy-related long non-coding RNAs (lncRNAs) and demonstrated their role in predicting immune efficacy for PAAD patients. The univariate and multivariate Cox proportional hazards analyses were used to construct a prognostic risk model based on six autophagy- and Wnt/β-catenin-related lncRNAs (warlncRNAs): LINC01347, CASC8, C8orf31, LINC00612, UCA1, and GUSBP11. The high-risk patients were significantly associated with poor overall survival (OS). The receiver operating characteristic (ROC) curve analysis was used to assess the predictive accuracy of the prognostic risk model. The prediction efficiency was supported by the results of an independent validation cohort. Subsequently, a prognostic nomogram combining warlncRNAs with clinical indicators was constructed and showed a good predictive efficiency for survival risk stratification. Furthermore, functional enrichment analysis demonstrated that the signature according to warlncRNAs is closely linked to malignancy-associated immunoregulatory pathways. Correlation analysis uncovered that warlncRNAs' signature was considerably associated with immunocyte infiltration, immune efficacy, tumor microenvironment score, and drug resistance.

Impact of Arterial Calcification of the Lower Limbs on Long-Term Clinical Outcomes in Patients on Hemodialysis

Lower limbs' arterial calcification is significantly associated with the clinical severity of lower extremity artery disease (LEAD) in patients undergoing hemodialysis (HD). However, the association between arterial calcification of the lower limbs and long-term clinical outcomes in patients on HD has not been elucidated. Calcification scores of the superficial femoral artery (SFACS) and below-knee arteries (BKACS) were quantitatively evaluated in 97 HD patients who were followed for 10 years. Clinical outcomes, including all-cause and cardiovascular mortality, cardiovascular events, and limb amputation were evaluated. Risk factors for clinical outcomes were evaluated using univariate and multivariate Cox proportional hazard analyses. Furthermore, SFACS and BKACS were divided into three groups (low, middle, and high), and their associations with clinical outcomes were evaluated using Kaplan-Meier analysis. SFACS, BKACS, C-reactive protein, serum albumin, age, diabetes, presence of ischemic heart disease, and critical limb-threatening ischemia were significantly associated with 3-year and 10-year clinical outcomes in the univariate analysis. Multivariate analysis showed that SFACS was an independent factor associated with 10-year cardiovascular events and limb amputations. Kaplan-Meier life table analysis showed that higher SFACS and BKACS levels were significantly associated with cardiovascular events and mortality. In conclusion, long-term clinical outcomes and the risk factors in patients undergoing HD were evaluated. Arterial calcification of the lower limbs was strongly associated with 10-year cardiovascular events and mortality in patients undergoing HD.

A methylomics-associated nomogram predicts the overall survival risk of stage III to IV ovarian cancer.

Accumulating studies demonstrated that DNA methylation may be potential prognostic hallmarks of various cancers. However, few studies have focused on the power of DNA methylation for prognostic prediction in patients with stage III to IV ovarian cancer (OC). Therefore, constructing a methylomics-related indicator to predict overall survival (OS) of stage III to IV OC was urgently required. A total of 520 OC patients with 485,577 DNA methylation sites from TCGA database were selected to develop a robust DNA methylation signature. The 520 patients were clustered into a training group (70%, n = 364 samples) and an internal validation group (30%, n = 156). The training group was used for digging a prognostic predictor based on univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) as well as multivariate Cox regression analysis. The internal and external validation group (ICGC OV-AU project) were used for validating the predictive robustness of the predictor based on receiver operating characteristic (ROC) analysis and Kaplan-Meier survival analysis. We identified a 21-DNA methylation signature-based classifier for stage III-IV OC patients' OS. According to ROC analysis in the internal validation, external validation and entire TCGA set, we proved the high power of the 21-DNA methylation signature for predicting OS (area under the curve [AUC] at 1, 3, 5 years in internal validation set (0.782, 0.739, 0.777, respectively), external validation set (0.828, 0.760, 0.741, respectively), entire TCGA set (0.741, 0.748, 0.781, respectively). Besides, a nomogram was developed via methylation risk score as well as a few clinical variables, and the result showed a high ability of the predictive nomogram. In summary, we used integrated bioinformatics approaches to successfully identified a DNA methylation-associated nomogram, which can predict effectively the OS of patients with stage III to IV OC.

Development of a Pocket Nomogram to Predict Cancer and Disease Specific Survival After Radical Cystectomy For Bladder Cancer: The CRAB Nomogram.

To develop an easy tool to predict cancer specific (CSS) and disease-free survival (DFS) in patients with bladder cancer treated with radical cystectomy. Data from a consecutive series of 2395 patients with primitive or progression to muscle invasive bladder cancer (MIBC) undergone to radical cystectomy and lymph nodes dissection in 5 centers were evaluated. Using Cox proportional hazards analyses, the Cancer of the bladder risk assessment (CRAB) nomogram was generated. Accuracy of the nomogram was evaluated by Harrell's C test. Internal validation of the model was performed using 200 bootstraps. Median age was 66 (IQR 58/73) years; 612/2395 (26%) patients presented an advanced pathological stage (≥pT3a); 478/2395 (20%) presented positive lymph nodes. Overall, 729/2395 (30%) presented local or distant recurrence with a median DFS of 42 (IQR 14/89) months. Overall, 642/2395 (27%) died of bladder cancer with a median follow up of 48 (IQR 22/92) months. On univariate Cox proportional hazards analyses, age, stage, and lymph nodes density were a significant predictor of 3 and5 years CSS and DFS. Accuracy of the CRAB nomogram was 0.73 and 0.71 respectively. CRAB nomogram can be a practical and easily applicable tool that may help urologists to classify the long-term CSS and DFS of patients treated with radical cystectomy and to predict the oncological outcome.

The impact of race on outcomes following ruptured abdominal aortic aneurysm repair

ObjectivesRacial differences in elective abdominal aortic aneurysm (AAA) repair outcomes have been previously reported; however, data on racial differences in ruptured AAA (rAAA) repair outcomes remain limited. This study assessed in-hospital and long-term mortality after rAAA repair in Black versus White patients. MethodsThe Vascular Quality Initiative database was queried to identify all Black and White patients who underwent open or endovascular rAAA repair between 2003 and 2019. Baseline demographic and clinical characteristics were recorded, and independent t test and χ2 test were performed to assess differences between groups. In-hospital and 8-year mortality rates were the primary outcomes. Univariate and multivariate logistic regression and Cox proportional hazards analyses were conducted to analyze associations between race and outcomes. ResultsOverall, 310 Black patients and 4679 White patients underwent rAAA repair. A greater proportion of Black patients underwent endovascular repair (73.2% vs 56.1%). Black patients had a lower mean age and were more likely to be female, with a greater proportion being Medicaid insured (9.7% vs 2.1%) or uninsured (4.8% vs 3.3%). Although Black patients were more likely to be current smokers and have hypertension, diabetes, and congestive heart failure, they were not more likely to receive risk reduction medications. The time from symptom onset to incision or access was higher for Black patients (median, 12.0 hours vs 7.0 hours). Similarly, the time from hospital admission to intervention was higher for Black patients (median, 2.8 hours vs 1.3 hours). In-hospital mortality was lower in Black patients (20.0% vs 28.6%; odds ratio [OR], 0.63; 95% confidence interval [CI], 0.47-0.83); however, this did not persist after adjusting for baseline characteristics (adjusted OR, 0.58; 95% CI, 0.30-1.07; P = .09). Furthermore, the 8-year survival was not different between groups (50.4% vs 46.6%; hazard ratio, 0.85; 95% CI, 0.57-1.26; P = .42), even when stratified by repair type. ConclusionsThis study identified racial differences in demographic, clinical, and procedural characteristics for patients undergoing rAAA repair. In particular, the door-to-intervention time for Black patients of 2.8 hours does not meet the Society for Vascular Surgery recommendation of 90 minutes. Despite these differences, the 8-year mortality is similar for Black and White patients. These differences should be investigated further, and there are opportunities to improve rAAA care for Black patients.

Effect of metformin on outcomes of patients treated with immune checkpoint inhibitors: a retrospective cohort study.

Immune checkpoint inhibitors have transformed the treatment landscape of cancer treatment, but only a fraction of patients responds to treatment, leading to an increasing effort to repurpose clinically approved medications to augment ICI therapy. Metformin has been associated with improved survival outcomes in patients undergoing conventional chemotherapy. However, whether metformin provides survival benefits in patients receiving immune checkpoint inhibitors (ICIs) is unknown. We performed a retrospective cohort study at two tertiary referral centers in Taiwan. All adult diabetes mellitus patients who were treated with ICIs between January 2015 and December 2021 were included. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. In total, 878 patients were enrolled in our study, of which 86 patients used metformin and 78 patients used non-metformin diabetes medications. Compared with non-users, metformin users had a longer median OS (15.4 [IQR 5.6-not reached] vs. 6.1 [IQR, 0.8-21.0] months, P = 0.003) and PFS (5.1 [IQR 2.0-14.3] vs. 1.9 [IQR 0.7-8.6] months, P = 0.041). In a univariate Cox proportional hazard analysis, the use of metformin was associated with a reduction in the risk of mortality (HR: 0.53 [95% confidence interval: 0.35-0.81], P = 0.004) and disease progression (HR: 0.69 [95% CI 0.49-0.99], P = 0.042). The use of metformin remained associated with a lower risk of mortality after adjusting for baseline variables such as age, cancer stage, and underlying comorbidities (OS, HR: 0.55 [95% CI 0.34-0.87], P = 0.011). Similarly, the use of metformin was associated with a lower risk of disease progression. Importantly, the use of metformin before ICI initiation was not associated with a reduction in mortality (HR: 0.61 [95% CI 0.27-1.42], P = 0.25) or disease progression (HR: 0.69 [95% CI 0.33-1.43], P = 0.32). The use of metformin is associated with survival benefits in patients undergoing immunotherapy. Prospective clinical trials are warranted to define the role of metformin in augmenting immunotherapy.

LGALS1 was related to the prognosis of clear cell renal cell carcinoma identified by weighted correlation gene network analysis combined with differential gene expression analysis.

Understanding the molecular mechanism of clear cell renal cell carcinoma (ccRCC) is essential for predicting the prognosis and developing new targeted therapies. Our study is to identify hub genes related to ccRCC and to further analyze its prognostic significance. The ccRCC gene expression profiles of GSE46699 from the Gene Expression Omnibus (GEO) database and datasets from the Cancer Genome Atlas Database The Cancer Genome Atlas were used for the Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis. We screened out 397 overlapping genes from the four sets of results, and then performed Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways. In addition, the protein-protein interaction (PPI) network of 397 overlapping genes was mapped using the STRING database. We identified ten hub genes (KNG1, TIMP1, ALB, C3, GPC3, VCAN, P4HB, CHGB, LGALS1, EGF) using the CytoHubba plugin of Cytoscape based on the Maximal Clique Centrality (MCC) score. According to Kaplan-Meier survival analysis, higher expression of LGALS1 and TIMP1 was related to poorer overall survival (OS) in patients with ccRCC. Univariate and multivariate Cox proportional hazard analysis showed that the expression of LGALS1 was an independent risk factor for poor prognosis. Moreover, the higher the clinical grade and stage of ccRCC, the higher the expression of LGALS1. LGALS1 may play an important role in developing ccRCC and may be potential a biomarker for prognosis and treatment targets.

Clinical significance of prognostic nutritional index in myelodysplastic syndrome

ABSTRACTBackgroundPrognostic nutritional index has been found to be related to the clinical outcomes of patients with cancer. However, its role in myelodysplastic syndromes (MDS) patients is unclear. We aimed to assess the value of nutritional status in predicting the prognosis of MDS patients.MethodsTotally 121 MDS patients were analyzed retrospectively. The prognostic nutritional index (PNI) was used to assess nutritional status of the patients. The bio-informatics tool X-tile was used to define the threshold, and accordingly patients were divided into PNIlow and PNIhigh groups, the characteristics were compared between two groups.ResultsThe PNIhigh was associated with better OS (Overall Survival) than PNIlow in MDS patients (Median OS, 28.03 months versus 19.63 months, P = 0.0205). But there were no statistical differences in PFS (Progression-Free-Survival) between the two groups (P = 0.9373). The univariable and multivariable COX proportional hazard analysis adjusted for age, gender, platelet count, HB level and IPSS-R scores, and the results showed that PNI is a useful index in the evaluation of the OS of MDS (HR 0.588, 95%CI 0.374–0.926, P = 0.024).ConclusionPNI would be a simple and immediately available tool for predicting the prognosis of MDS.

Whether Renal Pathology Is an Independent Predictor for End-Stage Renal Disease in Diabetic Kidney Disease Patients with Nephrotic Range Proteinuria: A Biopsy-Based Study.

Aims: To investigate whether renal pathology is an independent predictor for end-stage renal disease (ESRD) in diabetic kidney diseases (DKD) with nephrotic range proteinuria. Methods: A total of 199 DKD patients with nephrotic range proteinuria underwent renal biopsy and were divided into an ESRD group and a non-ESRD group. A Kaplan−Meier analysis was used to compare renal survival rate, and univariate and multivariate Cox proportional hazard analyses were used to determine the predictors of the ESRD. Results: The mean age of included patients was 51.49 ± 9.12 years and 113 patients (56.8%) progressed to ESRD. The median follow-up period was 16 (12−28) months. The glomerular pathology class III is the most common type (54.3%). In the Kaplan−Meier analysis, compared with patients without ESRD, patients with ESRD had a longer duration of diabetes (≥6 years), lower eGFR (<60 mL/min/1.73 m2), lower albumin (<30 g/L), lower hemoglobin (<120 g/L), and a higher grade of glomerular stage (class III + IV vs. class I + II) (p < 0.05). The hemoglobin and e-GFR, but not the histopathological damage, were significantly associated with a higher risk of ESRD in both the univariate and multivariate Cox analyses. Conclusions: In patients with diabetic kidney disease characterized by nephrotic range proteinuria, histopathological damage (glomerular alterations, interstitial fibrosis and tubular atrophy (IFTA), interstitial inflammation, and arteriolar hyalinosis) is not associated with poor renal outcomes, but hemoglobin and e-GFR could predict poor renal outcomes.

Tumor stiffness measurement using magnetic resonance elastography can predict recurrence and survival after curative resection of hepatocellular carcinoma

BackgroundTumor stiffness measurement using magnetic resonance elastography can assess tumor mechanical properties and predict hepatocellular carcinoma recurrence. This study aimed to investigate preoperative tumor stiffness on magnetic resonance elastography as a predictor of overall survival and recurrence-free survival in patients with solitary nodular hepatocellular carcinoma who underwent curative resection. MethodsSeventy-eight patients with solitary nodular hepatocellular carcinoma who underwent preoperative magnetic resonance elastography and curative resection were retrospectively analyzed. Potential associations of tumor stiffness and other clinicopathological variables with overall survival and recurrence-free survival were analyzed in both univariate and multivariate Cox proportional hazards analyses. The optimal tumor stiffness cutoff value was determined using the minimal P value approach. ResultsIn multivariate analysis, tumor stiffness (hazard ratio 1.31; 95% confidence interval, 1.07–1.59; P = .008) and vascular invasion (hazard ratio 2.62; 95% confidence interval, 1.27–5.17; P = .010) were independent predictors of recurrence-free survival. For overall survival, tumor stiffness (hazard ratio, 1.33; 95% confidence interval, 1.02–1.76; P = .037) was the only independent predictor. The optimal tumor stiffness cutoff value was 5.81 kPa for both overall survival and recurrence-free survival. Patients with tumor stiffness ≥5.81 kPa had a significantly greater risk of death (hazard ratio 6.10; 95% confidence interval, 2.11–21.90; P < .001) than those with tumor stiffness <5.81 kPa. ConclusionPreoperative tumor stiffness as measured by magnetic resonance elastography was a predictor of overall survival and recurrence-free survival in hepatocellular carcinoma patients who underwent curative resection. Higher tumor stiffness was associated with higher risk of recurrence and death.

Post-treatment serum triglyceride: An effective biomarker for body fat mass and overall survival in esophageal squamous cell cancer patients treated with chemoradiotherapy.

Although lipids have been assessed for their possible roles in cancer survival prediction, studies on the association between serum triglyceride (TG) levels and the prognosis of esophageal squamous cell carcinoma (ESCC) patients are limited. This study aimed to evaluate whether serum TG is associated with outcomes in patients with ESCC and investigate any interaction between serum TG and clinical parameters, especially body fat mass. We conducted a prospective case study on patients diagnosed with ESCC between March 2012 and November 2018. We measured patients' serum TG levels before and after treatment. The association between serum TG and overall survival (OS) was evaluated using hazard ratios. We sought to determine a threshold point using optimal stratification. Survival analysis was performed using Kaplan-Meier curves and a Cox proportional hazards model. Of the 257 participants diagnosed with ESCC, 200 (77.8%) were men. Median follow-up time was 22.4 months (range 3.3-92.4 months). Using univariate Cox proportional hazard analysis and subsequent multivariate analysis, post-TG levels, Karnofsky performance scores, T stages, and chemotherapy cycles were shown to be independent prognostic factors for OS (p < 0.05). The post-TG cut-off point to best classify patients with respect to time to mortality was 1.47 mmol/L. A post-TG level of ≥ 1.47 mmol/L could independently predict a better OS (hazard ratio: 0.55, 95% confidence interval: 0.37-0.79). The associations were consistent across the subtypes of clinical parameters. Furthermore, the post-body mass index, post-subcutaneous adipose tissue area, post-visceral adipose tissue area, post-total adiposity tissue area, and post-total adipose density exhibited a strong positive association with post-TG levels. Post-TG levels were found to be a significant positive prognostic biomarker for body fat mass and OS in ESCC patients.

A six lipid metabolism related gene signature for predicting the prognosis of hepatocellular carcinoma

Globally, hepatocellular carcinoma (HCC) is one of the most lethal malignant tumors. Studies have shown that alterations in the tumor immune microenvironment (TIME) play a significant role in the pathogenesis and progression of HCC, and notably, lipid metabolism has been shown to regulate TIME. Therefore, in predicting the prognosis and efficacy of immunotherapy in patients with HCC, lipid metabolism-related prognostic factors are highly relevant. mRNA expression data of HCC were obtained from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and gene expression omnibus (GEO) databases. and lipid metabolism-related genes were also obtained from the GSEA databases. Least absolute shrinkage and selection operator regression analysis, univariate and multivariate Cox proportional hazards analysis were used to explore lipid metabolism-related prognostic genes and further construct a prognostic signature in the training set, ICGC and GSE54236 were used to validate the accuracy of the signature. qRT-PCR was used to detect the mRNA levels of lipid metabolism-related prognostic genes in HCC tissues and their paired adjacent tissues. Nile red staining was used to demonstrate lipid content in HCC tissues. Immunofluores-cence and ELISA were used to detect immune cells and immune responses in HCC tissues and serum. Six lipid metabolism-related genes (ADH1C, APEX1, ME1, S100A10, ACACA and CYP2C9) were identified as independent prognostic factors, which were used for risk model construction for HCC patients. The areas under the 1-, 2-, and 3-year ROC curves for the TCGA cohort were 0.758, 0.701 and 0.671, respectively. Compared with paired paracancerous tissues, qRT-PCR revealed that APEX1, ME1, S100A10 and ACACA were up-regulated in HCC tissues, whereas ADH1C and CYP2C9 were down-regulated in HCC tissues. Nile red staining indicated that this study showed that both the HCC tissue and serum of patients in the high-risk group exhibited lipid accumulation. Our identified prognostic model comprising six lipid metabolism-related genes could provide survival prediction. Moreover, HCC drug therapy target selection and molecular marker research can be guided by our predictive model.

Prognostic value of desmoplastic stromal reaction, tumor budding and tumor-stroma ratio in stage II colorectal cancer

Existing high-risk factors are insufficient to accurately predict the postoperative recurrence risk of stage II colorectal cancer (CRC). The discovery of additional prognostic markers may be the key to improving the current status of stage II CRC treatment. The present study aimed to evaluate the relationship among desmoplastic reaction (DR), tumor budding (TBd), the tumor-stroma ratio (TSR) and their prognostic value for relapse-free survival (RFS). In this study, 207 patients with histologically confirmed stage II CRC from January 2012 to August 2018 were retrospectively reviewed from a single center; the cohort was divided into subgroups based on low or high TSR, and low, intermediate or high DR and TBd. Kaplan-Meier curve analysis and log-rank test were applied to examine RFS among subgroups. Univariate and multivariate Cox proportional hazards analyses were used to identify independent factors associated with RFS, and a nomogram was subsequently developed. Abnormal CA242, CEA, T4 stage, presence of hypertension, internal obstruction or perforation (IOP), lymphovascular or/and perineural invasion (PNI), number of nodes examined less than 12, low-frequency microsatellite instability (MSI-L), higher Ki-67 and immature DR were associated with a lower RFS. In multivariable analysis, DR (HR =2.111; 95% CI: 1.184-3.766; P=0.011), LVI (HR =1.919; 95% CI: 1.004-3.669; P=0.049) and PNI (HR =2.724; 95% CI: 1.362-5.448; P=0.005) were prognostic factors for RFS. On this basis, a nomogram that integrated DR and clinicopathologic predictors for predicting RFS passed the calibration and had an area under the curve of 0.826. The prognostic significance of DR outperformed TBd and TSR, therefore, we recommend adding DR as a biomarker in routine pathological reports. The novel nomogram combining these factors may be used as a reliable and effective tool for the prediction of RFS in stage II CRC, thus helping optimize therapeutic regimens under cooperation of oncologists and surgeons. Further multicentric studies are required for validation of this novel, simple and cost-effective prognostic model.

Clinical impact of number of lymph nodes dissected on postoperative survival in node-negative small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal histologic subtype of lung cancer. Although the Commission on Cancer recommends pathological examination of at least 10 lymph nodes dissected (LNDs) for resected early-stage non-small cell lung cancer, its survival benefit of LNDs in patients with early-stage SCLC is unknown. The National Cancer Database was queried for SCLC patients with clinical stage I-II and clinical N0, NX disease per AJCC 7th edition who had undergone lobectomy between 2004 and 2017. Overall survival of SCLC patients by the number of LNDs was compared using Log-rank tests. Univariate and multivariable Cox proportional hazards analyses were performed. In total, 688 (42%), 311 (20%), 247 (16%), 196 (12%), 126 (8%), and 36 (2%) of 1,584 patients with early-stage SCLC had ≥10, 7-9, 5-6, 3-4, 1-2, and 0 LNDs, respectively. The sequential improvement in the HRs was no longer evident if the number of LNDs exceeds 4. Patients with ≥3 LNDs (n = 1,422) had a significantly longer overall survival than those with <3 LNDs (n = 162) (hazard ratio for death: 0.76, 95% confidence interval: 0.62-0.94, P = 0.0087). Multivariate analysis revealed that ≥3 LNDs was an independent factor for predicting overall survival (hazard ratio for death: 0.76, 95% confidence interval: 0.61-0.93, P = 0.0083). Although we are reluctant to recommend a definitive "optimal number" of LNDs, our findings suggest the prognostic and therapeutic roles for performing ≥3 LNDs in patients with early-stage SCLC who undergo lobectomy.

Identification of Key microRNAs As Predictive Biomarkers of Nilotinib Response in Chronic Myeloid Leukemia: A Sub-Analysis of the Enestxtnd Clinical Trial

Despite the effectiveness of tyrosine kinase inhibitors (TKIs) against chronic myeloid leukemia (CML), acquired drug resistance often leads to relapse. CML has unique microRNA (miRNA) expression profiles at different disease stages and in response to TKI-treatment. However, the predictive utility of miRNAs is not yet conclusive and there is a need to identify key biomarkers for prognostic tools to be used in the clinic. We have recently generated global transcriptome profiles on treatment-naïve CD34+ CML cells with known subsequent imatinib (IM) responses and identified several differentially expressed miRNAs, including miR-185 and miR-145, in IM-nonresponders as compared to IM-responders. We also reported that IM response could be predicted in treatment-naïve CD34+ cells by an in vitro colony forming cell (CFC) assay. In this study, we evaluated miRNA expression changes in CD34+ CML cells pre- and post-nilotinib (NL) therapy from 58 CML patients enrolled in the Canadian sub-analysis of the ENESTxtnd phase IIIb clinical trial and assessed a potential correlation between miRNA expression and sensitivity of CD34+ cells to TKIs in CFC assays, to predict NL response in these patients. CFC assays were performed by plating pre-treated CD34+ cells with methylcellulose-medium ± Imatinib (IM), NL and Dasatinib (DA) and showed that only NL was able to differentiate responses between NL-responders and NL-nonresponders (p=0.011) and predict NL response (p=0.00016) based on calculated cutoffs. Microfluidic qRT-PCR and a univariate Cox proportional hazard (CoxPH) analysis on miRNA expression profiles were then performed in CD34+cells obtained at diagnosis (BL), 1-month (M1) and 3-month post-NL treatment (M3) from 58 CML patients; this showed that 17 out of 47 miRNAs examined were significantly associated with NL response (p<0.05). Further Welch t-test analysis revealed that nine of these miRNAs were differentially expressed between NL-responders and NL-nonresponders. These miRNA candidates were then subject to a multivariate CoxPH analysis ± CFC assay data from each patient, which demonstrated that miR-145 (p=0.013) and miR-708 (p=0.009) together could improve predictive power at the BL state. Additionally, receiver-operating-characteristic (ROC) and precision-recall (PR) area-under-curve (AUC) values (1.2-fold) of performance plots generated by random forest (RF) and Naïve-Bayes (NB) machine learning algorithms were increased in this multivariate panel compared to individual miRNA variables. At M1 and M3, four miRNAs were found to be stably associated with NL response individually and a combination of miR-150 (M1 p<0.001, M3 p=0.01) and miR-185 (M1 p=0.009, M3 p=0.01) was significantly associated with treatment response in multivariate CoxPH analysis. Again, the multivariate analysis improved ROC and PR AUC values, especially for miR-185 (1.2 to 2-fold). Most interestingly, incorporation of NL-CFC output consistently increased AUC values up to 2-fold at both BL and M1/M3 time points that enhanced predictive performance. Together, these findings offer two predictive models for NL response in treatment-naïve or post-treatment CML patients, which could be developed into prognostic biomarkers. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autologous Hematopoietic Cell Transplant Consolidation for First Response Is Associated with Longer Survival in Patients with Nodal Peripheral T-Cell Lymphoma

Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of T-cell lymphoma generally characterized by aggressive behaviors. Nodal PTCL encompasses four major subtypes, PTCL-NOS, angioimmunoblastic T cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), ALK-positive (pos) or ALK-negative (neg). The role of autologous hematopoietic cell transplant (auto HCT) during the first response post upfront chemotherapy in nodal-PTCL is still debated. The largest prospective cohort trial (COMPLETE) showed that overall survival (OS) was not statistically different between auto HCT during the first remission compared to nontransplant at the median follow-up of 2.8 years (Park et al. Cancer 2019). This study aims to compare the survival outcomes of patients who received auto HCT to those who did not receive auto HCT during the first response in nodal PTCL. Methods We retrospectively reviewed clinical data on 133 patients at Moffitt Cancer Center who achieved complete response (CR) or partial response (PR) after receiving upfront chemotherapy from 2/2005 to 3/2021. Patients who had stable or progressive disease after the first course of chemotherapy were excluded. Clinical data were abstracted in accordance with institutional review board-approved protocol. Patients were divided into two subgroups: cohort A) patients who received auto HCT during the first response and cohort B) patients who did not receive auto HCT during the first response. The baseline clinical data of two cohorts were summarized using descriptive statistics and compared using Kruskal-Wallis tests for continuous variables and Chi-squared tests for categorical variables. Overall survival (OS) was calculated from the start date of upfront chemotherapy to death or censored to the last follow-up. Median OS (mOS) was calculated using the Kaplan Meier method and compared two cohorts with a log-rank test. Univariate and multivariate COX proportional hazard (PH) analysis was used to evaluate the association of OS. Results Out of 133 patients, 81 (61%) patients were assigned to cohort A. The remaining 52 (39%) patients in cohort B included 30 patients who received auto HCT at CR2 or higher and 22 patients who did not undergo HCT. Of the whole cohort, more than half of the patients (62%) had intermediate-risk diseases based on IPI. The histology subtype included 4% ALK-pos ALCL, 17% ALK-neg ALCL, 48% PTCL-NOS, and 21% AITL. Most patients (83%) in our cohort received CHOP-based therapy upfront and 86% of patients achieved CR after upfront chemotherapy. Clinical characteristics were not significantly different between the two cohorts (table 1). The mOS for patients in cohort A (auto HCT in CR1/PR1) was significantly higher than cohort B (mOS: not reached [95% CI: 60-131 months] for cohort A, and 70 months [95% CI: 39-101 months] for cohort B, p=0.038). The 3-year OS rate in cohort A was 73% as compared to 43% in cohort B (p=0.18). In the univariate analysis, receiving auto HCT during CR1/PR1 was associated with a hazard ratio (HR) of 0.580 (p=0.042). When adjusted for age at diagnosis, sex, histology subtype, types of induction therapy, and response after upfront chemotherapy in the multivariate analysis, receiving auto HCT during CR1/PR1 remained a favorable factor for survival with an HR of 0.52 (p=0.02). Among 26 patients who died in cohort A at the study cut-off time, 14 patients (54%) died from relapsed PTCL post auto HCT. Conclusion Our data showed that auto HCT during the first response was associated with longer survival in transplant-eligible patients with nodal PTCL who achieved CR or PR after first-line chemotherapy. This is despite the fact that 57% of the patients in cohort B received an auto HCT at a later time. Our results highlight a benefit to performing auto HCT during first remission instead of later in the disease course. Large studies are needed to validate our conclusion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 10222: Impact of Bleeding Event for New Cancer Diagnosis in Patients With Antiplatelet Therapy After Percutaneous Coronary Intervention

Background: It has been reported that the bleeding event represents unmasking of an occult cancer in anticoagulated patients with atrial fibrillation. However, the impact of bleeding event in patients with antiplatelet therapy after percutaneous coronary intervention (PCI) for new cancer diagnosis remains unclear. Methods and Results: Consecutive 1796 patients with coronary artery disease who underwent PCI and taking antiplatelet therapy were enrolled. Patients taking oral anticoagulants were excluded, and relationships between bleeding event and new cancer diagnosis were examined. Among 1565 patients, 189 (12.0%) experienced any bleeding events defined as Bleeding Academic Research Consortium (BARC) type-2/3/5 bleeding, 78 (4.9%) experienced minor bleeding events defined as BARC type-2 bleeding, and 116 (7.4%) were diagnosed with new cancer during a mean follow-up period of 1528 days. Patients with any bleeding were older (71.3 vs. 68.8 years, P = 0.005) and had higher prevalence of being at Academic Research Consortium criteria for high bleeding risk (62.4% vs. 43.8%, P &amp;lt; 0.001) than those without bleeding event. Of 189 patients with any bleeding and 78 patients with minor bleeding events, 31 (16.4%) and 16 (20.5%) were diagnosed with new cancer, respectively. In the univariate Cox proportional hazard analysis, the incidence of new cancer diagnosis was higher in patients with any bleeding and minor bleeding events than those without bleeding event (hazard ratio [HR] 3.19, P &amp;lt; 0.001 and HR 5.70, P &amp;lt; 0.001, respectively). In the multivariate analysis after adjusting for confounding factors, any bleeding and minor bleeding events were the independent predictors of new cancer diagnosis (HR 2.27, P = 0.003 and HR 3.93, P &amp;lt; 0.001, respectively). In addition, any gastrointestinal bleeding and minor bleeding events were associated with higher rates of new gastrointestinal cancer diagnosis (HR 4.46, P = 0.041 and HR 6.73, P = 0.009, respectively). Conclusion: In patients with antiplatelet therapy after PCI, any bleeding and minor bleeding events were associated with subsequent new cancer diagnosis. Even minor bleeding should be taken care as the first manifestation of underlying cancer during antiplatelet therapy.

Abstract 11434: Soluble Programed Cell Death Ligand-1 is Associated With Future Heart Failure Hospitalization in Patients With Atherosclerotic Cardiovascular Disease

&lt;Background&gt; Heart failure following atherosclerotic cardiovascular disease (ASCVD) is a significant problem worldwide. Chronic inflammation is a crucial pathogenesis both in heart failure and ASCVD. Programmed cell death-1(PD-1) and its ligand (PD-L1) regulate immune response through T cell proliferation and secretion of cytokines as immune checkpoint protein. However, the prognostic significance of immune checkpoint protein on ASCVD and heart failure is unknown. We investigated the association between the serum levels of PD-L1 (sPD-L1) and heart failure-related events in patients with ASCVD. &lt;Methods&gt; We prospectively measured sPD-L1 using a commercially available enzyme-linked immunosorbent assay kit in patients with ASCVD admitted to Kumamoto University Hospital. The occurrence of cardiovascular events was observed between December 2017 and January 2020. The primary outcome was heart failure hospitalization. We excluded patients complicated with cancer, hemodialysis, active collagen diseases, and inflammatory diseases. &lt;Results&gt; We screened 792 patients with ASCVD. 200 patients met exclusion criteria. Finally, 592 patients with ASCVD were enrolled. Median follow-up period was 490 days. A total of 37 events were recorded during study period. Kaplan-Meier curve revealed that the higher sPD-L1 group (sPD-L1≧136pg/dL, median) showed significantly higher rate of heart failure hospitalization than the lower sPD-L1 group (9.1% vs. 3.4%, log-rank test: P =0.006). Univariate Cox proportional hazards analysis identified estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP), and higher sPD-L1 as significant factors associated with heart failure hospitalization. Multivariable Cox proportional hazards analysis by significant factors from univariate analysis identified that higher sPD-L1 [hazard ratio (HR): 1.003, 95% confidence interval (CI): 1.000-1.005, P =0.042) and BNP (HR: 1.001, 95% CI: 1.000-1.001, P =0.007)] were significantly and independently associated with heart failure hospitalization. &lt;Conclusion&gt; The higher levels of sPD-L1 were significantly associated with future heart failure hospitalization in patients with ASCVD.

Abstract 10314: Clinical Impact of C-Reactive Protein to Albumin Ratio on Prognosis in Patients With Stable Coronary Artery Disease After Percutaneous Coronary Intervention

Background : The C-reactive protein/albumin (CRP/Alb) ratio is known to be a novel marker of inflammation and is associated with outcome in septic patients. However, the effect of CRP/Alb ratio for clinical outcomes in patients with stable coronary artery disease (CAD) after percutaneous coronary intervention (PCI) has not been well evaluated. Methods : The subject comprised 500 consecutive stable angina patients who underwent successfully elective PCI using second-generation drug-eluting stents and intravascular ultrasound. We investigated between the clinical factors including CRP/Alb ratio and the incidences of both all-cause death and major cardiovascular and cerebrovascular events (MACCE). Results: Median of age was 69 years (62-76) and 356 cases (71%) were male. Thirty-seven patients (7%) died after PCI, and the incidence of MACCE including all-cause death was 47 cases (9%). Age, dyslipidemia, hemodialysis, statin use , estimated glomerular filtration rate and CRP/Alb ratio correlated significantly with all-cause death and MACCEin the univariate cox proportional hazards analysis. A multivariate Cox proportional hazards regression analysis modeling relevant factors from univariate analysis showed CRP/Alb ratio was significantly associated with both all-cause death (HR: 1.24, 95%CI: 1.11-1.35, p&lt;0.001) and MACCE (HR: 1.21, 95%CI: 1.09-1.32, p&lt;0.001). The optimal cut-off on the receiver-operating characteristic curve of CRP/Alb ratio for predicting for all-cause death and MACCE were both 0.30 [all-cause death; the area under the curve (AUC) = 0.75, Sensitivity = 57%, Specificity = 87%, p&lt;0.001 and MACCE; AUC = 0.73, Sensitivity = 49%, Specificity = 87%, p&lt;0.001). Kaplan-Meier analysis showed a significantly lower survival rate after PCI in low CRP/Alb ratio (&lt; 0.30) group than high CRP/Alb ratio (≥ 0.30) group (p&lt;0.001). Similarly, cumulative incidence of MACCE was significantly higher in the high CRP/Alb ratio group than in the low CRP/Alb ratio group (p&lt;0.001). Conclusion: The CRP/Alb ratio may have a potential for predicting the all-cause death and MACCE in patients with stable CAD after PCI.