Non-linear and Interaction Analyses of Biomarkers for Organ Dysfunctions as Predictive Markers for Sepsis: A Nationwide Retrospective Study

The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated. This retrospective observational study used a large-scale database containing about 30 million patients. Among them, we included 38,869 adult patients with sepsis from 2006 to 2019. The cardiovascular and neurological subscores were calculated by a modified method. Associations between the biomarkers of the SOFA components and mortality were examined using restricted cubic spline analyses, which showed that an increase in the total modified SOFA score was linearly associated with increased mortality. However, the prognostic association of subscores varied widely: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association. We also evaluated interaction effects on mortality between an increase of one subscore and another. The joint odds ratios on mortality of two modified SOFA subscores were synergistically increased compared to the sum of the single odds ratios, especially in cardiovascular-neurological, coagulation-hepatic, and renal-hepatic combinations. In conclusion, total modified SOFA score was associated with increased mortality despite the varied prognostic associations of the subscores, possibly because interactions between subscores synergistically enhanced prognostic accuracy.

Non-Linear And Cross-Interaction Analyses of SOFA Subscores As Predictive Markers For Sepsis: A Nationwide Retrospective Study

Background: The Sequential Organ Failure Assessment (SOFA) score is predominantly used to assess the severity of organ dysfunction in sepsis and is definitely proved to be associated with mortality. However, differences in prognostic value between SOFA subscores have not been sufficiently evaluated so far, and detailed evaluation of subscores is required to verify the clinical significance of the SOFA score. The present study aimed to evaluate the non-linear prognostic association of SOFA subscores and the cross-interaction effects on mortality when SOFA subscores were simultaneously increased.Methods: This retrospective observational study used a part of a large-scale database containing about 30 million patients. Among them, we included all adult patients requiring unplanned hospital admission and were diagnosed as having sepsis by Sepsis-3 criteria from February 2006 to December 2019. A proven/suspected infection was defined as having any of the ICD-10 codes for infection. Associations between the SOFA components and in-hospital mortality were examined using linear and non-linear logistic regression analyses. We also evaluated two-way interaction effects on mortality between an increase of one SOFA subscore and another.Results: The final study cohort included 38,869 patients with sepsis. Restricted cubic spline analyses showed that an increase in total SOFA score was sharply and linearly associated with increased mortality. However, the prognostic association of SOFA subscores was non-linear and varied widely by biomarker: platelet count showed a J-shaped association, creatinine showed an inverted J-shaped association, and bilirubin showed only a weak association with mortality. The mortality odds ratios of SOFA scores were synergistically increased when another SOFA subscore was higher than 2 points, and the effect modifications were statistically significant in almost all subgroups. Especially in patients with cardiovascular or hepatic subscores of ≥ 2 points, odds ratios of the other SOFA subscores were remarkably increased (double to triple) compared to those in the whole study population.Conclusion: Despite the widely varied prognostic associations of SOFA subscores, total SOFA score was sharply and almost linearly associated with increased mortality. Cross-interactions between subscores synergistically enhanced its prognostic associations and might be responsible for the high prognostic accuracy of the total SOFA score.

Clinicopathologic and Prognostic Association of GRP94 Expression in Colorectal Cancer with Synchronous and Metachronous Metastases

Patients with advanced colorectal cancer (CRC) with distant metastases have a poor prognosis. We evaluated the clinicopathological relevance of GRP94 expression in these cases. The immunohistochemical expression of GRP94 was studied in 189 CRC patients with synchronous (SM; n = 123) and metachronous metastases (MM; n = 66), using tissue microarray; the association between GRP94 expression, outcome, and tumor-infiltrating lymphocytes (TILs) was also evaluated. GRP94 was expressed in 64.6% (122/189) patients with CRC; GRP94 positivity was found in 67.5% and 59.1% patients with SM and MM, respectively. In the SM group, high GRP94 expression was more common in patients with a higher density of CD4+ TILs (p = 0.002), unlike in the MM group. Survival analysis showed that patients with GRP94 positivity had significantly favorable survival (p = 0.030); after multivariate analysis, GRP94 only served as an independent prognostic factor (p = 0.034; hazard ratio, 0.581; 95% confidence interval, 0.351–0.961) in the SM group. GRP94 expression was detected in 49.4% of metastatic sites and showed significant heterogeneity between primary and metastatic lesions (p = 0.012). GRP94 is widely expressed in CRC with distant metastases; its expression was associated with favorable prognosis in the SM group, unlike in the MM group.

Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer

Late diagnosis, unreliable prognostic assessment, and poorly-guided therapeutic planning result in dismal survival of ovarian cancer (OC) patients. Therefore, identifying novel functional biomarker(s) is highly desired for improved clinical management. MYB is an oncogenic transcription factor with emerging functional significance in OC. Here we examined its clinicopathologic significance by immunohistochemistry and TCGA/GTex data analyses. Aberrant MYB expression was detected in 94% of OC cases (n = 373), but not in the normal ovarian tissues (n = 23). MYB was overexpressed in all major epithelial OC histological subtypes exhibiting the highest incidence (~ 97%) and overall expression in serous and mucinous carcinomas. MYB expression correlated positively with tumor grades and stages. Moreover, MYB exhibited race-specific prognostic association. Moderate-to-high MYB levels were significantly associated with both poor overall- (p = 0.02) and progression-free (p = 0.02) survival in African American (AA), but not in the Caucasian American (CA) patients. Consistent with immunohistochemistry data, we observed significantly higher MYB transcripts in OC cases (n = 426) than normal ovary (n = 88). MYB transcripts were significantly higher in all epithelial OC subtypes, compared to normal, and its greater levels predicted poor survival in AA OC, but not CA OC, patients. Thus, MYB appears to be a useful clinical biomarker for prognostication, especially in AA patients.

Prognostic Value of Long Non-Coding RNAs MALAT1 in Colorectal Cancer Patients: A Pooled Analysis of Two Cohorts.

Background: Previous researches have shown that the aberrant expression of Metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in tumour tissues may serve as a biomarker for colorectal cancer (CRC) prognosis. However, these previous studies have small sample sizes and lacked validation from independently external populations. We therefore aimed to clarify the prognostic value of MALAT1 expression status in CRC patients using a large cohort and validate the findings with another large external cohort. Methods: The prognostic association between MALAT1 expression status and CRC outcomes was evaluated initially in a prospective cohort in China (n=164) and then validated in an external TCGA population (n=596). In the initial cohort, MALAT1 expression levels were quantified by quantitative reverse transcriptase polymerase chain reaction. Propensity score (PS) adjustment method was used to control potential confounding biases. The prognostic significance was reported as PS-adjusted hazard ratio (HR) and corresponding 95% confidence interval (CI). Results: There was no statistically significant association between MALAT1 expression status and CRC patient overall survival (OS) or disease free survival (DFS) in both initial cohort and external validation cohort populations. When combining these populations together, the results did not change materially. The summarized HRPS-adjusted were 1.010 (95%CI, 0.752-1.355, P=0.950) and 1.170 (95%CI, 0.910-1.502, P=0.220) for OS and DFS, respectively. We performed extensive sensitivity analyses, and demonstrated a very robustness of these results. Conclusions: The MALAT1 expression status was not associated with prognostic outcomes in CRC patients. Our findings did not support a prognostic association of MALAT1 expression with CRC outcomes.

Association Between Tumor Budding Grade and T Stage in Predicting Recurrence in High-risk Stage Ii Colorectal Cancer

In pathological stage (pStage) II colon cancer, factors such as T stage (T) are high-risk features (HRF) for recurrence. The SACURA trial showed that tumor budding (BD) grade was also associated with recurrence: the 5-year recurrence-free survival (RFS) rate was lower in patients in the BD3 group compared with that of other groups. Interestingly, the BD3 group had a higher proportion of patients with T4. We investigated the prognostic association between T4 and BD3 for recurrence in pStage II colorectal cancer (pII-CRC) with HRF. We analyzed pII-CRC patients with HRF between 2013–2018 at our hospital, Japan. Inclusion criteria were as follows: ≥1 HRF [<12 lymph nodes examined (<12LN), lymph/vascular-invasion, perineural-invasion, T, BD, and histologic-type]. We primarily analyzed the relationship between each factor and RFS. Among 2,920 pII-CRC patients, 448 had HRF. Of these, 43 (9.6%) had T4 and 236 (52.7%) had BD3. On initial analysis, <12LN (P=0.0412), tumor location (P=0.0023), T4 (P=0.0023), and BD3 (P=0.0396) were independent prognostic factors for RFS. Among 257 patients with BD3 and/or T4, the 5-year RFS rates were 81.3%, 74.6%, and 66.2% for patients with BD3 (214 patients), T4 (22 patients), and BD3 plus T4 (21 patients), respectively (hazard ratio 3.08, P=0.0079). pII-CRC patients with BD3 plus T4 had poorer prognosis than those with other factors.

Prognostic association between common laboratory tests and overall survival in men with de novo metastatic castration-sensitive prostate cancer: A population-based study.

149 Background: Despite significant advancements in the treatment of metastatic prostate cancer, a validated prognostic tool for patients with de novo metastatic castration-sensitive prostate cancer (mCSPC) is still lacking. Using population-based data from Ontario, Canada, we sought to examine the prognostic association between common laboratory tests and survival for patients with mCSPC. Methods: A population-based cohort of men aged 66 years and older diagnosed with de novo metastatic prostate cancer between 2014-2019 were included. We assessed the association between laboratory tests at the time of cancer diagnosis and overall survival (OS). Utilizing a complete case analysis, we used Cox proportional hazards models to assess the association between these laboratory tests and OS while adjusting for patient and disease characteristics. Results: A total of 3,556 men with de novo mCSPC were included. On multivariable analysis, there were significant associations between OS and neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, albumin, hemoglobin, PSA decrease and PSA nadir <0.1 ng/mL (please see table). Conclusions: Commonly available laboratory tests provide important prognostic information for patients with newly diagnosed mCSPC given demonstrated associations to overall survival. Apart from PSA kinetics, none of these baseline tests were performed in more than 57% of patients indicating underutilization of these low-cost prognostic biomarkers. [Table: see text]