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Predicting and improving the response of rectal cancer to second primary cancers (SPCs) remains an active and challenging field of clinical research. Identifying predictive risk factors for SPCs will help guide more personalized treatment strategies. In this study, we propose that experience data be used as evidence to support patient-oriented decision-making. The proposed model consists of two main components: a pipeline for extraction and classification and a clinical risk assessment. The study includes 4402 patient datasets, including 395 SPC patients, collected from three cancer registry databases at three medical centers; based on literature reviews and discussion with clinical experts, 10 predictive variables were considered risk factors for SPCs. The proposed extraction and classification pipelines that classified patients according to importance were age at diagnosis, chemotherapy, smoking behavior, combined stage group, and sex, as has been proven in previous studies. The C5 method had the highest predicted AUC (84.88%). In addition, the proposed model was associated with a classification pipeline that showed an acceptable testing accuracy of 80.85%, a recall of 79.97%, a specificity of 88.12%, a precision of 85.79%, and an F1 score of 79.88%. Our results indicate that chemotherapy is the most important prognostic risk factor for SPCs in rectal cancer survivors. Furthermore, our decision tree for clinical risk assessment illuminates the possibility of assessing the effectiveness of a combination of these risk factors. This proposed model may provide an essential evaluation and longitudinal change for personalized treatment of rectal cancer survivors in the future. [ABSTRACT FROM AUTHOR]

Objectives: Recently, molecular medicine targeting Folate Receptor Alpha (FOLR1), which mediates intracellular folate uptake and tumor cell proliferation, has been identified in several malignancies. However, the association between FOLR1 expression and rectal cancer remains unclear. Methods: Immunostaining of FOLR1 was performed on biopsy specimens from 172 rectal cancer patients undergoing preoperative chemoradiotherapy (CRT). FOLR1 expression was measured and divided into low (0+-2+) or high (3+-4+) level. Correlations between FOLR1 status and clinicopathologic features, tumor regression grade, disease-specific survival (DSS), local recurrence-free survival, and metastasis-free survival (MeFS) were analyzed, retrospectively. Results: High FOLR1 expression was significantly associated with advanced post-treatment tumor and nodal status (T3-4; N1-2, P =.001), vascular invasion (P =.042), perineural invasion (P =.012), and poor regression change after CRT (P =.001). In uni- and multi-variable survival analysis, FOLR1 overexpression remained a significant predictor of lower DSS (hazard ratio [HR], 2.328; 95% confidence interval [CI], 1.014-5.344; P =.046) and MeFS (HR, 2.177; 95% CI, 1.000-1.1286; P =.050). Conclusion: These results indicate that high FOLR1 status is associated with aggressive tumor behavior, poor response to CRT, and worse survival. Therefore, FOLR1 expression at initial biopsy may be useful in predicting outcomes and also be a target for the exploration of FOLR1-based therapeutic agents. [ABSTRACT FROM AUTHOR]

Purpose: For locally advanced rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) allows tumor downstaging and makes curative radical proctectomy possible. However, we lack a genetic biomarker to predict cancer prognosis or treatment response. We investigated the association between ubiquitin D (UBD) expression and clinical outcomes in rectal cancer patients receiving CCRT. Patients and Methods: We analyzed the genes associated with the protein modification process (GO:0036211) and identified the UBD gene as the most relevant among the top 7 differentially expressed genes associated with CCRT resistance. We collected tissue specimens from 172 rectal cancer patients who had received CCRT followed by a curative proctectomy. We examine the relationship between UBD expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MeFS) and disease-specific survival. Results: Upregulated UBD expression was associated with lower pre-CCRT tumor T stage (P = 0.009), lower post-CCRT tumor T stage (P < 0.001), lower post-CCRT nodal stage (P < 0.001), less vascular invasion (P = 0.015), and better tumor regression (P < 0.001). Using univariate analysis, we found that high UBD expression was correlated with better disease-free survival (DFS) (P < 0.0001), local recurrence-free survival (LRFS) (P < 0.0001) and MeFS (P < 0.0001). Moreover, multivariate analysis demonstrated that high UBD expression was associated with superior DFS (P < 0.001), LRFS (P = 0.01), and MeFS (P = 0.004). Conclusion: UBD upregulation was linked to better clinical prognosis, favorable pathological features, and good treatment response in rectal cancer patients undergoing CCRT. These results suggest UBD is a biomarker for rectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: A lymph node (LN) yield ≥ 12 is required to for accurate determination of nodal status for colorectal cancer but cannot always be achieved after neoadjuvant therapy. This study aims to determine the difference in LN yield from rectal cancer patients treated with and without neoadjuvant therapy and the effects of specific LN yields on survival. Patients and Methods: The study cohort included a total of 4344 rectal cancer patients treated between January 2007 and December 2015, 2260 (52.03%) of whom received neoadjuvant therapy. Data were retrieved from the Taiwan nationwide cancer registry database. The minimum acceptable LN yield below 12 was investigated using the maximum area under the ROC curve. Results: The median LN yield was 12 (8– 17) for patients who received neoadjuvant therapy and 17 (13– 24) for those who did not. The recommended LN yield ≥ 12 was achieved in 82.73% of patients without and 57.96% of those with neoadjuvant therapy (p < 0.0001). Patients with LN yield ≥ 12 had a higher OS probability than did those with LN < 12 (OR, 1.33; 95% CI, 1.06– 1.66; p = 0.0124). However, the predictive accuracy for survival was greater for LN yield ≥ 10 (AUC, 0.7767) than cut-offs of 12, 8, or 6, especially in patients with pathologically-negative nodes (AUC, 0.7660). Conclusion: Neoadjuvant therapy significantly reduces the LN yield in subsequent surgery. A lower yield (LN ≥ 10) may be adequate for nodal evaluation in rectal cancer patients after neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

Background/Aim: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. Methods: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). Results: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). Conclusion: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the prognostic value of cytoplasmic (−C) and nuclear epidermal growth factor receptor (EGFR-N) expression in rectal cancer patients following neoadjuvant concurrent chemoradiotherapy (CCRT). A total of 172 newly diagnosed rectal cancer patients post-neoadjuvant CCRT and curative surgery, treated between January 1998 to December 2008, were included. Pathological tissues used for evaluation were biopsy specimens obtained prior to CCRT, and specimens collected at surgery. EGFR expression in the nucleus and cytoplasm was assessed by immunohistochemistry tests. An intensity of 3+ EGFR reactivity in the cytoplasm (and/or membrane) of tumor cells was defined as overexpression of EGFR-C. The cutoff percentage of immunoreactive tumor cells for EGFR-N overexpression was 50%. Expression levels of EGFR-C and EGFR-N were further analyzed by clinicopathological features for 5-year survival disease-specific survival (DSS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS). The results revealed that 20.9 and 23.3% of the cohort had high EGFR-N and EGFR-C expression, respectively. EGFR-N overexpression was significantly associated with advanced pre-treatment tumor stage (T3 and 4; P=0.017) and post-treatment tumor stage (T3 and 4; P<0.001). In univariate analysis, EGFR-N overexpression was significantly associated with poorer DSS (P=0.0005), MeFS (P=0.0182), and LRFS (P=0.0014). Furthermore, it remained an independent prognosticator of worse DSS [P=0.007, hazard ratio (HR)=2.755] and LRFS (P=0.0164, HR=3.026) in multivariate analysis. Overexpression of EGFR-N, and not EGFR-C, may help identify rectal cancer patients who have an increased risk of local recurrence and poor survival following neoadjuvant CCRT. [ABSTRACT FROM AUTHOR]

Data mining of a public transcriptomic rectal cancer dataset (GSE35452) from the Gene Expression Omnibus, National Center for Biotechnology Information identified the melanophilin (MLPH) gene as the most significant intracellular protein transport-related gene (GO:0006886) associated with a poor response to preoperative chemoradiation. An MLPH immunostain was performed on biopsy specimens from 172 rectal cancer patients receiving preoperative chemoradiation; samples were divided into high- and low-expression groups by H-scores. Subsequently, the correlations between MLPH expression and clinicopathologic features, tumor regression grade, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) were analyzed. MLPH expression was significantly associated with CEA level (p = 0.001), pre-treatment tumor status (p = 0.022), post-treatment tumor status (p < 0.001), post-treatment nodal status (p < 0.001), vascular invasion (p = 0.028), and tumor regression grade (p < 0.001). After uni- and multi-variable analysis of five-year survival, MLPH expression was still associated with lower DSS (hazard ratio (HR), 10.110; 95% confidence interval (CI), 2.178–46.920; p = 0.003) and MeFS (HR, 5.621; 95% CI, 1.762–17.931; p = 0.004). In conclusion, identifying MLPH expression could help to predict the response to chemoradiation and survival, and aid in personal therapeutic modification. [ABSTRACT FROM AUTHOR]

Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now the standard care for patients with advanced rectal cancer. Because a certain proportion of these patients have poor response to CCRT, the risk stratification of survival outcomes needs to be investigated. DNA repair responses in tumor cells can regulate malignant potential and therapy resistance. In this study, we analyzed the clinical significance of principal DNA repair effectors in patients with rectal cancer. We applied data mining for DNA repair pathways in a published transcriptome for rectal cancer cases, and identified that tumors with BRCA2 downregulation correlated with poor response to CCRT. We next examined BRCA2 expression by using immunohistochemistry staining in tumor tissues of 172 patients with rectal cancer. The correlation between BRCA2 expression levels and clinical variables was further analyzed in this rectal cancer cohort. Among clinical and pathological factors, low BRCA2-expression was significantly correlated with higher pre-treatment (Tx) tumor status (P =.013), post-Tx tumor (P <.001) and nodal status (P =.044), vascular invasion (P =.008), and poor tumor regression grades (P <.001). In analyses of survival outcomes, patients with low BRCA2-expression were associated with shorter local recurrence-free survival (LRFS; P =.0005) and disease-specific survival (P =.0269). Multivariate analyses confirmed the independent prognostic value of low BRCA2-expression for shorter LRFS (P =.045, hazard ratio = 4.695). Low BRCA2-expression is a significant predictor for tumors in advanced stages, poor response to CCRT, and shorter survivals in patients with rectal cancer. Poly (adenosine diphosphate-ribose) polymerase inhibitors targeting DNA repair response in cells have demonstrated clinical efficacy in BRCA2 -mutated patients with cancer. Further studies evaluating the efficacy of CCRT combined with these inhibitors in low BRCA2-expressing rectal cancers are encouraged. [ABSTRACT FROM AUTHOR]