Lymphocyte-to-monocyte, platelet-to-albumin and platelet-to-lymphocyte ratios as prognostic biomarkers for neoadjuvant treatment response in rectal cancer patients.

INTRODUCTION: Systemic inflammatory response (SIR) indicators are an emerging category of serum biomarkers with significant potential as prognostic and predictive factors in various types of cancers The primary focus of our study was to determine the prognostic value of the lymphocyte-to-monocyte ratio (LMR), platelet-to-albumin ratio (PLR) and platelet-to-albumin ratio (PAR) in evaluating the response to neoadjuvant treatment for patients with rectal cancer. MATERIALS AND METHODS: We included 99 consecutive patients with rectal cancer which were admitted for surgery in our institution after completing a standard neoadjuvant radio-chemotherapy regimen. Several hematologic parameters, including LMR, PAR and PLR, were calculated by collecting and analyzing blood samples preoperatively. Cases were divided into groups using ROC curve analysis to determine optimal cutoff values for each of the investigated parameters. Treatment response was assessed through histopathological analysis of the resected specimens. RESULTS: PLR values over 215.2 were correlated with the presence of lymph node metastasis. A similar correlation was observed between PAR values over 41.89 and lymph node positivity. A significant correlation was observed between the presence of tumor budding on histopathological analysis and high-PAR values. A statistically significant correlation between a high PLR and a good response to neoadjuvant treatment was determined. CONCLUSIONS: High PLR values may be associated with a more favorable treatment response to neoadjuvant radio-chemotherapy. A high PAR may be associated with unfavorable histopathological characteristics. Further studies on these readily available biomarkers are required in order to validate their clinical utility.

The Role of Circulating Tumor DNA for Management of Patients With Rectal Cancer: Challenges and Opportunities.

ABSTRACT: Recently, organ preservation with total neoadjuvant therapy resulted in substantial progress in the management of locally advanced rectal cancer (LARC). The PROSPECT trial showed noninferiority of de-escalation of radiotherapy for patients with low-risk LARC who do not need abdominoperineal resection. Although these escalation and de-escalation approaches offer more personalized therapeutic approaches, the current state of care for patients with rectal cancer is far from individualized management. Circulating tumor DNA (ctDNA) is known to be one of the most powerful prognostic factors for early relapse and has been investigated in several interventional clinical trials to offer more precise treatment algorithms. In this review article, we discuss recent updates from studies examining the role of ctDNA for the prediction of treatment response and recurrence for patients with rectal cancer. We also elaborate on the future potential use of ctDNA in treatment escalation and de-escalation approaches for more personalized therapeutic interventions.

Dynamic Changes in Circulating Methylated Markers in Response to Antitumor Therapy of Rectal Cancer.

BACKGROUND: Rectal cancer (RC) occupies a leading position in the structure of oncological morbidity and mortality. Aberrant methylation of tumor-suppressor genes and hypomethylation of retrotransposons were shown to be detectable in cell-free DNA, circulating in the blood (cfDNA) of cancer patients, indicating the possibility to use them as diagnostic and prognosis markers. PURPOSE: Evaluation of the changes in the methylation level of LINE-1 elements and SEPTIN9 and IKZF1 genes in the cell-surface-bound cfDNA (csb-cfDNA) from the blood of RC patients after antitumor therapy at a long-term follow-up. METHODS: Blood samples were obtained from RC patients (n = 25) before treatment, after preoperative chemotherapy (3 courses according to the XELOX scheme), 10-15 days after surgery, and every 3 months during 12 months of dynamic observation. The methylation level of LINE-1, SEPTIN9, and IKZF1 in the csb-cfDNA was evaluated by quantitative methyl-specific PCR. RESULTS: The LINE-1 methylation level in the csb-cfDNA increased 1.6 times in RC patients after chemotherapy and 3 times after tumor resection versus methylation level before therapy. The SEPTIN9 gene methylation level in the csb-cfDNA decreased by 1.7 times in RC patients after chemotherapy and by 2.3 times after tumor resection compared with the values before the treatment. The IKZF1 gene methylation level decreased by 2 times in RC patients after combined therapy. Notably, all patients with relapses (n = 5) showed an increase in methylation level for the SEPTIN9 and IKZF1 genes and a decrease of methylation level for the LINE-1 elements by 2 times or more in comparison with the level 10-15 days after surgery. There were no changes in the circulating SEPTIN9, IKZF1, and LINE-1 methylation levels during the 12-month follow-up period after the combined therapy of RC patients (n = 20) without relapses. CONCLUSION: The results indicate that SEPTIN9, IKZF1, and LINE-1 methylation levels in the csb-cfDNA are potential markers of the effectiveness of antitumor therapy and early detection of relapse in RC patients.

ctDNA as a predictor of outcome after curative resection for locally advanced rectal cancer: systematic review and meta-analysis.

AIM: To assess the efficacy of ctDNA measurement at different time intervals in predicting response and prognosis in patients diagnosed with locally advanced rectal cancer (LARC) who underwent neoadjuvant treatment prior to curative resection. METHOD: English language randomized controlled trials and observational studies, published from 1946 to January 2024, comparing outcomes between ctDNA-positive and ctDNA-negative patients with LARC undergoing neoadjuvant treatment prior to curative surgical resection were included in the search. The search included Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR). RESULTS: Data for 1022 patients were analysed. Patients with positive ctDNA in the preoperative period had more than five times the risk of developing distant metastasis (RR [95% CI] 5.03 [3.31-7.65], p < 0.001), while those with positive ctDNA in the postoperative period had more than six times the risk (RR [95% CI] 6.17 [2.38-15.95], p < 0.001). There was no significant relationship between ctDNA status at baseline, pre-, or postoperative periods and achievement of pCR (RR [95% CI] 1.21 [0.86-1.7], 1.82 [0.94-3.55], 1.48 [0.78-2.82], p = 0.27, 0.08, and 0.23, respectively). However, patients with positive ctDNA in the pre- and postoperative periods had more than 13 and 12 times the risk of overall disease relapse after curative-intent treatment (RR [95% CI] 13.55 [7.12-25.81], 12.14 [3.19-46.14], p < 0.001), respectively. CONCLUSION: ctDNA could potentially guide treatment and follow-up in LARC, predicting high-risk patients for disease relapse, allowing individualized surveillance and treatment strategies. Prospective studies are needed for standardization.

Assessing circulating tumour DNA (ctDNA) as a prognostic biomarker in locally advanced rectal cancer: a systematic review and meta-analysis.

INTRODUCTION: Circulating tumour DNA (ctDNA) has emerged as a promising biomarker in various cancer types, including locally advanced rectal cancer (LARC), offering potential insights into disease progression, treatment response and recurrence. This review aims to comprehensively evaluate the utility of ctDNA as a prognostic biomarker in LARC. METHODS: PubMed, EMBASE and Web of Science were searched as part of our review. Studies investigating the utility of ctDNA in locally advanced rectal cancer (LARC) were assessed for eligibility. Quality assessment of included studies was performed using the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, ctDNA details and survival data. A meta-analysis was performed on eligible studies to determine pooled recurrence-free survival (RFS). RESULTS: Twenty-two studies involving 1676 participants were included in our analysis. Methodological quality categorised by the Newcastle Ottawa Scale was generally satisfactory across included studies. ctDNA detected at various time intervals was generally associated with poor outcomes across included studies. Meta-analysis demonstrated a pooled hazard ratio of 8.87 (95% CI 4.91-16.03) and 15.15 (95% CI 8.21-27.95), indicating an increased risk of recurrence with ctDNA positivity in the post-neoadjuvant and post-operative periods respectively. CONCLUSION: Our systematic review provides evidence supporting the prognostic utility of ctDNA in patients with LARC, particularly in identifying patients at higher risk of disease recurrence in the post-neoadjuvant and post-operative periods.

Combined DNA Analysis from Stool and Blood Samples Improves Tumor Tracking and Assessment of Clonal Heterogeneity in Localized Rectal Cancer Patients.

Objectives: In this study, stool samples were evaluated for tumor mutation analysis via a targeted next generation sequencing (NGS) approach in a small patient cohort suffering from localized rectal cancer. Introduction: Colorectal cancer (CRC) causes the second highest cancer-related death rate worldwide. Thus, improvements in disease assessment and monitoring that may facilitate treatment allocation and allow organ-sparing "watch-and-wait" treatment strategies are highly relevant for a significant number of CRC patients. Methods: Stool-based results were compared with mutation profiles derived from liquid biopsies and the gold standard procedure of tumor biopsy from the same patients. A workflow was established that enables the detection of de-novo tumor mutations in stool samples of CRC patients via ultra-sensitive cell-free tumor DNA target enrichment. Results: Notably, only a 19% overall concordance was found in mutational profiles across the compared sample specimens of stool, tumor, and liquid biopsies. Conclusion: Based on these results, the analysis of stool and liquid biopsy samples can provide important additional information on tumor heterogeneity and potentially on the assessment of minimal residual disease and clonal tumor evolution.

The association of preoperative hematologic parameters with short-term clinical outcomes in rectal cancer: A feature importance analysis.

BACKGROUND: Various hematologic parameters have been proposed as prognostic factors in rectal cancer management, but data are conflicting and unclear. This study is designed to investigate the prognostic factor capability of preoperative hematologic parameters with postoperative morbidities and mortality in rectal cancer patients undergoing curative resection. METHODS: All 200 consecutive rectal cancer patients diagnosed at Ghaem University Hospital from 2017 to 2022 were retrospectively evaluated. The receiver operating characteristic (ROC) curves and machine learning (ML) algorithms of Random Forest, Recursive Feature Elimination, simulated annealing, Support Vector Machine, Decision Tree, and eXtreme Gradient Boosting were administered to investigate the role of preoperative hematologic parameters accompanied by baseline characteristics on three clinical outcomes including surgical infectious complications, recurrence, and death. RESULTS: The frequency of infectious complications was correlated with the surgical procedure, while tumor recurrence was significantly influenced by T stage and N stage. In terms of mortality, alongside T and N stage, the status of resection margin involvement was significantly correlated. Based on the ROC analysis, the NLR >2.69, MPV ≤9 fL, and PDW ≤10.5 fL were more classified patients to mortality status. Likewise, the PLT >220 109/L, MPV ≤9 fL, PDW ≤10.4 fL, and PLR >13.6 were correlated with recurrence. However, all factors examined in this study were not significant classifiers for the outcome of surgical infectious complications. The results of ML algorithms were also in line with ROC analysis. CONCLUSION: According to the results of both ROC analysis and ML models, preoperative hematologic parameters are considerable prognostic factors of postoperative outcomes in rectal cancer patients, and are recommended to be monitored by clinicians to prevent unfavorable outcomes.

IFN-Type-I Response and Systemic Immunity in Rectal Adenocarcinoma Patients Treated with Conventional or Hypofractionated Neoadjuvant Radiotherapy.

The IFN-type-I pathway is involved in radiotherapy (RT)-mediated immune responses. Large RT fractions have been suggested to potently induce this pathway. Neoadjuvant hypofractionated short-course (scRT) and conventional long-course (lcRT) RT applied for the treatment of locally advanced rectal adenocarcinoma patients provides a unique model to address the immuno-stimulatory properties of RT on a systemic level. We prospectively analyzed the IFNß plasma levels and lymphocyte counts (LCs) of rectal adenocarcinoma patients before and after treatment with scRT (n = 22) and lcRT (n = 40). Flow cytometry was conducted to assess the effects on lymphocytic subpopulations in a subset of 20 patients. A statistically significant increase in the post-RT IFNß plasma levels was noted in patients undergoing scRT (p = 0.004). Improved pathological tumor regression was associated with elevated post-RT IFNß levels (p = 0.003). Although all patients experienced substantial lymphopenia after treatment, the post-RT LC of patients treated with scRT were significantly higher compared to lcRT (p = 0.001). Patients undergoing scRT displayed significantly lower percentages of regulatory CD4+/CD25+ T-cells after therapy (p = 0.02). scRT enables effective stimulation of the IFN-type-I pathway on a systemic level and confers decreased lymphocytic cytotoxicity and limited regulatory T-cell activation compared to lcRT, supporting its increasing role in immuno-RT trials.

Investigation of Long Non-coding RNAs H19 and LINC00675 in Colorectal Cancers in Terms of Histopathological Features and Correlations With Plasma Markers.

BACKGROUND/AIM: Functional and bioinformatic studies provide strong evidence that long non-coding RNAs (lncRNAs) can alter the molecular mechanisms of cancer through their interactions with DNA, RNAs, and proteins. This study aimed to evaluate the role of H19 and LINC00675 lncRNAs in colorectal cancers (CRCs) in terms of clinicopathological features. MATERIALS AND METHODS: Tumor and tumor-free surrounding tissue samples were obtained from 51 CRC cases. Total RNA isolation and cDNA synthesis were performed. qPCR was performed using the TaqMan non-coding lncRNA assay specific for H19 and LINC00675. Preoperative levels of plasma markers, lncRNA expression, and clinicopathological characteristics of the cases were evaluated statistically. RESULTS: Expression of H19 in tumor tissue was found to be 2.11 times higher than that of tumor-free surrounding tissue (p<0.001). LINC00675 levels were found to be approximately three times higher in colon tumors than tumors with rectal involvement (p=0.019). There was a correlation between H19 expression and creatinine (r=0.408; p=0.003). In addition, correlations were detected between LINC00675 with albumin (r=0.303; p=0.03), and between LINC00675 with globulin (r=0.332; p=0.02). CONCLUSION: H19 is a candidate biomarker that can be evaluated in terms of prognosis and antineoplastic treatment response, while LINC00675 may be an important marker of the microenvironment of advanced stage tumors, especially in tumors with rectal involvement.

Serum apolipoprotein B to apolipoprotein A-I ratio is an independent predictor of liver metastasis from locally advanced rectal cancer in patients receiving neoadjuvant chemoradiotherapy plus surgery.

BACKGROUND: The ratio of serum apolipoprotein B (apoB) to apolipoprotein A-I (apoAI) had been reported as a prognostic factor in colorectal cancer. This retrospective study aimed to assess the implication of apoB-to-apoAI ratio in predicting liver metastasis from rectal cancer (RC). METHODS: The clinical data of 599 locally advanced RC patients treated with chemoradiotherapy followed by surgery were reviewed. Serum apoAI, apoB and apoB-to-apoAI ratio were analyzed for their correlation with the liver-metastasis-free, other-metastasis-free and overall survivals, together with the pretreatment and postsurgical pathoclinical features of the patients. Univariate and multivariate survival analyses were realized through the Kaplan-Meier approach and Cox model, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for independent predictors. RESULTS: Carbohydrate antigen 19 - 9 ≥ 26.3 U/ml, apoB-to-apoAI ratio ≥ 0.63, tumor regression grade 5 - 3, pT4 and pN + stage emerged as independent predictors of poorer liver-metastasis-free survival. The hazard ratios were 1.656 (95% CI, 1.094-2.506), 1.919 (95% CI, 1.174-3.145), 1.686 (95% CI, 1.053-2.703), 1.890 (95% CI, 1.110-3.226) and 2.012 (95% CI, 1.314-2.077), respectively. Except apoB-to-apoAI ratio, the other 4 factors were also independent predictors of poorer other-metastasis-free and overall survivals. And the independent predictors of poorer overall survival also included age ≥ 67 years old, distance to anal verge < 5 cm. CONCLUSIONS: Serum apoB-to-apoAI ratio could be used as a biomarker for prediction of liver metastasis risk in locally advanced RC.

ctDNA on liquid biopsy for predicting response and prognosis in locally advanced rectal cancer: A systematic review.

BACKGROUND: The management of locally advanced rectal cancer (LARC) requires a multidisciplinary approach, with an increasing interest for non-operative strategies. Liquid biopsy for obtaining circulating tumor DNA (ctDNA) can provide information on neoadjuvant chemoradiotherapy (nCRT) pathological response and cancer-specific prognosis, and therefore might be a promising guide for these treatments. METHODS: A systematic review of the studies available in literature has been performed to assess the role of ctDNA as a predictive and prognostic biomarker in LARC patients. RESULTS: We retrieved 21 publications, of which 17 full-text articles and 4 abstracts. Results have been labelled into two groups: predictive and prognostic. Data about the usefulness of liquid biopsy in this setting is still inconclusive. However, baseline higher levels of longer fragments of cell-free DNA and integrity index, tumor-specific mutations and certain methylated genes could predict non-responders. Also, undetectable baseline ctDNA and decrease of common rectal cancer mutations throughout treatment (dynamic monitoring) were predictive factors of pathological complete response. The continuous detection of ctDNA in different timepoints of treatment (minimal residual disease) was consistently associated with worse prognosis. CONCLUSIONS: ctDNA is a promising biomarker that could assist predicting treatment response to nCRT and prognosis in patients with LARC. The ideal methods and timings for the liquid biopsy still have to be defined.

Prognostic Significance of Lymphocyte-to-Monocyte and Platelet-to-Lymphocyte Ratio in Rectal Cancer: A Systematic Review, Meta-analysis, and Meta-regression.

BACKGROUND: The low lymphocyte-to-monocyte ratio and high platelet-to-lymphocyte ratio have been reported to be poor prognostic indicators in various solid tumors, but the prognostic significance in rectal cancer remains controversial. OBJECTIVES: We sought to determine the prognostic value of the lymphocyte-to-monocyte ratio and the platelet-to-lymphocyte ratio following curative-intent surgery for rectal cancer. DATA SOURCES: Following PRISMA guidelines (PROSPERO, ID: CRD42020190880), PubMed and Embase databases were searched through January 2021 including 3 other registered medical databases. STUDY SELECTION: Studies evaluating the impact of pretreatment lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio on overall or disease-free survival in patients undergoing curative rectal cancer resection were selected. MAIN OUTCOMES MEASURES: The main outcome measures were overall and disease-free survival. RESULTS: A total of 23 studies (6683 patients) were included; lymphocyte-to-monocyte ratio and platelet-to-lymphocyte ratio were evaluated in 14 and 16 studies. A low lymphocyte-to-monocyte ratio was associated with poorer overall survival (HR, 1.57; 95% CI, 1.29-1.90; p < 0.001) and disease-free survival (HR, 1.29; 95% CI, 1.13-1.46; p < 0.001). However, when the analysis was limited to patients treated with surgery alone or to those with stage I to III tumors, lymphocyte-to-monocyte ratio was not a predictor of overall survival and disease-free survival. The platelet-to-lymphocyte ratio did not predict for overall or disease-free survival, regardless of the treatment modality, studied population, tumor stage, or cutoff value. Finally, a low lymphocyte-to-monocyte ratio, but not a high platelet-to-lymphocyte ratio, was inversely correlated with complete pathologic response rate. LIMITATIONS: The retrospective nature of most included studies was a limitation. CONCLUSIONS: Pretreatment lymphocyte-to-monocyte ratio, but not platelet-to-lymphocyte ratio, correlates with tumor response to neoadjuvant chemoradiotherapy and poorer prognosis after curative-intent surgery for rectal cancer, and it potentially represents a simple and reliable biomarker that could help optimize individualized clinical decision-making in high-risk patients. REGISTRATION: https://www.crd.york.ac.uk/prospero/; ID: CRD42020190880.

Can pretreatment blood biomarkers predict pathological response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer?

Aims: To investigate the value of previously described pretreatment hematological and biochemical biomarkers as predictors of pathological response. Methods: The authors performed a retrospective analysis of 191 patients with locally advanced rectal cancer who underwent long-course neoadjuvant chemoradiotherapy at two Portuguese centers. The authors performed logistic regression analysis to search for predictive markers of pathological complete and good response. Results: High platelet-neutrophil index (p = 0.042) and clinical tumor stage >2 (p = 0.015) were predictive of poor response. None of the analyzed biomarkers predicted pathological complete response in this study. Conclusion: A high platelet-neutrophil index before neoadjuvant chemoradiotherapy could help predict poorer pathological response in patients with locally advanced rectal cancer. However, no other blood biomarker predicted incomplete or poor response in this study.

Mutational status of plasma exosomal KRAS predicts outcome in patients with metastatic colorectal cancer.

Liquid biopsy has become a useful alternative in metastatic colorectal cancer (mCRC) patients when tissue biopsy of metastatic sites is not feasible. In this study we aimed to investigate the clinical utility of circulating exosomes DNA in the management of mCRC patients. Exosomes level and KRAS mutational status in exosomal DNA was assesed in 70 mCRC patients and 29 CRC primary tumor and were analysed at different disease steps evaluating serial blood samples (240 blood samples). There was a significant correlation between the extension of disease and exosomes level and the resection of primary localized tumor was correlated with a decrease of KRAS G12V/ D copies and fractional abundance in metastatic disease. CEA expression and liver metastasis correlated with a higher number of KRAS G12V/D copies/ml and a higher fractional abundance; in the subgroup of mCRC patients eligible for surgery, the size of tumor and the radiological response were related to exosomes level but only the size was related to the number of KRAS WT copies; both KRAS wild-type and mutated levels were identified as a prognostic factor related to OS. Finally, we found that 91% of mutated mCRC patients became wild type after the first line chemotherapy but this status reverted in mutated one at progression in 80% of cases. In a prospective cohort of mCRC patients, we show how longitudinal monitoring using exosome-based liquid biopsy provides clinical information relevant to therapeutic stratification.

Serum hsa-miR-30e As a Potential Biomarker to Predict the Effect of Neoadjuvant Chemoradiation Therapy in Locally Advanced Rectal Cancer.

Objective: To identify serum microRNAs (miRNAs) correlated with response to neoadjuvant chemoradiation therapy (NCRT) in locally advanced rectal cancer (LARC) patients using in silico analysis and laboratory validation studies. Methods: GSE68204 and GSE68204 data sets were analyzed to identify differentially expressed (DE) miRNAs in NCRT responders using the GEO2R Limma package within the R software suite. Then we used quantitative real-time polymerase chain reaction to detect the upregulated target miRNAs in the serum of 20 LARC patients. Logistic regression was used to evaluate the effect of serum miRNA level on response. Gene Ontology and pathway enrichment analyses were performed to predict the corresponding functions of the DE miRNAs. Correlation between the expression of the hub target genes and the abundance of tumor-infiltrating lymphocytes was further investigated. Results: hsa-miR-30e and hsa-miR-210 were verified to be upregulated in tumor tissues of NCRT responders. Subsequent liquid-biopsy studies revealed that the serum level of miR-30e was associated with a 2.47-fold increased incidence of NCRT-responsive patients in comparison with nonresponders (p-value = 0.038, Mann-Whitney test). Nine hub target genes of hsa-miR-30e were enriched in pathways including immune regulation. The expression of these hub target genes was correlated with abundance of tumor-infiltrating lymphocytes. Conclusion: In summary, hsa-miR-30e was determined to be upregulated in rectal cancer tissues of NCRT-responders. Further investigations showed that increased serum levels of hsa-miR-30e were associated with an effective NCRT response in LARC patients.

Circulating Tumor DNA Predicts Pathologic and Clinical Outcomes Following Neoadjuvant Chemoradiation and Surgery for Patients With Locally Advanced Rectal Cancer.

PURPOSE: This study was designed to assess the ability of perioperative circulating tumor DNA (ctDNA) to predict surgical outcome and recurrence following neoadjuvant chemoradiation for locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Twenty-nine patients with newly diagnosed LARC treated between January 2014 and February 2018 were enrolled. Patients received long-course neoadjuvant chemoradiation prior to surgery. Plasma ctDNA was collected at baseline, preoperatively, and postoperatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital polymerase chain reaction was used to assess mutation fraction in ctDNA. RESULTS: The median age was 54 years. The overall margin-negative, node-negative resection rate was 73% and was significantly higher among patients with undetectable preoperative ctDNA (n = 17, 88%) versus patients with detectable preoperative ctDNA (n = 9, 44%; P = .028). Undetectable ctDNA was also associated with more favorable neoadjuvant rectal scores (univariate linear regression, P = .029). Recurrence-free survival (RFS) was calculated for the subset (n = 19) who both underwent surgery and had postoperative ctDNA available. At a median follow-up of 20 months, patients with detectable postoperative ctDNA experienced poorer RFS (hazard ratio, 11.56; P = .007). All patients (4 of 4) with detectable postoperative ctDNA recurred (positive predictive value = 100%), whereas only 2 of 15 patients with undetectable ctDNA recurred (negative predictive value = 87%). CONCLUSION: Among patients treated with neoadjuvant chemoradiation for LARC, patients with undetectable preoperative ctDNA were more likely to have a favorable surgical outcome as measured by the rate of margin-negative, node-negative resections and neoadjuvant rectal score. Furthermore, we have confirmed prior reports indicating that detectable postoperative ctDNA is associated with worse RFS. Future prospective study is needed to assess the potential for ctDNA to assist with personalizing treatment for LARC.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Peripheral blood CD45RO+T cells is a predictor of the effectiveness of neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

ABSTRACT: To investigate the relationship between the changes in circulating CD45RO+T lymphocyte subsets following neoadjuvant therapy for rectal cancer in patients with locally advanced rectal cancer.The clinicopathological data of 185 patients with rectal cancer who received neoadjuvant therapy in the General Surgery Department of Beijing Chaoyang Hospital affiliated to Capital Medical University from June 2015 to June 2017 were analyzed. Venous blood samples were collected 1 week before neoadjuvant therapy and 1 week before surgery, and the expression of CD45RO+T was detected by flow cytometry. The receiver operating characteristic curve analysis was used to determine the optimal cut-off point of CD45RO+ratio. Log-rank test and multivariate Cox regression were used to analyze the overall survival rate (OS) and disease-free survival rate (DFS) associated with CD45RO+ratio.Circulating CD45RO+ratio of 1.07 was determined as the optimal cut-off point and CD45RO+ratio-high was associated with lower tumor regression grade grading (P = .031), T stage (P = .001), and tumor node metastasis (TNM) stage (P = .012). The 3-year DFS and OS rate in the CD45RO+ratio-high group was significantly higher than that in the CD45RO+ratio-low group (89.2% vs 60.1%, P<.001; 94.4% vs 73.2%, P<.001). The multivariate Cox analysis revealed that elevated CD45RO+ratio was an independent factor for better DFS (OR, 0.339; 95% CI, 0.153-0.752; P = .008) and OS (OR, 0.244; 95% CI,0.082-0.726; P = .011).Circulating CD45RO+ratio could predict the tumor regression grade of neoadjuvant therapy for rectal cancer, as well as long-term prognosis. These findings could be used to stratify patients and develop alternative strategies for adjuvant therapy.

Sex disparities in vitamin D status and the impact on systemic inflammation and survival in rectal cancer.

BACKGROUND: We reported previously that rectal cancer patients given curative-intent chemotherapy, radiation, and surgery for non-metastatic disease had enhanced risk of metastatic progression and death if circulating levels of 25-hydroxyvitamin D [25(OH) D] were low. Here we investigated whether the association between the vitamin D status and prognosis pertains to the general, unselected population of rectal cancer patients. METHODS: Serum 25(OH) D at the time of diagnosis was assessed in 129 patients, enrolled 2013-2017 and representing the entire range of rectal cancer stages, and analyzed with respect to season, sex, systemic inflammation, and survival. RESULTS: In the population-based cohort residing at latitude 60°N, 25(OH) D varied according to season in men only, who were overrepresented among the vitamin D-deficient (< 50 nmol/L) patients. Consistent with our previous findings, the individuals presenting with T4 disease had significantly reduced 25(OH) D levels. Low vitamin D was associated with systemic inflammation, albeit with distinct modes of presentation. While men with low vitamin D showed circulating markers typical for the systemic inflammatory response (e.g., elevated erythrocyte sedimentation rate), the corresponding female patients had elevated serum levels of interleukin-6 and the chemokine (C-X-C motif) ligand 7. Despite disparities in vitamin D status and the potential effects on disease attributes, significantly shortened cancer-specific survival was observed in vitamin D-deficient patients irrespective of sex. CONCLUSION: This unselected rectal cancer cohort confirmed the interconnection of low vitamin D, more advanced disease presentation, and poor survival, and further suggested it may be conditional on disparate modes of adverse systemic inflammation in men and women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01816607 ; registration date: 22 March 2013.

Associations between hepatitis B virus exposure and the risk of extrahepatic digestive system cancers: A hospital-based, case-control study (SIGES).

OBJECTIVES: This case-control study was aimed to investigate associations between HBV infection and extrahepatic digestive system cancers. METHODS: The patients of gastric, small intestinal, colonic, rectal, anal, biliary tract, and pancreatic cancers were retrospectively collected between 2016.5 and 2017.12. Simultaneously, the healthy controls were collected from the health check-up registry, and cancer-free status was confirmed based on medical records. Propensity score matching was performed to reduce bias. Multinomial logit model and conditional logistic regression model were used to assess the risk of individual cancer according to HBV serological markers and classifications. RESULTS: Totally, 4748 patients involving seven cancers, and 57,499 controls were included. After matching, HBsAg was associated with increased risk of gastric cancer (aOR = 1.39, 95% CI: 1.05-1.85), and anti-HBs served as a protective factor for gastric (aOR = 0.72, 95% CI: 0.61-0.85), colonic (aOR = 0.73, 95% CI: 0.60-0.89), rectal (aOR = 0.73, 95% CI: 0.63-0.85), and pancreatic (aOR = 0.58, 95% CI: 0.42-0.82) cancers. Compared to subgroups with non-infection and vaccination status, inactive HBsAg carriers and active HBV infection subgroup were correlated with gastric carcinogenesis (aOR = 1.41, 95% CI: 1.03-1.93). However, no clear association was found between HBV infection and other cancers. CONCLUSIONS: HBV infection was potentially associated with an increased risk of gastric cancer. The development mechanism of HBV-associated gastric cancer needs to investigate further.