Browsing by Author "Fijneman, Remond J. A. (55879267200)"

Introduction: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT). To select patients who would benefit the most from nCRT, there is a need for predictive biomarkers. The aim of this study was to evaluate the role of clinical, pathological, radiological, inflammation-related genetic, and hematological parameters in the prediction of post-nCRT response. Materials and methods: In silico analysis of published transcriptomics datasets was conducted to identify candidate genes, whose expression will be measured using quantitative Real Time PCR (qRT-PCR) in pretreatment formaline-fixed paraffin-embedded (FFPE) samples. In this study, 75 patients with LARC were prospectively included between June 2020—January 2022. Patients were assessed for tumor response in week 8 post-nCRT with pelvic MRI scan and rigid proctoscopy. For patients with a clinical complete response (cCR) and initially distant located tumor no immediate surgery was suggested (“watch and wait” approach). The response after surgery was assessed using histopathological tumor regression grading (TRG) categories from postoperative specimens by Mandard. Responders (R) were defined as patients with cCR without operative treatment, and those with TRG 1 and TRG 2 postoperative categories. Non-responders (NR) were patients classified as TRG 3-5. Results: Responders group comprised 35 patients (46.6%) and NR group 53.4% of patients. Analysis of published transcriptomics data identified genes that could predict response to treatment and their significance was assessed in our cohort by qRT-PCR. When comparison was made in the subgroup of patients who were operated (TRG1 vs. TRG4), the expression of IDO1 was significantly deregulated (p < 0.05). Among hematological parameters between R and NR a significant difference in the response was detected for neutrophil-to-monocyte ratio (NMR), initial basophil, eosinophil and monocyte counts (p < 0.01). According to MRI findings, non-responders more often presented with extramural vascular invasion (p < 0.05). Conclusion: Based on logistic regression model, factors associated with favorable response to nCRT were tumor morphology and hematological parameters which can be easily and routinely derived from initial laboratory results (NMR, eosinophil, basophil and monocyte counts) in a minimally invasive manner. Using various metrics, an aggregated score of the initial eosinophil, basophil, and monocyte counts demonstrated the best predictive performance. Copyright © 2023 Marinkovic, Stojanovic-Rundic, Stanojevic, Ostojic, Gavrilovic, Jankovic, Maksimovic, Stroggilos, Zoidakis, Castellví-Bel, Fijneman and Cavic.

Introduction: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT). To select patients who would benefit the most from nCRT, there is a need for predictive biomarkers. The aim of this study was to evaluate the role of clinical, pathological, radiological, inflammation-related genetic, and hematological parameters in the prediction of post-nCRT response. Materials and methods: In silico analysis of published transcriptomics datasets was conducted to identify candidate genes, whose expression will be measured using quantitative Real Time PCR (qRT-PCR) in pretreatment formaline-fixed paraffin-embedded (FFPE) samples. In this study, 75 patients with LARC were prospectively included between June 2020—January 2022. Patients were assessed for tumor response in week 8 post-nCRT with pelvic MRI scan and rigid proctoscopy. For patients with a clinical complete response (cCR) and initially distant located tumor no immediate surgery was suggested (“watch and wait” approach). The response after surgery was assessed using histopathological tumor regression grading (TRG) categories from postoperative specimens by Mandard. Responders (R) were defined as patients with cCR without operative treatment, and those with TRG 1 and TRG 2 postoperative categories. Non-responders (NR) were patients classified as TRG 3-5. Results: Responders group comprised 35 patients (46.6%) and NR group 53.4% of patients. Analysis of published transcriptomics data identified genes that could predict response to treatment and their significance was assessed in our cohort by qRT-PCR. When comparison was made in the subgroup of patients who were operated (TRG1 vs. TRG4), the expression of IDO1 was significantly deregulated (p < 0.05). Among hematological parameters between R and NR a significant difference in the response was detected for neutrophil-to-monocyte ratio (NMR), initial basophil, eosinophil and monocyte counts (p < 0.01). According to MRI findings, non-responders more often presented with extramural vascular invasion (p < 0.05). Conclusion: Based on logistic regression model, factors associated with favorable response to nCRT were tumor morphology and hematological parameters which can be easily and routinely derived from initial laboratory results (NMR, eosinophil, basophil and monocyte counts) in a minimally invasive manner. Using various metrics, an aggregated score of the initial eosinophil, basophil, and monocyte counts demonstrated the best predictive performance. Copyright © 2023 Marinkovic, Stojanovic-Rundic, Stanojevic, Ostojic, Gavrilovic, Jankovic, Maksimovic, Stroggilos, Zoidakis, Castellví-Bel, Fijneman and Cavic.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30–3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16–14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20–3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576–6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246–5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198–2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248–0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels. Copyright © 2024 Stanojevic, Spasic, Marinkovic, Stojanovic-Rundic, Jankovic, Djuric, Zoidakis, Fijneman, Castellvi-Bel and Cavic.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30–3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16–14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20–3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576–6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246–5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198–2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248–0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels. Copyright © 2024 Stanojevic, Spasic, Marinkovic, Stojanovic-Rundic, Jankovic, Djuric, Zoidakis, Fijneman, Castellvi-Bel and Cavic.

(1) Background: This study aimed to develop a machine learning model based on radiomics of pretreatment magnetic resonance imaging (MRI) 3D T2W contrast sequence scans combined with clinical parameters (CP) to predict neoadjuvant chemoradiotherapy (nCRT) response in patients with locally advanced rectal carcinoma (LARC). The study also assessed the impact of radiomics dimensionality on predictive performance. (2) Methods: Seventy-five patients were prospectively enrolled with clinicopathologically confirmed LARC and nCRT before surgery. Tumor properties were assessed by calculating 2141 radiomics features. Least absolute shrinkage selection operator (LASSO) and multivariate regression were used for feature selection. (3) Results: Two predictive models were constructed, one starting from 72 CP and 107 radiomics features, and the other from 72 CP and 1862 radiomics features. The models revealed moderately advantageous impact of increased dimensionality, with their predictive respective AUCs of 0.86 and 0.90 in the entire cohort and 0.84 within validation folds. Both models outperformed the CP-only model (AUC = 0.80) which served as the benchmark for predictive performance without radiomics. (4) Conclusions: Predictive models developed in this study combining pretreatment MRI radiomics and clinicopathological features may potentially provide a routine clinical predictor of chemoradiotherapy responders, enabling clinicians to personalize treatment strategies for rectal carcinoma. © 2024 by the authors.