Left-sided Colorectal Cancer Patients Research Articles

Microsatellite Instability Testing and Prognostic Implications in Colorectal Cancer.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

Activated tissue resident memory T-cells (CD8+CD103+CD39+) uniquely predict survival in left sided "immune-hot" colorectal cancers.

Characterization of the tumour immune infiltrate (notably CD8+ T-cells) has strong predictive survival value for cancer patients. Quantification of CD8 T-cells alone cannot determine antigenic experience, as not all infiltrating T-cells recognize tumour antigens. Activated tumour-specific tissue resident memory CD8 T-cells (TRM) can be defined by the co-express of CD103, CD39 and CD8. We investigated the hypothesis that the abundance and localization of TRM provides a higher-resolution route to patient stratification. A comprehensive series of 1000 colorectal cancer (CRC) were arrayed on a tissue microarray, with representative cores from three tumour locations and the adjacent normal mucosa. Using multiplex immunohistochemistry we quantified and determined the localization of TRM. Across all patients, activated TRM were an independent predictor of survival, and superior to CD8 alone. Patients with the best survival had immune-hot tumours heavily infiltrated throughout with activated TRM. Interestingly, differences between right- and left-sided tumours were apparent. In left-sided CRC, only the presence of activated TRM (and not CD8 alone) was prognostically significant. Patients with low numbers of activated TRM cells had a poor prognosis even with high CD8 T-cell infiltration. In contrast, in right-sided CRC, high CD8 T-cell infiltration with low numbers of activated TRM was a good prognosis. The presence of high intra-tumoural CD8 T-cells alone is not a predictor of survival in left-sided CRC and potentially risks under treatment of patients. Measuring both high tumour-associated TRM and total CD8 T-cells in left-sided disease has the potential to minimize current under-treatment of patients. The challenge will be to design immunotherapies, for left-sided CRC patients with high CD8 T-cells and low activate TRM,that result in effective immune responses and thereby improve patient survival.

Prognostic relevance of primary tumor sidedness in stage II/III colorectal cancer: An integrated analysis of JCOG0205, JCOG0404, JCOG0910, and JCOG1006 (JCOG2003A).

197 Background: The prognostic relevance of primary tumor sidedness (PTS) in early-stage colorectal cancer (CRC) is still debated. Several epidemiologic studies have yielded different results due to the wide variation in the quality of CRC surgery and perioperative management. This integrated analysis aimed to investigate the true prognostic relevance of PTS in stage II/III CRC among patients who received standardized surgery and perioperative management. Methods: This analysis included patients from 4 randomized controlled trials (RCTs) conducted by the Japan Clinical Oncology Group (JCOG): JCOG0205, JCOG0404, JCOG0910, and JCOG1006. All patients enrolled in these RCTs received standardized surgery with Japanese D2/D3 lymphadenectomy, and adjuvant 5-FU monotherapy was planned for all stage III patients as a protocol treatment. The data were collated, and patients with stage II/III adenocarcinoma of the colon and upper rectum were identified. For comparison, all eligible patients were categorized into a right-sided (cecum to transverse colon) group or a left-sided (descending colon to upper rectum) group. Primary outcome measures were relapse-free survival (RFS) and overall survival (OS) after primary surgery, and secondary outcome measures included OS after recurrence. Results: A total of 4,113 patients from the 4 RCTs satisfied the eligibility criteria and were divided into two groups; 1,349 right-sided and 2,764 left-sided CRC patients. Five-year RFS after primary surgery for right-sided and left-sided CRC was 79.7% and 79.9% in all patients, 89.7% and 86.9% in stage II and 77.0% and 78.3% in stage III, respectively. There was no significant difference in RFS after adjustment for patient and treatment characteristics (HRadjusted 1.024 [95% CI 0.886-1.183] in all patients, 1.327 [0.852-2.067] in stage II and 0.990 [0.850-1.154] in stage III). Five-year OS after primary surgery was 89.7% and 91.7% in all patients, 97.2% and 96.0% in stage II and 87.6% and 90.7% in stage III, respectively. There was also no remarkable difference in OS after adjustment (HRadjusted 0.879 [95% CI 0.726-1.064] in all patients, 1.517 [0.738-3.115] in stage II and 0.840 [0.689-1.024] in stage III). In total, 795 patients, including 257 right-sided and 538 left-sided CRC, had any recurrence after primary surgery. Five-year OS after a recurrence of right-sided and left-sided CRC were 39.8% and 49.8%, respectively. After adjustment, right-sided CRC had significantly worse OS after recurrence (HRadjusted 0.773 [95% CI 0.627-0.954]). Conclusions: Our results provide more robust evidence for no impact of PTS on recurrence risk and survival after standard surgery and perioperative management for stage II/III CRC. These results indicate that treatment stratification based on PTS is not necessary in early-stage CRC.

P-206 Association between primary tumor site of colorectal cancer and RAS/BRAF mutational status with venous thromboembolism: A retrospective-prospective cohort study from 3 Croatian oncology centers

Right-sided colorectal cancer (RCRC) is associated with several negative clinicopathological and molecular features and also with worse survival than left-sided colorectal cancer (LCRC). A recent study has shown an association between RCRC and increased incidence of venous thromboembolism (VTE). However, the role of RAS/BRAF mutations considering the risk of VTE in metastatic colorectal cancer (mCRC) remains unclear. The aim of our study was to examine impact of tumor sidedness and RAS/BRAF status regarding VTE occurrence in a cohort of patients with mCRC. We conducted a multicenter, combined retrospective-prospective, observational study, with 234 patients (n=234) and known KRAS/NRAS/BRAF status who were treated with first-line chemotherapy with or without biological therapy for mCRC in three Croatian oncologic centers (General Hospital of Šibenik-Knin County, General Hospital Zadar and General Hospital Dubrovnik) from June 2013 to March 2020. Considering prospective arm of the study 40 patients with informed consent were enrolled with minimum follow-up of 1 year. The primary endpoint was incidence of VTE and its association with location of the primary tumor and RAS/BRAF status. VTE was defined as deep venous thrombosis and/or pulmonary embolism occurred 6 months before or at any time after the diagnosis of mCRC. Numerical data were described by the median and the interquartile range (IQR). Categorical variables were tested by Chi-square test and by Fisher's exact test. The normality of the distribution was tested by the Shapiro-Wilk test. Differences between two independent groups were tested by Mann-Whitney's U test. Logistic regression analysis was used to analyze the independent factors associated with VTE. All P values were two-sided. The level of significance was set at Alpha of 0.05. The median follow-up time was 21 months (IQR13-33). Of 234 patients included in analysis 26% had RCRC and 74% had LCRC. KRAS, NRAS and BRAF mutations were detected in 50%, 3% and 5% of patients, respectively. KRAS/NRAS mutations were more common in RCRC than in LCRC (62% vs 50% p=0.001) and the same finding has been noticed with BRAF mutations (12% vs 2% p =0.001). A total of 56 (24%) patients experienced VTE. The incidence was 43% in RCRC patients and 17.3% in LCRC patients (p < 0.001). According to mutational status, incidence was 48.2% in KRAS/NRAS-mutated patients, 10.7% in BRAF-mutated patients and 41% in KRAS/NRAS/BRAF wilde type patients. The results of logistic regression adjustment for known predictors of VTE including Khorana score, use of bevacizumab or anti-EGFR therapy and chemotherapy confirmed that RCRC was significant predictor of VTE (OR=4.7; 95% CI 1.74 – 12.57). However KRAS/NRAS/BRAF mutations were not associated with VTE (OR =0.86; 95% CI 0.11-6.59). In our study, primary tumor sidedness has been associated with VTE in patients with mCRC. Our results have not confirmed an association between biomarker status (KRAS, NRAS and BRAF) and an increased risk of VTE in mCRC patients.

Associations of Complete Blood Count Parameters with Disease-Free Survival in Right- and Left-Sided Colorectal Cancer Patients.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Some complete blood count (CBC) parameters are found to be associated with CRC prognosis. In this study, ninety-seven pretreated CRC patients were included, and the patients were divided into two groups: left-sided and right-sided, depending on the anatomical location of the tumor. Based on clinicopathologic features including tumor budding, disease stages, and tumor anatomical location, levels of CBC parameters were compared, and disease-free survivals (DFS) were determined. There were differences between patients with different tumor budding scores for only three parameters, including red cell distribution width (RDW), numbers of platelets, and mean platelet volume (MPV). Furthermore, numbers of WBCs, monocytes, and MPV in CRC patients with early disease stages were higher than those with advanced stages. However, levels of eosinophil in CRC patients with advanced stages were higher than those with early stages. Depending on the tumor anatomical location, we observed that numbers of red blood cells (RBCs), hemoglobin (Hgb), and hematocrit (Hct) in CRC patients with left-sided tumors were higher than those with right-sided tumors. We found that low levels of MPV were associated with shorter DFS. However, high levels of eosinophils were associated with shorter DFS in all CRC patients. When patients were divided based on the tumor anatomical location, higher levels of MPV, MCHC, and Hgb were associated with better DFS in the left-sided but not right-sided CRC patients. However, left-sided, but not right-sided, CRC patients with high levels of eosinophil and RDW had shorter DFS. Furthermore, right-sided, but not left-sided, CRC patients with high levels of platelets tended to have a shorter DFS. Our data show that MPV and eosinophils could serve as potential prognostic biomarkers in pre-treatment CRC patients, regardless of the tumor anatomical location. Additionally, lower levels of MPV, MCHC, and Hgb, and high levels of eosinophils and RDW could be negative predictive biomarkers in left-sided CRC patients.

Correlation between Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Tumor-Infiltrating Lymphocytes (TILs) in Left-Sided Colorectal Cancer Patients.

Simple SummaryColorectal cancer (CRC) is one of the most common cancers worldwide. Novel markers have been investigated in order to better predict the course of disease and adjust the treatment. Markers associated with cancer-related inflammation (CRI), both in the bloodstream and the tumor tissue, have been in the spotlight for years. In this study, we investigate whether blood-based markers: lymphocyte-to-monocyte ratio, neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio, correlate with tissue-based markers, such as tumor-infiltrating lymphocytes. We retrospectively analyzed 87 patients with locally advanced left-sided CRC treated with radical surgery. Fifty patients were found suitable for the study. We compared the results of their blood tests from the time of the surgical intervention and the density of lymphocytes in the resected tumors. We found no correlation between local and peripheral markers of CRI. Further prospective studies are needed to confirm the results.Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Novel markers are required in order to select high-risk patients and better adjust the treatment. Both peripheral and local markers of cancer-related inflammation (CRI) such as lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR) and tumor-infiltrating lymphocytes (TILs) have been thoroughly investigated in recent years and deemed to be highly prognostic. We hypothesized that there is an association between local and peripheral CRI indices and that blood-based biomarkers may serve as a surrogate of TILs. We retrospectively analyzed 87 patients with locally advanced left-sided CRC treated with radical-intent surgery in the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between January 2014 and December 2015. Fifty patients were found eligible for the study. The patients were divided in terms of pre-treatment values of systemic inflammatory response (SIR) markers into LMR/NLR/PLR-high and low groups. We evaluated the resected specimens by immunohistochemistry in order to assess the densities of CD3+ and CD8+ lymphocytes in the center of the tumor and in the invasive margin. We found that the level of CD3+ lymphocytes in the center of the tumor was statistically significantly higher in patients with low pre-treatment NLR (p = 0.044); however, no correlation between any of the SIR markers and CD3+ or CD8+ TILs was observed. Five-year overall survival (OS) was longer in patients with high LMR (p < 0.001), low NLR (p = 0.001) and low PLR (p = 0.095). No correlation between the density of TILs and OS was demonstrated. In conclusion, based on our study, peripheral blood-based markers and CD3+ and CD8+ TILs are not interrelated.

Para-aortic lymph node dissection in left-sided colorectal cancer: Risk factors, prognostic impact, and therapeutic value.

This study aimed to clarify risk factors, prognostic impact, and the therapeutic value of para-aortic lymph node (PALN) dissection in left-sided colorectal cancer. One hundred and fifty-four patients who underwent primary tumor resection and PALN dissection for left-sided colorectal cancer were included. Logistic regression analysis was used to identify risk factors for PALN metastasis. Cox regression analysis was performed to identify risk factors for overall survival (OS). PALN metastasis was pathologically confirmed in 47 patients (30.5%). Postoperative complications occurred in 42 patients (27.3%). Pathological N stage (OR = 4.661, p = 0.034) and inferior mesenteric artery LNs metastasis (OR = 6.048, p = 0.003) remained to be independently associated with PALN metastasis, the 5-year OS rate and median survival in patients with PALN metastasis was 37.7% and 24 months. Elevated preoperative serum CA19-9 level (HR = 1.006, p = 0.007), number of positive LNs > 7 (HR = 7.263, p = 0.001), and mucinous adenocarcinoma or signet ring cell carcinoma (HR = 6.511, p = 0.001) were independently associated with OS in patients with PALN metastasis. PALN dissection in addition to primary tumor resection have acceptable postoperative complications and may be oncologically beneficial in selected left-sided colorectal cancer patients with clinically suspicious PALN metastasis.

Short and long-term outcomes of elderly patients undergoing left-sided colorectal resection with primary anastomosis for cancer

BackgroundThe proportion of elderly colorectal cancer (CRC) patients requiring surgery is increasing. Colorectal resection for left-sided cancers is the most controversial as the primary anastomosis or end-colostomy and open or minimally invasive approaches are available. Therefore, this study was conducted to investigate the short- and long-term outcomes in elderly patients after resection with primary anastomosis for left-sided CRC.MethodsThe cohort study included left-sided colorectal cancer patients who underwent resection with primary anastomosis. The participants were divided into non-elderly (≤75 years) and elderly (> 75 years) groups. Short- and long-term postoperative outcomes were investigated.ResultsIn total 738 (82%) and 162 (18%) patients were allocated to non-elderly and elderly groups, respectively. Minimally invasive surgery (MIS) was less prevalent in the elderly (42.6% vs 52.7%, p = 0.024) and a higher proportion of these suffered severe or lethal complications (15.4% vs 9.8%, p = 0.040). MIS decreased the odds for postoperative complications (OR: 0.41; 95% CI: 0.19–0.89, p = 0.038). The rate of anastomotic leakage was similar (8.5% vs 11.7%, p = 0.201), although, in the case of leakage 21.1% of elderly patients died within 90-days after surgery. Overall- and disease-free survival was impaired in the elderly. MIS increased the odds for long-term survival.ConclusionsElderly patients suffer more severe complications after resection with primary anastomosis for left-sided CRC. The risk of anastomotic leakage in the elderly and non-elderly is similar, although, leakages in the elderly seem to be associated with a higher 90-day mortality rate. Minimally invasive surgery is associated with decreased morbidity in the elderly.

Comparison of Treatment Outcomes between Right- and Left-sided Colorectal Adenocarcinoma after Adjuvant Chemotherapy

Objective: The survival outcomes of patients with metastatic colorectal adenocarcinoma based on tumor laterality has already been established based on large-scale retrospective studies. As for the non-metastatic disease, the data is much more conflicting. Local data in this population is also scarce. In this study, we determined the difference in survival of right-sided versus left-sided colorectal cancer patients after surgery and adjuvant chemotherapy. Patients and Methods: This retrospective study analyzed a total of 124 patients who were diagnosed with early to locally advanced (stage I to IVA) colorectal adenocarcinoma and underwent definitive surgery and adjuvant systemic treatment per physician’s preference. The patients were stratified according to the primary tumor laterality: Right-Sided Colon cancer (RCC) and Left-sided Colon cancer (LCC). The primary outcome being investigated is the disease-free survival (DFS) at 3 years and 5 years. Secondary outcomes are overall survival (OS) at 3 years and 5 years, and site of disease recurrence across laterality.Results: The findings did not show a significant difference in the 3-year and 5-year DFS between RCC and LCC after surgery and adjuvant chemotherapy (3-year DFS: 50.0% in the RCC group and 54.3% in the LCC group; P=.671; 5-year DFS: 36.7% in the RCC group and 36.2% in the LCC group, P=.474). The OS difference was also not significant at 3 years and 5 years (3-year OS: 68.8% in the RCC group and 73.9% in the LCC group, P=.572; 5-year OS: 31.3% in the RCC group and 26.1% in the LCC group, P=.474). The overall recurrence rate was not significantly different in both groups (65.6% in the RCC group and 66.3% in the LCC group; P=.944). Majority of the recurrences were at a distant site in both groups (61.1% in the RCC group and 69.6% in the LCC group; P=.501) and the most common were in the lungs, and liver. Conclusion: The survival outcome of non-metastatic colorectal adenocarcinoma was not significantly different between RCC and LCC after surgery and adjuvant chemotherapy. The outcome was also similar after stratification of the population into early and locally advanced disease. More diverse clinical characteristics other than tumor location may be prognostic of disease-free and survival outcomes in the non-metastatic setting of colorectal cancer. Further studies with a larger sample size are needed to validate the correlation of survival to the specific stage and anatomic location.

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer.

This study aims to determine differences in the on- and off-tumor microbiota between patients with right- and left-sided colorectal cancer. Microbiome profiling of tumor and tumor-adjacent biopsies from patients with right-sided (n = 17) and left-sided (n = 7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Off-tumor alpha and beta diversity were significantly different between right- and left-sided colorectal cancer patients. However, no differences in on-tumor diversity were observed between tumor locations. Comparing the off-tumor microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas, and Ruminococcus genera. Whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders, in contrast, the on-tumor microbiota showed relatively fewer differences in bacterial taxonomy between tumor sites, with left tumors being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia, and Ruminococcus 2 genera. Patients with left-sided colorectal cancer had large taxonomic differences between their paired on- and off-tumor microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences. Collectively, this suggests that the right and left colon show distinctive bacterial populations; however, the presence of a colonic tumor leads to a more consistent microbiota between locations.

Intraoperative perfusion assessment of the proximal colon by a visual grading system for safe anastomosis after resection in left-sided colorectal cancer patients

We aimed to evaluate the clinical feasibility of a new visual grading system. We included 50 patients who underwent resection of primary colorectal cancer. Before anastomosis, the marginal vessel was cut and the perfusion status was assessed by a visual grading system. The visual grading system is comprised of five grades according to the bleeding from the marginal vessel and is categorized into 4 groups: good (grade A and B), moderate (grade C), poor (grade D) and none (grade E). Colorectal anastomosis was performed only in the good and moderate groups. We compared postoperative outcomes between the good and moderate groups and analysed the factors affecting the perfusion grade. Among the patients, 48% were grade A, 12% were grade B, and 40% were grade C. There was no anastomotic leakage. Only one patient with grade C showed ischemic colitis and needed reoperation. Age was the only factor correlated with perfusion grade in multivariate analysis (OR 1.080, 95% CI 1.006–1.159, p = 0.034). The perfusion grades were significantly different between > 65 and < 65 year-old patients (> 65, A 29.2% B 12.5% C 58.3% vs. < 65, A 65.4% B 11.5% C 23.1%, p = 0.006). Our intraoperative perfusion assessment that uses a cutting method and a visual grading system is simple and useful for performing a safe anastomosis after colorectal resection. If the perfusion grade is better than grade C, an anastomosis can be performed safely. Age was found to be an important factor affecting the perfusion grade.

Resection and Primary Anastomosis versus Hartmann’s Operation in Emergency Surgery for Acute Mechanical Obstruction due to Left-Sided Colorectal Cancer

In cases of obstructed left-sided colorectal cancer, Hartmann’s operation or resection and primary anastomosis are alternative surgical methods. Our aim was to compare the outcomes of the two different surgical techniques performed in emergency cases. Obstructed left-sided colorectal cancer patients operated on between 2011 and 2018 were evaluated. Demographics, preoperative laboratory results, American Society of Anesthesiologists scores, types of operative procedures, intraoperative findings, and surgical outcomes were recorded and analyzed. p 0.05). Creatinine levels were higher in the Hartmann’s operation group (p 0.05). Since there were no significant differences between the use of either Hartmann’s operation or primary anastomosis regarding postoperative complications and mortality rates, primary anastomosis may be preferred to Hartmann’s operation to avoid the need for a second intervention in emergency surgical cases of obstructed left-sided colorectal cancer.

Primary tumor location affects recurrence-free survival for patients with colorectal liver metastases after hepatectomy: a propensity score matching analysis

BackgroundWhether primary tumor location of colorectal cancer (CRC) affects survival of patients after resection of liver metastases remains controversial. This study was conducted to investigate the differences in clinicopathological characteristics and prognosis between right-sided CRC and left-sided CRC patients with liver metastases after hepatectomy.MethodsFrom 2002 to 2018, 611 patients with colorectal liver metastases (CRLM) who underwent hepatectomy at our center were reviewed. Primary tumors located from the cecum to transverse colon were defined as right-sided group (n = 141); tumors located from the splenic flexure to rectum were defined as left-sided group (n = 470). Patients were compared between two groups before and after a 1:1 propensity score matching (PSM) analysis.ResultsBefore PSM, median survival time and 5-year overall survival (OS) rate in right-sided group were 77 months and 56.3%, and those in left-sided group were 64 months and 51.1%, respectively. After PSM, median survival time and 5-year OS rate in right-sided group were 77 months and 55.9%, and those in left-sided group were 58.8 months and 47.3%, respectively. The OS rates did not differ between two groups before and after PSM (P = 0.575, P = 0.453). However, significant different recurrence-free survival (RFS) rate was found before and after PSM between right-sided and left-sided group (P = 0.028, P = 0.003).ConclusionsCompared to patients with left-sided primary tumors, patients with right-sided primary tumors had a worse RFS but similar OS. Careful preoperative evaluation, intensive preoperative chemotherapy, and frequent follow-up to detect early recurrence might be justified for CRLM patients with right-sided primary tumors.

Differences in oncological outcomes and inflammatory biomarkers between right-sided and left-sided stage I-III colorectal adenocarcinoma.

BackgroundThe aim of this study was to investigate the differences in oncological outcome and inflammatory biomarkers between right‐sided colon cancer (RCC) and left‐sided colorectal cancer (LCRC).MethodsWe retrospectively analyzed 339 patients with stage I‐III colorectal cancer, including 125 RCC patients and 214 LCRC patients, who underwent radical resection from January 2012 to January 2014. Comparison of neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and lymphocyte‐to‐monocyte ratio (LMR) between RCC and LCRC was evaluated using the Mann‐Whitney U test. Overall survival (OS) and disease‐free survival (DFS) were analyzed using Kaplan‐Meier analysis and compared using the log‐rank test. Univariate and multivariate Cox regression analyses were used to identify the prognostic value of inflammatory markers.ResultsPatients with RCC had higher NLR (P = .002) and PLR (P < .001) but lower LMR (P = .002) compared to LCRC. In stage I‐III, RCC showed poorer OS and DFS than LCRC (61.6% vs 71.5%, P = .018; 64.8% vs 76.2%, P = .006). Univariate and multivariate analyses indicated that NLR, PLR, and LMR were independent predictors for both OS and DFS in RCC, whereas only PLR was found to be an independent prognostic predictor in LCRC.ConclusionThe prognosis and prognostic value of inflammatory biomarkers were significantly different between RCC and LCRC. Novel therapeutic strategies are needed, and proper prognostic predictors should be selected according to colorectal tumor location.

Additively protective effects of vitamin D and calcium against colorectal adenoma incidence, malignant transformation and progression: A systematic review and meta-analysis.

Colorectal cancer (CRC) exhibits a linear progression from normal colonic epithelium, adenoma initiation, carcinoma transformation and even to metastasis. Diet changes might influence carcinogenesis and prognosis. We aimed to determine the effects of vitamin D and calcium on colorectal adenoma incidence, malignancy development and prognosis. Systematic literature searches (PubMed, Embase, and Cochrane Library databases) and hand searches were performed by September 30, 2019. A random-effects model was adopted to pool relative ratios (RRs) for colorectal tumour incidence or hazard ratios (HRs) for CRC mortality. Stratified analyses were performed by gender, tumour location, calcium intake level and ethnic group. Total 854,195 cases from 166 studies were included. The colorectal adenoma incidence was inversely correlated with the circulating 25-hydroxyvitamin D [25(OH)D] level (RR: 0.80, 95% CI: 0.71-0.89), vitamin D intake (RR: 0.87, 95% CI: 0.82-0.92) and calcium intake (RR: 0.86, 95% CI: 0.81-0.91). The CRC incidence was decreased by circulating 25(OH)D (RR: 0.67, 95% CI: 0.59-0.77), vitamin D intake (RR: 0.85, 95% CI: 0.78-0.93) and calcium intake (RR: 0.75, 95% CI: 0.70-0.79). High-level circulating 25(OH)D triggered better overall survival (HR: 0.67, 95% CI: 0.57-0.79) and CRC-specific survival (HR: 0.63, 95% CI: 0.53-0.74). Stratified analyses showed that vitamin D and calcium significantly suppressed colorectal tumour incidence among women. Left-sided CRC risk was reversely related to circulating 25(OH)D (RR: 0.60, 95% CI: 0.41-0.88) and vitamin D intake (RR: 0.73, 95% CI: 0.57-0.93). Circulating 25(OH)D decreased colorectal adenoma (RR: 0.63, 95% CI: 0.48-0.82) and CRC (RR: 0.69, 95% CI: 0.56-0.86) risk in populations with higher calcium intake. European and American populations benefited more from vitamin D intake against colorectal tumour. A significant dose-response relationship was observed between intake of vitamin D or calcium and colorectal tumour incidence. Vitamin D and calcium play additively chemopreventive roles in colorectal adenoma incidence, malignant transformation and progression, especially for women and left-sided CRC patients.

T Regulatory CD4+CD25+FoxP3+ Lymphocytes in the Peripheral Blood of Left-Sided Colorectal Cancer Patients

Background and objectives: T regulatory lymphocytes (Treg) are one of the subsets of T-lymphocytes involved in the interaction of neoplastic tumors and the host immune system, and they may impair the immune reaction against cancer. It has been shown that Treg are increased in the peripheral blood of patients with various cancers. In colorectal cancer, the prognostic role of Treg remains controversial. Colorectal cancer is a heterogenous disease, with many variations stemming from its primary tumor location. The aim of this study is to analyse the relationship between the amount of Treg in the peripheral blood of patients with left-sided colorectal cancer in various stages of disease and long-term survival. Materials and Methods: A prospective analysis of 94 patients with left-sided colorectal cancer and a group of 21 healthy volunteers was carried out. Treg levels in peripheral blood were analysed using flow cytometry. Results: There was a statistically significant difference between the amount of Treg in the Ist and IInd TNM stages (p = 0.047). The number of Treg in the entire study group was significantly lower than in the control group (p = 0.008) and between patients in stages II and III and the control group (p = 0.003 and p = 0.018). The group of pT3+pT4 patients also had significantly lower Treg counts in their peripheral blood than the control group (p = 0.005). In the entire study group, the level of Treg cells in the peripheral blood had no influence on survival. The analysis of the TNM stage subgroups also showed no difference in survival between patients with “low” and “high” Treg counts. Conclusion: The absolute number of Treg in the peripheral blood of patients with left-sided colorectal cancer was significantly decreased in comparison to healthy controls, especially for patients with stage II+III disease. Treg presence in the peripheral blood had no impact on survival.

Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Additively Protective Effects of Vitamin D and Calcium Against Colorectal Adenoma Incidence, Malignant Transformation and Progression: A Systematic Review and Dose-Response Meta-Analysis

Background: Colorectal cancer (CRC) exhibits a classical linear progression from normal colonic epithelium, adenoma initiation, malignant transformation to carcinoma and even to metastasis. Diet and lifestyle changes might have significant effects on carcinogenesis, recurrence and metastasis. We sought to determine the effects of vitamin D and calcium on colorectal adenoma incidence, malignancy development and prognosis. Methods: We searched and extracted data in the PubMed, Embase, and Cochrane Library databases by Dec 31, 2018 and pooled the relative ratio (RRs) for colorectal tumour incidence or the hazard ratio (HRs) for CRC overall mortality using random-effects model. Then dose-response meta-analysis and stratified analysis by gender, tumour location, calcium intake level and ethnic group were performed. Findings: Total 488722 cases from 146 studies were incorporated into this study. Both colorectal adenoma and cancer incidence were negatively correlated with circulating 25(OH)D, vitamin D intake and calcium intake. However, high-level circulating 25(OH)D was associated with better overall survival and CRC-specific survival. The stratified analysis showed that vitamin D and calcium played significant suppressor roles only in female colorectal adenoma and CRC incidence. Interestingly, there is a inverse relationship between left-sided CRC and circulating 25(OH)D and vitamin D intake. Moreover, populations with higher levels of circulating 25(OH)D showed a lower risk of colorectal adenoma and CRC in higher calcium intake groups. Additionally, European and American populations benefited more from the protective effect of vitamin D intake against colorectal adenoma and CRC. Moreover, a significant dose-response relationship was observed between vitamin D or calcium intake and incidence of colorectal adenoma and CRC. Interpretation: Vitamin D and calcium play additively chemopreventive roles in colorectal adenoma incidence, malignant transformation and progression, especially among females and left-sided CRC patients. Funding: The National Natural Science Foundation of China and the Fundamental Research Funds for the Central Universities and the 111 Project. Declaration of Interest: The authors declare no potential conflicts of interest.

The prognostic significance of the expression of monocarboxylate transporter 4 in patients with right- or left-sided colorectal cancer.

Monocarboxylate transporter 4 (MCT4) is a proton pump that exchanges lactate through the plasma membrane. The present study investigated the clinical significance of the expression of MCT4 in patients with right- or left-sided colorectal cancer (CRC). Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-MCT4 antibodies. The relationships among the MCT4 expression, the clinicopathological factors, and the prognosis were evaluated. Thirty-six (62.1%) of 58 patients with right-sided CRC and 95 (53.1%) of 179 patients with left-sided CRC showed the high expression of MCT4. The MCT4 expression was significantly correlated with gender and lymph node metastasis in patients with right-sided CRC, and size, depth of invasion, distant metastasis, and tumor-node-metastasis stage in patients with left-sided CRC. A univariate analysis demonstrated that the expression of MCT4 was a significant prognostic factor in both right- and left-sided CRC patients. A multivariate analysis demonstrated the expression of MCT4 was a significantly independent prognostic factor in patients with left-sided CRC, but not in those with right-sided CRC. Our results suggest that the high expression of MCT4 is a useful marker for tumor progression and a poor prognosis in CRC patients, especially those with left-sided CRC.

Prognostic Significance of Mitochondrial Transcription Factor A Expression in Patients with Right- or Left-sided Colorectal Cancer.

Mitochondrial transcription factor A (mtTFA) is necessary for both the transcription and maintenance of mitochondrial DNA (mtDNA). The present study investigated the clinical significance of mtTFA in patients with right- and left-sided colorectal cancer (CRC). Surgical specimens from 237 CRC patients were immunohistochemically stained with polyclonal anti-mtTFA antibody. The relationships among the mtTFA expression, clinicopathological factors and prognosis were evaluated. Thirty-five (60.3%) of 58 right-sided CRC patients and 82 (45.8%) of 179 left-sided CRC patients showed high mtTFA expression. The mtTFA expression significantly correlated with lymph node metastasis, distant metastasis, the TNM stage and lymphatic invasion in left-sided CRC patients and did not correlate with any factors in right-sided CRC patients. Univariate and multivariate analyses revealed the mtTFA expression to be a significant prognostic factor in left-sided CRC patients but not in right-sided CRC patients. These results suggest that a high mtTFA expression is a useful marker for tumor progression and a poor prognosis in left-sided CRC patients.