Surgical Colorectal Cancer Patients Research Articles

Decrease in hemoglobin following colorectal surgery - A cohort study with focus on iron deficiency

BackgroundOccurrence of anemia following colorectal cancer surgery is common and has been associated with decreased overall survival. We examine the perioperative hemoglobin change following minimally invasive colorectal cancer surgery. The aim is to assess if an association between decreasing hemoglobin and the existence of preoperative iron deficiency exists. MethodsRegistry based single center cohort study. Surgical colorectal cancer patients (2013–2019) being non-anemic prior to surgery and who underwent intended laparoscopic and curatively planned surgery were included. Hemoglobin change from pre-surgery to discharge was compared between patients with and without preoperative iron deficiency. Analysis was done using multivariate linear regression analysis. Changes in hydration status and inflammation were also accessed and compared to the change in hemoglobin. ResultsOut of a consecutive cohort of 1228 patients, 353 fulfilled the eligibility criteria and were available for analysis. The mean change in hemoglobin-concentration for all patients was -2.02 g/dl (SD +- 1.28) and an intraindividual decrease occurred in 95 % of the patients. Preoperative iron deficiency was not associated with the decrease in hemoglobin (correlation =-0.13, 95 % CI -0.43 – 0.18, p = 0.41). There was a statistically significant association between decreasing albumin levels and decreasing hemoglobin levels. ConclusionsFollowing minimally invasive laparoscopic surgery, 95 % of non-anemic surgical colorectal cancer patients experienced a decreasing hemoglobin level. The median hemoglobin decrease was 2 g/dl during hospitalization. Preoperative iron deficiency was not associated with the decrease in hemoglobin levels.

Preoperative intravenous iron treatment – a cohort study on colorectal cancer recurrence

BackgroundIntravenous (i.v.) iron treatment has been speculated to increase the malignant potential of colorectal malignancies but also to enhance the immune systems potential to fight the invasive tumor. Clinical data however is very limited. We investigate if preoperative i.v. iron treatment is associated with colorectal cancer (CRC) recurrence. MethodsRetrospective cohort study on surgical CRC patients with iron deficiency anemia (1st March 2013 - 31st December 2019). Patients were grouped based on whether they had received preoperative treatment with i.v. iron. Local data was combined with data from the National Danish Health registries to identify recurrences, death, and emigration. Survival analysis, including Kaplan-Meyer curves and multivariate competing risk analysis adjusting for sex, age, ASA-group, tumor stage, surgical radicality, and miss match repair status was performed. ResultsOf 1228 patients, 125 were available for analysis. 89 patients had received preoperative i.v. iron and 36 had not. The two groups were comparable on baseline and surgical characteristics. Median follow-up times were 4.74 in iron treated patients and 5 years in patients not receiving iron treatment. Five-year rate of non-recurrence was 85 % (0.74–0.91) in the i.v. iron treated group vs. 82 % (0.64–0.91) in the control group, non-significant difference. Multivariate survival analysis did not find iron treatment to be associated with recurrence rates (Hazard Ratio 0.88 (95 % ci; 0.31–2.51). ConclusionNo association between preoperative i.v. iron treatment and the five-year cancer recurrence rate in iron deficient anemic CRC patients was found.

Preoperative Intravenous Iron Treatment in Colorectal Cancer: Experience From Clinical Practice.

Anemia is associated with increased postoperative morbidity and mortality in abdominal surgery. In clinical trials, preoperative i.v. iron treatment increases the preoperative hemoglobin (Hb) concentration but the effect on transfusion rates are not consistent. This study reports on the experience with preoperative i.v. iron treatment in surgical colorectal cancer (CRC) patients in clinical practice. A registry-based cohort study. Surgical colorectal cancer patients with iron deficiency anemia were compared after division into two groups; those who preoperatively received i.v. iron treatment and those who did not. Primary outcomes were preoperative changes in Hb and the difference in perioperative red blood cell transfusion (RBCT) rates. Postoperative complications and mortality rates were analyzed and a descriptive analysis on what triggered blood transfusions were performed. A total of 170 patients were included. Of these, 122 had received preoperative i.v. iron treatment and 48 had not. The perioperative transfusion rate was 45% (55/122) in the treatment group and 40% (19/48) in the control group (non-significant difference). The preoperative changes in Hb levels were not different between the two groups. Transfusion practice appeared more liberal and preceded by higher Hb levels that was guided by the National transfusion guideline. I.v. iron treated patients had a higher rate of postoperative complications. No differences were found on length of stay (LOS) or postoperative mortality. Preoperative i.v. iron treatment was neither associated with a rise in Hb concentrations at the time of surgery, nor with a reduction in the likelihood of receiving perioperative red blood cell transfusions (RBCT) in colorectal cancer (CRC) patients with iron deficiency anemia.

Combined detection of preoperative neutrophil to lymphocyte ratio and interleukin-6 as an independent prognostic factor for patients with non-metastatic colorectal cancer.

This study sought to explore the value of the neutrophil to lymphocyte ratio (NLR) and interleukin-6 (IL-6) in predicting the prognosis of patients with non-metastatic colorectal cancer (CRC). The data of 88 surgical CRC patients were retrospectively analyzed. A receiver operating characteristic (ROC) curve analysis was conducted to determine the patients' thresholds for the NLR and IL-6. Kaplan-Meier curve and Cox regression models were used to assess the prognostic values. A ROC analysis was conducted to calculate the NLR cut-off value. The area under the curve (AUC) of the NLR was 0.739 [95% confidence interval (CI): 0.634 to 0.844] for overall survival (OS), and 0.799 (95% CI: 0.705 to 0.892) for disease-free survival (DFS). The AUC of IL-6 was 0.773 (95% CI: 0.670 to 0.876) for OS, and 0.817 (95% CI: 0.728 to 0.906) for DFS. The AUC of NLR + IL-6 was 0.805 (95% CI: 0.710 to 0.899) for OS and 0.853 (95% CI: 0.774 to 0.933) for DFS, which were higher than the NLR or IL-6 alone AUCs for OS and DFS. In addition, a high NLR and IL-6 value was significantly correlated with tumor differentiation and tumor-node-metastasis staging. The NLR was positively correlated with IL-6 level (r=0.481). The results of the Kaplan-Meier analysis showed that a high NLR + IL-6 value was correlated with worse OS and DFS. A high NLR and IL-6 value is a better independent prognostic biomarker of CRC than the NLR or IL-6 level alone, and may be applied in clinical practice to identify high-risk patients.

The prognostic value of serum bilirubin in colorectal cancer patients with surgical resection.

Serum bilirubin plays an important role in antioxidant and anticancer processes. The inverse association between serum bilirubin and cancer risk have been widely reported in multiple cancers. The aim of this retrospective study was to investigate the prognostic impact of serum bilirubin in colorectal cancer patients undergoing surgical resection. The value of serum bilirubin including total bilirubin, direct bilirubin, and indirect bilirubin were tested at pre-operatively in 330 colorectal cancer patients. The optimal cut-off values for these three biomarkers were determined by X-tile program. The relationship between serum bilirubin and outcomes were examined using Kaplan-Meier curves log-rank test, univariate and multivariate cox regression. Moreover, a number of risk factors were used to form a nomogram for evaluating risk of survival. The optimal cut-off points of serum total bilirubin, direct bilirubin, and indirect bilirubin were 19.5 μmol/L, 5.0 μmol/L and 8.1 μmol/L, respectively. Elevated total bilirubin and direct bilirubin were significantly associated with overall survival in surgical colorectal cancer patients. Additionally, predictive nomogram including total bilirubin and direct bilirubin for overall survival was established for predicting overall survival in surgical colorectal cancer patients. These findings indicated that preoperative elevated total bilirubin and direct bilirubin could be considered as independent prognostic biomarkers for poor overall survival of colorectal cancer patients.

High-Grade Inflammation Attenuates Chemosensitivity and Confers to Poor Survival of Surgical Stage III CRC Patients.

Background: Heterogeneous clinical and molecular characteristics are reported in colorectal cancer (CRC) with different tumor laterality. However, the outcome of left- and right-sided patients with stage I–III CRC and the role of chronic inflammation in survival differences between them remain unclear.Method: A prospective study including 1,181 surgical patients with stage I–III CRC was carried out to investigate the involvement of circulating fibrinogen-to-pre-albumin (Alb) ratio (FPR) and primary tumor sidedness in the clinical outcome of those patients. We further investigated the effect of FPR on adjuvant chemotherapy response and recurrence in stage III patients.Results: Our study showed that the right tumor location was significantly associated with poor recurrence-free survival (RFS) (p = 0.04, adjusted HR = 1.41, 95% CI = 1.02–1.94) and overall survival (OS) (p = 0.04, adjusted HR = 1.55, 95% CI = 1.01–2.38) only in the stage III disease. In these patients, T4 stage distribution (83.39 vs. 70.94%, p < 0.01) within right-sided cases was significantly higher than left-sided patients. Moreover, preoperative FPR within right-sidedness (p < 0.01), T4 stage (p < 0.05), and large cancer bulk (≥5 cm) (p < 0.05) subgroups was significantly elevated compared to their counterparts, and it was gradually rising following the increased cancer bulk (p trend < 0.01). High-FPR distribution (52.30 vs. 27.00%, p < 0.01) within right-sided patients with the stage III disease was significantly higher than that in the left-sided cases. RFS (plog−rank < 0.01) and OS (plog−rank < 0.01) of the high-FPR patients were extremely inferior to the low-FPR cases, and the significant associations were observed when they were adjusted by other confounders including primary tumor location (p < 0.01, adjusted HR = 1.96, 95% CI = 1.42–2.70 for RFS; p < 0.01, adjusted HR = 2.44, 95% CI = 1.59–3.75 for OS). Additionally, RFS of adjuvant chemotherapy-treated high-FPR patients was superior to the patients without chemotherapy (plog−rank = 0.01) but was inferior to the low-FPR patients undergoing the treatment, especially in the 5-FU- and XELOX-treated subgroup.Conclusion: These findings indicate that chronic high-grade inflammation weakens chemotherapy efficacy and contributes to the poor prognosis of stage III surgical CRC patients.

The Role of Cancer-Elicited Inflammatory Biomarkers in Predicting Early Recurrence Within Stage II–III Colorectal Cancer Patients After Curable Resection

BackgroundSmoldering cancer-related inflammation attenuates chemotherapy efficacy and contributes to unsatisfactory outcome for patients of colorectal cancer (CRC). Various inflammation-based biomarkers were reported to predict the survival of the disease, however, it remains unclear which is the best inflammation-based biomarker. The aim of present study was to compare the prognostic role of those biomarkers and to establish superior survival score for post-recurrence survival in radically operative patients with stage II–III CRC.Patients and MethodsPreoperative peripheral neutrophil, lymphocyte, monocyte, platelet, serum albumin (Alb), pre-Alb, and plasma fibrinogen (Fib) were detected in the discovery and validation cohort which included a total of 1533 stage II–III surgical CRC patients. We calculated and compared fourteen inflammation-based biomarkers for predicting recurrence-free survival (RFS) of the patients with stage II–III CRC.ResultsIn this study, the platelet to lymphocyte ratio (PLR), lymphocyte to monocyte (LMR), systemic inflammation response index (SIRI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), modified systemic inflammation score (mSIS), fibrinogen and neutrophil to lymphocyte ratio score (F-NLR), ratio of Alb to Fib (AFR), and ratio of Fib to pre-Alb (FPR) were all related to the RFS of the patients in both discovery and validation cohorts, however, only the LMR, SIRI, PNI, mSIS, F-NLR, AFR and FPR remained independent predictors for RFS in multivariate analysis. Both the C-index of the FPR (0.629 for 36 months) and the areas under the time-dependent receiver operating characteristic (ROC) curves (0.625 for 12 months, 0.641 for both 24 and 0.637 months) showed that it was superior to the other inflammation-based prognostic scores for predicting the RFS of stage II–III surgical CRC patients. Moreover, elevated FPR was significantly associated with unsatisfactory RFS regardless of TNM stage and primary tumor location. Stage II low FPR patients showed the best RFS regardless of chemotherapy. The better RFS was observed in chemotherapy-treated stage II high FPR patients than those without the treatment, and the outcomes of patients with treatment of XELOX, capecitabine and XELOX were superior to the other regimens to treat patients in stage III low- and high-FPR populations, respectively. Additionally, the carcinoembryonic antigen (CEA)-FPR combined score one (adjusted HR=2.764, 95% CI=2.129–3.589) and two (adjusted HR=3.543, 95% CI=2.317–5.420) were extremely associated with RFS of these patients, and the predicted AUC of the combined score for 12, 24 and 36 months were 0.657, 0.657 and 0.653 in stage II–III patients, which were superior to the single CEA and FPR, respectively.ConclusionIn conclusion, FPR is superior to the other inflammatory biomarkers as a useful recurrence indicator in stage II–III surgical CRC patients in terms of prognostic ability; it helps to choose the effective chemotherapy regimen and to increase the predicted efficacy of CEA and the combined CEA and FPR score could effectively predict recurrence of the patients.

Paxillin knockdown suppresses metastasis and epithelial‑mesenchymal transition in colorectal cancer via the ERK signalling pathway.

Paxillin (PXN) is a cytoplasmic protein that plays an important role in regulating focal adhesion, cytoskeletal rearrangements and cell motility. The present study aimed to investigate the role of PXN in the metastasis of human colorectal cancer (CRC) and its possible mechanisms. Immunohistochemical staining of tissues from 102 surgical CRC patients revealed that high PXN expression was positively correlated with tumour-node-metastasis (TNM) stage, lymph node metastasis, distant metastasis, and recurrence at distant sites after radical surgery. In 24 cases of stage IV CRC, PXN expression in liver metastasis was higher than that in the matched primary tumour. The knockdown of PXN inhibited the proliferation, migration and invasion potential of SW480 cells in vitro and in vivo. Transmission electron microscopy revealed the effect of PXN on ultrastructural characteristics, observed mainly in microvilli and desmosomes. The downregulation of PXN decreased the activation of extracellular regulated protein kinase (ERK) and suppressed the epithelial-mesenchymal transition (EMT) process. Following the downregulation of PXN, the addition of an ERK activator or inhibitor restored or further suppressed EMT, respectively, accompanied by corresponding changes in cell migration and invasion. Collectively, the present results confirmed the important role of PXN in CRC metastasis and revealed that PXN regulated EMT progression via the ERK signalling pathway. PXN may represent a future therapeutic strategy to prevent the EMT-associated progression and invasion of CRC.

Correlation between emotional regulation and peripheral lymphocyte counts in colorectal cancer patients.

BackgroundColorectal cancer is one of the most common cancers worldwide. Psychological morbidity has an important impact on quality of life and major clinical outcomes. Several data have shown that the immune system may be a key player on the relation between psychological features and cancer outcomes. Natural Killer (NK) cells have been shown to be influenced by psychological factors. The aim of this investigation was to assess the impact of anxiety, depression, and anger state, trait, and expression on the immune response, particularly, their effect on NK cells and CD8+ T cells in surgical colorectal cancer patients.MethodsWe studied 54 surgical colorectal cancer patients and assessed patients pre-surgically, post-surgically, and 12 months after surgery (follow-up). We applied the Hospital Anxiety and Depression Scale and the State-Trait Anger Expression Inventory and measured peripheral T cells, CD8+ T cells, and NK cells. We did a cross-sectional analysis as well as a longitudinal assessment of the variables during the follow-up period.ResultsPre-surgical assessment: Trait anger, angry reaction, and anger-out had a significant negative correlation with NK cells. The lymphocytes values were unaffected by the presence of clinical anxiety or depression. Post-surgical assessment: Patients without clinical anxiety had higher levels of T cells. Angry reaction was negatively correlated with NK cells. Lymphocytes values were unaffected by the presence of clinical depression. Follow-up assessment: Patients without clinical depression had higher T cell counts. Trait anger and angry reaction were negatively correlated with the levels of NK cells. The lymphocytes values were unaffected by the presence of clinical anxiety. Longitudinal assessment: Angry-temperament, anger expression, and anger-in reduced significantly from the first to the second assessment. Anxiety, state anger, and trait anger significantly diminished from the pre-surgical to the follow-up assessment. Depression levels did not alter during the follow-up period. The lymphocyte count, and particularly T cells and CD8+ T cells, was significantly higher in the follow-up when compared with the pre-surgical assessment.ConclusionOur study suggests the existence of a relation between psychological response and immune response in colorectal cancer patients. We identified the importance of emotional regulation as a potential modulator for NK cell counts. Higher values of propensity to experience anger states and express them outwards seem to be associated with lower NK cell counts.

Preoperative C-reactive protein-to-albumin ratio predicts anastomotic leak in elderly patients after curative colorectal surgery.

Anastomotic leak (AL), as one of the most devastating complications, is the leading cause of mortality in colorectal cancer (CRC) patients after resection. This study was aimed to investigate potential risk factors for AL in elderly surgical CRC patients. A total of 1068 elderly subjects who underwent elective curative colorectal surgery from 2012 to 2018 were retrospectively evaluated and enrolled into this study population. The predictive value of C-reactive protein-to-albumin ratio (CAR) for AL in surgical CRC patients was evaluated by receiver operating characteristic (ROC) curve analysis. Potential risk factors for AL were assessed by the univariate and multivariate logistic regression analyses. Of all the 1068 enrolled patients, 81 patients have developed AL with an incidence of 7.6% (81/1068). Preoperative CAR was an effective predictor for AL with an area under the curve (AUC) of 0.758, 95% CI of 0.700-0.817, a cut-off value of 2.44, a sensitivity of 61.09% and a specificity of 80.25%, respectively (P< 0.001). Duration of operation (OR: 2.05, 95% CI: 1.21-3.44, P= 0.013) and preoperative CAR (OR: 1.94, 95% CI: 1.21-3.11, P= 0.007) were two independent risk factors for AL by the multivariate logistic regression analysis. Our study indicate that preoperative CAR level and duration of operation were two independent predictors for AL among elderly surgical CRC patients.

Major depression but not minor to intermediate depression correlates with unfavorable prognosis in surgical colorectal cancer patients underwent adjuvant chemotherapy

ABSTRACTThis study aimed to investigate the correlation of anxiety/depression with clinicopathological features, and the association of anxiety/depression degrees with overall survival (OS) in surgical colorectal cancer (CRC) patients. Three hundred and eighty-one surgical CRC patients were consecutively enrolled and underwent adjuvant chemotherapy accordingly. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Patients with no, minor, intermediate and major anxiety were 249 (65.4%), 79 (20.7%), 37 (9.7%) and 16 (4.2%), respectively, and patients with no, minor, intermediate and major depression were 231 (60.6%), 73 (19.2%), 44 (11.5%) and 33 (8.7%), respectively. Younger age, increased the pathological grade, elevated tumor, node and metastasis (TNM) stage, as well as higher education correlated with raised HADS-A score, while younger age, drinking history, increased pathological grade, elevated TNM stage and higher education associated with raised HADS-D score. There was no difference in OS among CRC patients with no anxiety, minor anxiety, intermediate anxiety and major anxiety. And CRC patients with major depression were of worse OS compared to those with no depression, minor depression or intermediate depression. Younger age, higher pathological grade, TNM stage and education associates with anxiety and depression, and major depression is negatively correlated with OS in surgical CRC patients underwent adjuvant chemotherapy.

Measuring electronic communication networks in virtual care teams using electronic health records access-log data

ObjectiveTo develop methods for measuring electronic communication networks in virtual care teams using electronic health records (EHR) access-log data. MethodsFor a convenient sample of 100 surgical colorectal cancer patients, we used time-stamped EHR access-log data extracted from an academic medical center’s EHR system to construct communication networks among healthcare professionals (HCPs) in each patient’s virtual care team. We measured communication linkages between HCPs using the inverse of the average time between access events in which the source HCPs sent information to and the destination HCPs retrieved information from the EHR system. Social network analysis was used to examine and visualize communication network structures, identify principal care teams, and detect meaningful structural differences across networks. We conducted a non-parametric multivariate analysis of variance (MANOVA) to test the association between care teams’ communication network structures and patients’ cancer stage and site. ResultsThe 100 communication networks showed substantial variations in size and structures. Principal care teams, the subset of HCPs who formed the core of the communication networks, had higher proportions of nurses, physicians, and pharmacists and a lower proportion of laboratory medical technologists than the overall networks. The distributions of conditional uniform graph quantiles suggested that our network-construction technique captured meaningful underlying structures that were different from random unstructured networks. MANOVA results found that the networks’ topologies were associated with patients’ cancer stage and site. ConclusionsThis study demonstrates that it is feasible to use EHR access-log data to measure and examine communication networks in virtual care teams. The proposed methods captured salient communication patterns in care teams that were associated with patients’ clinical differences.

An exploratory study of networks constructed using access data from an electronic health record

ABSTRACT Network analysis may be a powerful tool for studying interprofessional practice. Using electronic health record data and social network analysis, the network of healthcare professionals involved in colorectal cancer care at a large, urban academic medical center were mapped and studied. A total of 100 surgical colorectal cancer patients receiving treatment in 2013 and 2014 were selected at random. We used detailed access logs for the EHR to map the network of all healthcare professionals for each patient, including inpatient and outpatient settings. Approximately 2.45 million records of access logs from more than 6,800 unique users, representing over 150 roles or occupations were analyzed. Across all networks, professionals were connected to an average of 5.8 other professionals, but some were rarely connected with others while over 20 were very highly connected (> 100 other professionals). Housestaff, attending physicians, and nurses played central roles in the global network with a high number of inter- and intra-professional connections. Clusters of professionals with frequent interaction were demonstrated but, based on the size and complexity of the network, serendipitous interactions were unlikely. Settings for care seemed to influence these clusters. Patient-centric care networks were similar to the global network with some potentially important differences. Access-log information from electronic health records can be an important source of information about relationships between healthcare professionals. Findings from analyses such as this one may help define the state of current networks and potential targets for interventions to improve the quality of care.

The impact of complications on prolonged length of hospital stay after resection in colorectal cancer: A retrospective study of Taiwanese patients.

ObjectivesTo assess the impact of minor, major and individual complications on prolonged length of hospital stay in patients with colorectal cancer (CRC) after surgery using multivariate models.MethodsThis was a retrospective review of data from patients who underwent surgery for stage I–III CRC at two medical centres in southern Taiwan between 2005–2010. Information was derived from four databases. Multivariate logistic regression methods were used to assess the impact of complications on prolonged length of stay (PLOS) and prolonged postoperative length of stay (PPOLOS).ResultsOf 1658 study patients, 251 (15.1%) experienced minor or major postsurgical complications during hospitalizations. Minor and major complications were significantly associated with PLOS (minor, odds ratio [OR] 3.59; major, OR 8.82) and with PPOLOS (minor, OR 5.55; major, OR 10.00). Intestinal obstruction, anastomosis leakage, abdominal abscess and bleeding produced the greatest impact.ConclusionsMinor and major complications were stronger predictors of prolonged hospital stay than preoperative demographic and disease parameters. Compared with the PLOS model, the PPOLOS model better predicted risk of prolonged hospital stay. Optimal surgical and medical care have major roles in surgical CRC patients.

Colorectal cancer surgery for obese patients: Financial and clinical outcomes of a Dutch population-based registry.

The objective of this study was to explore the association among adverse events, body mass index (BMI), and hospital costs after colorectal cancer surgery in a country with an intermediate BMI distribution. All colorectal cancer procedures in 29 Dutch hospitals listed in a 2010-2012 population-based database and with a BMI > 18.5 were included (n = 8687). Hospital costs were measured uniformly and based on time-driven activity-based costing. The BMI classification of the World Health Organization was used. Patients in obesity classes 1 (23.6% [after risk-adjustment OR 1.245, CI 1.064-1.479, P = 0.007]) and ≥2 (28.1% [after risk-adjustment OR 1.816, CI 1.382-2.388, P < 0.001]) were associated with more severe complications and higher hospital costs (€14,294, +9.6%, after risk-adjustment +7.9%, P < 0.001; and €15,913 +22.0%, after risk-adjustment +21.2%, P < 0.001, respectively) than normal weight patients (20.8% and €13,040, respectively). Pre-obese patients had significantly lower mortality rates (2.7%, after risk-adjustment, OR 0.756, CI 0.577-0.991, P = 0.042) than normal-weight patients (3.9%). Obese surgical colorectal cancer patients in a country with an intermediate BMI distribution are associated with a significant increase in hospital costs because these patients suffer from more severe complications. This is the first study to provide evidence for the "obesity-paradox" for mortality in colorectal cancer surgery. J. Surg. Oncol. 2016;113:489-495. © 2016 Wiley Periodicals, Inc.

Abstract 5237: Monitoring minimal residual disease by urinary or plasma circulating tumor DNA of KRAS mutation burden in colorectal cancer patients with resectable liver metastases

Abstract Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer deaths. Over half of patients with CRC will develop liver metastases. Surgical resection, in combination with systemic therapies, greatly improves long-term outcomes, and around 40% of patients with resected liver limited disease are alive 5 years after diagnosis. While tumor staging and radicality of surgery are commonly used for prognostic assessment, better non-invasive markers are needed for monitoring chemo-responsiveness, following minimal residual disease (MRD), and guiding complex treatment decisions in these patients. This study evaluated the utility of quantitating KRAS mutation burden in urinary and plasma ctDNA as a means of monitoring MRD in surgical CRC patients with liver limited metastases. Methods: We developed a novel, NGS-based method for enrichment and quantitative detection of KRAS mutations in urinary and plasma ctDNA. A blinded retrospective study was conducted on 20 Stage I-IV CRC patients, 15 of whom had undergone curative or palliative intent surgical resection of primary tumor or liver metastases in combination with various systemic therapies. Results: Archived, matched urine and plasma samples were collected from 20 patients with KRAS positive primary tumor. For operable patients, specimens were collected prior to surgery, during and immediately after surgery, plus additional time points post-surgery. A total of 193 plasma and urine samples archived for 3-5 years were tested. All 101 of 101 plasma samples (100%) and 79 of 92 urine samples (86%) had sufficient DNA and were deemed evaluable. In a blinded analysis, a correct KRAS mutation that correlated with KRAS mutation in tissue was identified in 95% of evaluable baseline plasmas (19 of 20) and 92% of evaluable baseline urines (11 of 12). In one patient, a KRAS mutation distinct from that identified in the tumor biopsy was detected consistently across all serial ctDNA samples. Overall, we observed a clear correlation and highly comparable fold change between plasma and urinary ctDNA KRAS levels on treatment. Significantly, in all patients with curative intent surgery, ctDNA KRAS levels were undetectable in urine or plasma after surgery. In contrast, in 8 of 10 patients with incomplete, palliative surgery, the ctDNA KRAS signal remained detectable or increased after surgery. Further correlation between ctDNA KRAS and clinical outcomes will be discussed. Conclusion: We demonstrate for the first time that quantitative changes of mutational KRAS burden in plasma and urinary ctDNA are highly correlated. We further demonstrate clinical applicability of urinary ctDNA KRAS analysis for monitoring quantitatively, with single molecule sensitivity, the MRD post-surgery for CRC patients with liver resectable metastases. Supported by Grant no. 13660. Citation Format: Vlada Melnikova, Jason C. Poole, Cecile Rose T. Vibat, Lucie Benesova, Barbora Belsanova, Saege Hancock, Latifa Hassaine, Errin Samuelsz, Timothy T. Lu, Mark G. Erlander, Marek Minarik. Monitoring minimal residual disease by urinary or plasma circulating tumor DNA of KRAS mutation burden in colorectal cancer patients with resectable liver metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5237. doi:10.1158/1538-7445.AM2015-5237

Clinical significance of fibroblast growth factor (FGF) expression in colorectal cancer.

In this study, we serologically and pathologically examined the clinical significance of fibroblast growth factor (FGF) expression in patients with colorectal cancer. Serum basic FGF (bFGF) levels in 92 surgical colorectal cancer patients and 31 controls were measured, and the relationship between those levels and clinicopathological factors were examined. Immunohistochemical study was also conducted on specimens from 51 cancer patients, and the association between bFGF staining and serum levels were investigated. An examination of clinicopathological factors revealed significant differences in bFGF levels between stage 0-IIIb and stage IV cancers (P = 0.013). Lymphatic invasion was one factor that differed significantly. Patients with a tumor 30 mm or smaller had a bFGF level of 7.65 ± 1.11 pg/ml while patients with a tumor 31 mm or larger had a bFGF level of 8.53 ± 3.22 pg/ml; significant differences in these bFGF levels were noted (P < 0.05). Patients with a tumor that had no lymphatic invasion (ly0) had a bFGF level of 7.25 ± 0.66 pg/ml, those with a tumor that had minimal lymphatic invasion (ly1) had a bFGF level of 7.99 ± 1.68 pg/ml, and those with a tumor that had moderate lymphatic invasion (ly2) had a bFGF level of 9.17 ± 4.23 pg/ml. bFGF levels differed significantly for tumors with no/minimal lymphatic invasion (ly0-ly1) and those with moderate lymphatic invasion (ly2) (P < 0.0001). Serological examination of bFGF levels during the proliferation of colorectal cancer revealed that moderate lymphatic invasion can be readily distinguished.

Clinical relevance of alterations in quantity and quality of plasma DNA in colorectal cancer patients: based on the mutation spectra detected in primary tumors.

While circulating plasma DNA (cpDNA) likely originates in tumors, its utility is limited without knowledge of tumor mutations. This study assessed mutational spectra in primary tumors and clarified the utility of quantitative and qualitative cpDNA alterations in colorectal cancer (CRC) patients. Between 2005 and 2006, 191 surgical colorectal cancer patients at Taipei Veterans General Hospital were enrolled in a study of mutational spectra of 155 mutations in 74 genes. Concentrations of cpDNA in 133 patients were measured by Taqman qPCR. The measured endpoint was overall survival (OS) after surgery. The prognostic value was determined using the log-rank test and Cox regression analysis. Of 191 tumors, 208 mutations in 17 genes were found in 137 tumors (71.7 %). Mutation frequencies were 38.7 % in KRAS, followed by APC (23.0 %), TP53 (19.9 %), PIK3CA (7.3 %), and BRAF (4.2 %). The median cpDNA in stage I, II, and III patients was 4,300, 4,800, and 5,600 copies/mL, respectively, increasing to 13,000 copies/mL in stage IV disease (p = .003). From 90 primary tumors with mutations, the sensitivity of cpDNA mutations were 24.0, 45.0, and 27.3 % in the stage I, II, and III disease, respectively, increasing to 87.5 % in stage IV. The 5-year OS of CRC patients with low cpDNA was significantly better than that of patients with high cpDNA (p = .001). Stepwise elimination showed cpDNA to be a strong prognostic factor for OS. Plasma DNA alteration is a useful tool for clinical surveillance of colorectal cancer patients and might be an independent prognosticator.

Colorectal Surgery Patients’ Pain Status, Activities, Satisfaction, and Beliefs about Pain and Pain Management

This study describes surgical colorectal cancer patients’ pain levels, recovery activities, beliefs and expectations about pain, and satisfaction with pain management. A convenience sample of 50 adult inpatients who underwent colorectal surgery for cancer participated. Patients were administered the modified American Pain Society Patient Outcome Questionnaire on postoperative day 2 and asked to report on their status in the preceding 24 hours. Patients reported low current (mean 1.70) and average (mean 2.96) pain scores but had higher scores and greater variation for worst pain (mean 5.48). Worst pain occurred mainly while turning in bed or mobilizing, and 25% of patients experienced their worst pain at rest. Overall, patients expected to have pain after surgery and were very satisfied with pain management. Patients with worst pain scores >7 reported interference with recovery activities, mainly general activity (mean 5.67) and walking ability (mean 5.15). These patients were likely to believe that “people can get addicted to pain medication easily” (mean 3.39 out of 5) and that “pain medication should be saved for cases where pain gets worse” (mean 3.20 out of 5). These beliefs could deter patients from seeking pain relief and may need to be identified and addressed along with expectations about pain in the preoperative nursing assessment.

Influence of 5-fluorouracil and folinic acid on interleukin-18 production in colorectal cancer patients.

This study was carried out to evaluate the IL-18 blood concentrations of operated colorectal cancer patients and their possible variation in response to combination chemotherapy with 5-fluorouracil (5-FU) and folinic acid. IL-18 levels were assayed in sera of 18 healthy donors and 18 surgical colorectal cancer patients before and after adjuvant chemotherapy with 5-fluorouracil and folinic acid. An ELISA kit for human IL-18 was used for the assay. Colorectal cancer patients showed significantly higher baseline levels of IL-18 than healthy donors (p<0.005). Furthermore, serum IL-18 levels increased significantly with respect to baseline in patients receiving adjuvant chemotherapy (p<0.005). This study suggests that treatment with 5-fluorouracil and folinic acid may provoke an increase in IL-18 serum levels in colorectal cancer patients. This increase may help to explain the efficacy of adjuvant chemotherapy with 5-FU in colorectal cancer.