Curative Resection Of Colon Cancer Research Articles

Prognostic Value of Metastatic Lymph Node Ratio and Identification of Factors Influencing the Lymph Node Yield in Patients Undergoing Curative Colon Cancer Resection.

Due to the impact of nodal metastasis on colon cancer prognosis, adequate regional lymph node resection and accurate pathological evaluation are required. The ratio of metastatic to examined nodes may bring an additional prognostic value to the actual staging system. This study analyzes the identification of factors influencing a high lymph node yield and its impact on survival. The lymph node ratio was determined in patients with fewer than 12 or at least 12 evaluated nodes. The study included patients after radical colon cancer resection in UICC stages II and III. For the lymph node ratio (LNR) analysis, node-positive patients were divided into four categories: i.e., LNR 1 (<0.05), LNR 2 (≥0.05; <0.2), LNR 3 (≥0.2; <0.4), and LNR 4 (≥0.4), and classified into two groups: i.e., those with <12 and ≥12 evaluated nodes. The study was conducted on 7012 patients who met the set criteria and were included in the data analysis. The mean number of examined lymph nodes was 22.08 (SD 10.64, median 20). Among the study subjects, 94.5% had 12 or more nodes evaluated. These patients were more likely to be younger, women, with a lower ASA classification, pT3 and pN2 categories. Also, they had no risk factors and frequently had a right-sided tumor. In the multivariate analysis, a younger age, ASA classification of II and III, high pT and pN categories, absence of risk factors, and right-sided location remained independent predictors for a lymph node yield ≥12. The univariate survival analysis of the entire cohort demonstrated a better five-year overall survival (OS) in patients with at least 12 lymph nodes examined (68% vs. 63%, p = 0.027). The LNR groups showed a significant association with OS, reaching from 75.5% for LNR 1 to 33.1% for LNR 4 (p < 0.001) in the ≥12 cohort, and from 74.8% for LNR2 to 49.3% for LNR4 (p = 0.007) in the <12 cohort. This influence remained significant and independent in multivariate analyses. The hazard ratios ranged from 1.016 to 2.698 for patients with less than 12 nodes, and from 1.248 to 3.615 for those with at least 12 nodes. The LNR allowed for a more precise estimation of the OS compared with the pN classification system. The metastatic lymph node ratio is an independent predictor for survival and should be included in current staging and therapeutic decision-making processes.

The impact of anastomotic leakage after curative colon cancer resection on long-term survival: A retrospective cohort study

IntroductionAnastomotic leakage (AL) is one of the most feared postoperative complications in colon cancer surgery due to an association with increased morbidity and mortality, although its impact on long-term survival is not consensual. The aim of this study was to investigate the influence of AL on long-term survival of patients undergoing curative colon cancer resection. MethodsA single-centre retrospective cohort study was designed. Clinical records of all consecutive patients undergoing surgery at our institution between 01/01/2010 and 12/31/2019 were reviewed. Survival analysis was performed by Kaplan–Meier method to estimate overall and conditional survival and Cox regression to search for risk factors impacting survival. ResultsA total of 2351 patients submitted to colorectal surgery were screened for eligibility, of which 686 with colon cancer were included. AL occurred in 57 patients (8,3%) and was associated with higher postoperative morbidity and mortality, length of stay and early readmissions (P < 0,05). Overall survival was inferior in the leakage group (Hazard Ratio 2,08 [1,02–4,24]). Conditional overall survival at 30, 90 days and 6 months was also inferior in the leakage group (P < 0,05), but not at 1 year. Risk factors independently associated with reduced overall survival included AL occurrence, higher ASA classification and delayed/missed adjuvant chemotherapy. AL did not impact local and distant recurrence (P > 0,05). ConclusionAL has a negative impact on survival. Its effect is more pronounced on short-term mortality. AL does not appear to be associated with disease progression.

Short-term outcomes of single-incision robotic colectomy versus conventional multiport laparoscopic colectomy for colon cancer.

Since the da Vinci SP (dVSP) surgical system was introduced, single-incision robotic surgery (SIRS) for colorectal diseases has gained increasing acceptance. Comparison of the short-term outcomes between SIRS using dVSP and those of conventional multiport laparoscopic surgery (CMLS) was performed to verify its efficacy and safety in colon cancer. The medical records of 237 patients who underwent curative resection for colon cancer by a single surgeon were retrospectively reviewed. Patients were divided into two groups according to surgical modality: SIRS (RS group) and CMLS (LS group). Intra- and postoperative outcomes were analyzed. Of the 237 patients, 140 were included in the analysis. Patients in the RS group (n = 43) were predominantly female, younger, and had better general performance than those in the LS group (n = 97). The total operation time was longer in the RS group than in the LS group (232.8 ± 46.0 vs. 204.1 ± 41.7min, P < 0.001). The RS group showed faster first flatus passing (2.5 ± 0.9 vs. 3.1 ± 1.2days, P = 0.003) and less opioid analgesic requirement (analgesic withdrawal within 3 postoperative days: 37.2% vs. 18.6%, P = 0.018) than the LS group. The RS group showed a higher immediate postoperative albumin level (3.9 ± 0.3 vs. 3.6 ± 0.4g/dL, P < 0.001) and lower C-reactive protein level (6.6 ± 5.2 vs. 9.3 ± 5.5mg/dL, P = 0.007) than the LS group during the postoperative period. On multivariate analysis after adjusting for deviated patient characteristics, no significant difference was observed in short-term outcomes, except for operation time. SIRS with dVSP showed short-term outcomes comparable with those of CMLS for colon cancer.

The impact of anastomotic leakage after curative colon cancer resection on long-term survival: A retrospective cohort study

IntroductionAnastomotic leakage (AL) is one of the most feared postoperative complications in colon cancer surgery due to an association with increased morbidity and mortality, although its impact on long-term survival is not consensual. The aim of this study was to investigate the influence of AL on long-term survival of patients undergoing curative colon cancer resection. MethodsA single-centre retrospective cohort study was designed. Clinical records of all consecutive patients undergoing surgery at our institution between 01/01/2010 and 12/31/2019 were reviewed. Survival analysis was performed by Kaplan–Meier method to estimate overall and conditional survival and Cox regression to search for risk factors impacting survival. ResultsA total of 2351 patients submitted to colorectal surgery were screened for eligibility, of which 686 with colon cancer were included. AL occurred in 57 patients (8,3%) and was associated with higher postoperative morbidity and mortality, length of stay and early readmissions (P < 0,05). Overall survival was inferior in the leakage group (Hazard Ratio 2,08 [1,02–4,24]). Conditional overall survival at 30, 90 days and 6 months was also inferior in the leakage group (P < 0,05), but not at 1 year. Risk factors independently associated with reduced overall survival included AL occurrence, higher ASA classification and delayed/missed adjuvant chemotherapy. AL did not impact local and distant recurrence (P > 0,05). ConclusionAL has a negative impact on survival. Its effect is more pronounced on short-term mortality. AL does not appear to be associated with disease progression.

Long-term oncological outcomes for minimally invasive surgery versus open surgery for colon cancer-a population-based nationwide study with a non-inferiority design.

The study aimed to compare 5-year overall survival in a national cohort of patients undergoing curative abdominal resection for colon cancer by minimally invasive surgery (MIS) or by the open (OPEN) technique. All patients diagnosed between 2010 and 2016 in Sweden with pathological Union International Contre le Cancer Stages I-III colon cancer localized in the caecum, ascending colon, hepatic flexure or sigmoid colon and those who underwent curative right sided hemicolectomy, sigmoid resection or high anterior resection by MIS or OPEN were included. Patients were identified in the Swedish Colorectal Cancer Registry from which all data were retrieved. The analyses were performed as intention-to-treat and the relationship between surgical technique (MIS or OPEN) and overall mortality within 5 years was analysed. For the primary research question a non-inferiority hypothesis was assumed with a statistical power of 90%, a one-side type I error of 2.5% and a non-inferiority margin of 2%. For the secondary analyses, multilevel survival regression models with the patients matched by propensity scores were employed, adjusted for patient- and tumour-related variables. A total of 11 605 pathological Union International Contre le Cancer Stages I-III patients were included with 3297 MIS (28.4%) and 8308 OPEN (71.6%) and were followed until 31 December 2020. The primary analysis demonstrated superiority for MIS compared to OPEN. The multilevel survival regression analyses confirmed that 5-year overall survival was higher in MIS with a hazard ratio of 0.874 (95% confidence interval 0.791-0.965), and if excluding pT4 the outcome was similar, with a hazard ratio of 0.847 (95% confidence interval 0.756-0.948). This observational study demonstrated that MIS was favourable to OPEN with regard to 5-year overall survival. These results support the use of laparoscopic colon cancer surgery in routine practice.

Oncological outcomes of elective versus emergency surgery for colon cancer: A tertiary academic center experience.

In this study, we aimed to identify the oncological outcomes in colon cancer patients who underwent elective versus emergency curative resection. All patients who underwent curative resection for colon cancer between July 2015 and December 2019 were retrospectively reviewed and analyzed. Patients were divided into two groups based on the presentation into elective and emergency groups. A total of 215 patients with colon cancer were admitted and underwent curative surgical resection. Of those, 145 patients (67.4%) were elective cases, and 70 (32.5%) were emergency cases. Family history of malignancy was positive in 44 patients (20.5%) and significantly more common in the emergency group (P = 0.016). The emergency group had higher T and TNM stages (P = 0.001). The 3-year survival rate was 60.9% and significantly less in the emergency group (P = 0.026). The mean duration from surgery to recurrence, 3-year disease-free survival, and overall survival were 1.19, 2.81, and 3.11, respectively. Elective group was associated with better 3-year survival, longer overall, and 3-year disease-free survival compared to the emergency group. The disease recurrence rate was comparable in both groups, mainly in the first two years after curative resection.

Efficacy of Neutrophil-to-Lymphocyte Ratio for Cancer-Specific Survival in Elderly Patients with Localized Colon Cancer: A Single Center Propensity Score-Matched Analysis

The prognostic value of neutrophil-to-lymphocyte ratio (NLR) has been studied for colorectal cancer. Elderly patients in general tend to have comorbidities and decreased organ function that potentially influence the NLR score. The aim of this study was to investigate the relationship between NLR and cancer-specific survival in elderly patients with colon cancer, using a propensity score-matched analysis. A total of 203 patients aged over 75 years who underwent curative resection for colon cancer and were diagnosed pathologically with stage II/III disease were eligible for entry to the study. Patients were divided into two groups according to NLR score: NLR-High (NLR≥4.5) group (NLR-H, n=60) and NLR-Low (NLR<4.5) group (NLR-L, n=143). After propensity score matching, 57 patients in each group were matched. Before matching, Charlson comorbidity index was significantly higher in the NLR-H group (4 vs 2, p<0.001). After matching, all factors were similar between the groups. The median follow-up period was 43 months (range, 1-160 months). Five-year relapse-free-survival (69.8% vs 87.3%, p=0.030) and cancer-specific survival (83.0% vs 96.0%, p=0.042) were significantly lower in the NLR-H group. NLR appears to be a cancer-specific prognostic marker in elderly patients with colon cancer.

Prognostic Factors of Disease Recurrence and Overall Survival Following Curative Resection of Colon Cancer: A 10-year Cohort from a Referral Center.

Background: The growing incidence of colorectal cancer around the world highlights the significance of tumor recurrence and patient survival as 2 key elements of patient therapy. We aimed to study the factors linked with disease recurrence and survival in colon cancer. Methods: Patients with colon cancer who underwent tumor excision as their primary treatment were enrolled in this prospective cohort and monitored for 10 years. Various demographic and clinicopathologic factors of these patients were studied in association with the 2 primary outcomes of this study, including tumor recurrence and patient survival. Statistical tests and survival analysis were utilized to explore the study aims. Results: An overall number of 113 patients were included in this survey with a mean age of 54.7 (±SD, 14.1), and most of the patients were men (56.6%). The mean follow-up period was 28.3 (±25.5) months. Tumor recurrence occurred in 32 (28.3%) patients in the study period. The estimated mean survival of patients was 54.9 (95% CI, 45.3-64.4) months. N staging ( p = 0.036), T staging ( p = 0.009), and pathologic staging (P = .004) were the significant pathological factors to higher tumor recurrence and lower survival rates. Conclusion: Advanced tumor staging led to increased disease recurrence and lower survival of colon cancer patients in this survey. Further public health screening and education programs are needed to improve the early detection and prognosis of these patients in Iran.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292)

BackgroundStudies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer.Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy.ResultsFrom August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

The Impact of Colon Cancer Sites on Survival Rates after Curative Resection and Adjuvant Chemotherapy: A SingleCenter Study

Background: Most recent studies indicate that right-sided colon cancer is associated with a significantly higher mortality rate. Multivariate analyses showed that the patient’s age, sex, mode of presentation, co-morbidity, and the stage had significantly influenced their survival. Although the primary tumor location has an impact on the overall survival in metastatic settings, the laterality of early-stage colon cancer might also affect the disease-free survival and determine the duration of adjuvant chemotherapy for each side. This study aimed to compare overall survival and disease-free survival between left-sided and right-sided high-risk stage II and stage III colon cancer in patients from a single institute. Methods: This retrospective cohort study was conducted between January 2004 and December 2017. Data on 153 patients who underwent curative resection and adjuvant chemotherapy for colon cancer were retrieved from an existing database. Results: We found that the five-year disease-free survival rates were 63.20% for left-sided colon cancer and 51.11% for right-sided colon cancer (P-value &lt; 0.05). The five-year overall survival rates were 66.98% for left-sided colon cancer and 57.77% for right-sided colon cancer (P-value 0.063). The right-sided primary tumor location was associated with a significantly higher mortality rate (HR: 2.28; 95%CI 1.38–5.8; P-value: 0.004). Conclusion: The results of this study confirmed that patients with high-risk stage II and stage III colon cancer who had right-sided tumors were significantly more likely to have decreased disease-free survival and overall survival. Further prospective studies should focus on tumor genetics and proper durations of adjuvant chemotherapy to maximize the benefit of treatment with acceptable toxicity.

O103 The relationship between routine pre-operative clinicopathological factors and post-operative infective complications in patients undergoing elective potentially curative colon cancer resection

Abstract Introduction Post-operative complications, in particular infective complications, following elective colon cancer resection remain common. The present cohort study was designed to determine the influence of routinely reported clinicopathological factors on post-operative infective complications in a large regional cohort undergoing potentially curative colon cancer. Methods Patients who underwent elective potentially curative colon cancer resection between January 2011 and December 2014 were assessed for post-operative complications. Clinicopathological data were recorded in a prospectively maintained database. A multivariate binary logistic regression model was used to identify independent risk factors for infective complications. Results A total of 1887 patients were included with 29% of patients developing post-operative infective complications (POI). Multivariate analysis showed that factors associated for both POI complications and surgical site infections (SSI) were higher body mass index (BMI) (POI OR 1.29, 95% CI 1.15–1.46, p&amp;lt;0.001 and SSI OR 1.4, 95% CI 1.23–1.60, p&amp;lt;0.001), diabetes (POI OR 1.45, 95% CI 1.06–1.99, p=0.022 and SSI OR 1.58, 95% 1.12–2.22, p=0.009) and open or laparoscopic converted to open surgical approach (POI OR 0.66, 95% CI 0.52–0.84, p=0.001 and SSI OR 0.70, 95% CI 0.53–0.93, p=0.012). While 30-day mortality was associated with older age, high ASA grade and pre-operative systematic inflammatory grade. Conclusion Elevated BMI and diabetes were independently associated with infective complications and surgical site infections. Therefore, the BMI and diabetes status should be routinely determined in patients undergoing elective surgery for colon cancer. Take-home message Body mass index and diabetes status should be actively determined prior to elective surgical intervention to allow for risk stratification and pre-operative optimisations.

ASO Author Reflections: Toward the Prediction of Peritoneal Recurrence After Curative Resection for Colon Cancer.

ASO Author Reflections: Toward the Prediction of Peritoneal Recurrence After Curative Resection for Colon Cancer.

Short- and long-term outcomes of single-incision laparoscopic surgery for right colon cancer: A multicenter propensity score-matched analysis.

Single-incision laparoscopic surgery (SILS) for colon cancer is a recent innovation in minimally invasive surgery that can improve short-term outcome. However, several biases exist in current favorable comparisons of SILS with conventional laparoscopic (CL) surgery. Moreover, the oncological outcomes in SILS remain unclear. The aim of this study was to identify outcomes following SILS and CL for right colectomy using a propensity score-matched analysis. A total of 553 patients underwent curative resection for right colon cancer (58 SILS and 495 CL). After propensity score matching, 58 patients in each group were matched. Before matching, median age was younger (p=0.037) and clinical stage was lower (p < 0.001) in the SILS group. After matching, operation time was shorter (172 versus 193 min, p=0.007) and blood loss was less (12 versus 20 mL, p=0.037) in the SILS group. Most of the SILS cases were performed (43.1%) or supervised (51.7%) by an expert surgeon. Median follow-up duration was 30 and 37 mo in the SILS and CL groups, respectively. Three-year relapse-free survival was 92.5% and 92.4% (p=0.781); and overall survival was 100% versus 98.1% (p=0.177). Under the control of expert surgeons, SILS appeared to be a safe and feasible approach and had similar oncological outcomes compared with CL in a propensity score-matched cohort of patients with right-sided colon cancer.

Clinical Benefit of Preserving Inferior Mesenteric Vein in Laparoscopic Curative Resection for Descending and Splenic Flexure Colon Cancer: A Comparative Study of CT-based objective Evidence

Background: Although the presence of remnant long sigmoid colon after left hemicolectomy with inferior mesenteric vein (IMV) ligation is a major risk factor for venous ischemia, there is insufficient objective evidence to support the clinical benefit of IMV preservation in curative resection for distal transverse, descending and splenic flexure colon cancer. This study was to confirm the patency through CT after IMV preservation in laparoscopic left hemicolectomy for distal transverse, descending and splenic flexure colon cancer, and to analyze the clinical outcomes compared to the IMV ligation group.

The association between tumour sidedness, clinicopathological characteristics and outcomes in patients undergoing curative resection for colon cancer.

148 Background: Right-sided colon cancer is associated with worse outcomes than left-sided disease, likely due to an association between tumour/host factors and tumour sidedness. The present study analyses the association between tumour sidedness, clinicopathological features and common mutations to better understand this discrepancy in outcomes. Methods: The association between tumour sidedness, clinicopathological characteristics and survival was examined within a cohort of patients undergoing curative surgery for TNM I-III colon cancer. Results: 3,419 patients were identified. 54% of cases were right-sided and associated with worse 3-year OS/CSS. On multivariate analysis for clinical factors: sex (OR 0.63), Systemic Inflammatory Grade (SIG), anaemia and differentiation (OR 0.80/0.31/0.57) were associated with T3 cancer sidedness and: sex, anaemia and differentiation (OR 0.61/0.46/0.57) were associated with T4 cancer sidedness. On further MVA including mutational factors anaemia/BRAF status remained significant in T3/T4 cancer respectively (OR 0.08/0.09). BRAF mutant status was associated with SIG in all patients/T3 disease (p=0.046/0.016). Conclusions: Worse outcomes seen in right-sided colon cancer are likely explained predominantly by factors including tumour stage, SIG, anaemia and BRAF mutational status. BRAF mutations are associated with the Systemic Inflammatory Response and further research is required to better understand this relationship taking into the tumour microenvironment, microsatellite instability.[Table: see text]

Curative Resection of Transverse Colon Cancer with Duodenal Invasion and Tumor Thrombus of the Superior Mesenteric Vein—Report of a Case—

症例は84歳の男性で，貧血症状を契機に横行結腸癌と診断された．画像診断にて腫瘍は十二指腸下行脚に浸潤して瘻孔を伴い，さらに腫瘍から胃結腸静脈幹を経由して上腸間膜静脈に至る腫瘍塞栓を認めた．術中所見では腹膜播種や肝転移は認めずR0切除可能と判断し，右半結腸切除術および上腸間膜静脈合併切除再建を伴う亜全胃温存膵頭十二指腸切除術を施行した．病理組織学的検査所見は，pT4b（十二指腸），pN0，pStage IIc，R0，Cur Aであり，術後9カ月経過した現在，無再発生存中である．他臓器浸潤や腫瘍塞栓を伴う局所進行大腸癌でもR0切除できれば良好な予後が期待できるため，腫瘍の進展に応じた術式の工夫が必要である．

Comprehensive or specialty-specific cancer care in the United States: A story of continuing underperformance.

6577 Background: “Textbook oncologic outcome” (TOO) is a composite measure representing the “ideal” outcome for patients undergoing cancer surgery and is associated with improved survival. Using TOO as the primary outcome, we asked whether hospitals are high-performing across multiple cancer types. Methods: Patients undergoing potentially curative breast, colon, rectal, lung, or pancreatic cancer resection were identified within the National Cancer Database (2010-2016). Organ-specific TOO was defined as: adequate lymph node yield, R0 resection, non-length of stay outlier, no hospital readmission, no 90-day postoperative mortality, and receipt of guideline-concordant chemotherapy and/or radiation. Mixed-effects analyses estimated the risk-adjusted TOO rate for each hospital stratified by cancer type. Results: Among 1,094,550 cancer resections (breast = 690,442; colon = 213,918; lung = 121,771; rectum = 40,315; pancreas = 28,104), 434 hospitals performed ≥10 resections for each cancer type. Only 11 hospitals (2.5%) ranked in the top quartile for adjusted TOO rate for all five cancer types. Of the 323 hospitals (74.4%) that ranked in the top quartile for one cancer type, 149 hospitals (46.1%) also ranked in the bottom quartile for another cancer type. There was a weak correlation between hospital rankings across cancer types with the strongest correlations between colon and rectal cancer (R2= 0.148) and lung and pancreatic cancer (R2= 0.098). Conclusions: Most U.S. hospitals do not provide high-quality care across cancer types with respect to TOO. Perhaps this knowledge should be used to guide referral for oncology care.

Development and external validation of a nomogram predicting overall survival after curative resection of colon cancer.

ObjectiveTo develop and externally validate a prognostic nomogram to predict overall survival (OS) in patients with resectable colon cancer.MethodsData for 50,996 patients diagnosed with non-metastatic colon cancer were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were assigned randomly to the training set (n = 34,168) or validation set (n = 16,828). Independent prognostic factors were identified by multivariate Cox proportional hazards regression analysis and used to construct the nomogram. Harrell’s C-index and calibration plots were calculated using the SEER validation set. Additional external validation was performed using a Chinese dataset (n = 342).ResultsHarrell’s C-index of the nomogram for OS in the SEER validation set was 0.71, which was superior to that using the 7th edition of the American Joint Committee on Cancer TNM staging (0.59). Calibration plots showed consistency between actual observations and predicted 1-, 3-, and 5-year survival. Harrell’s C-index (0.72) and calibration plot showed excellent predictive accuracy in the external validation set.ConclusionsWe developed a nomogram to predict OS after curative resection for colon cancer. Validation using the SEER and external datasets revealed good discrimination and calibration. This nomogram may help predict individual survival in patients with colon cancer.

A Novel Fluorescent c-Met Targeted Imaging Agent for Intra-Operative Colonic Tumour Mapping: Translation from the Laboratory into a Clinical Trial

Background: Curative resection of colon cancer requires accurate intraoperative identification of tumour margins and lymph node (LN) burden. The c-Met protein is important for cell differentiation and migration and is overexpressed in many gastrointestinal cancers. We explored EMI-137, a novel c-Met targeting fluorescent probe, for application in fluorescence-guided colon surgery, in HT-29 colorectal cancer (CRC) cell line and an in vivo murine model. This informed a first-in-man clinical trial of EMI-137. Methods: HT-29 cells were used as a representative CRC model. SiRNA was used to demonstrate the specificity of EMI-137 for c-Met. A HT-29 CRC xenograft model was developed in female BALB/c mice. Tumours were cultured for 14 days to 10mm diameter. EMI-137 (0.18mg/kg) was injected into tail veins and biodistribution analysed through in vivo fluorescent imaging. Nine patients, aged 67-77 years, received a single intravenous dose of EMI-137 (0.13mg/kg), 1-3 hours before laparoscopic-assisted colon cancer resection surgery (NCT03360461). Tumour and LN fluorescence was assessed with a modified Karl Storz® laparoscope. Immunohistochemistry with a monoclonal antibody analysed c-Met expression in eight resected samples. Findings: c-Met expression in HT-29 cells was effectively silenced and imaged with EMI-137. Strong EMI-137 uptake in tumour xenografts was observed for up to 6 hours post-administration. At clinical trial, no serious adverse events related to EMI-137 were reported. Marked background fluorescence was observed in all trial participants, 4/9 showed an increase in tumour fluorescence over background; 5/9 had histological LN metastases; no fluorescent LN were detected intraoperatively. All primary tumours (8/8) and malignant LN (15/15) exhibited moderate to high c-Met protein expression. Interpretation: EMI-137, binds specifically to the human c-Met transmembrane protein, is safe in patients and with further refinement, shows potential for long-term application in fluorescence-guided colon surgery. Trial Registration: The trial was registered with ClinicalTrials.gov identifier NCT03360461. Funding: Research was supported by internal University of Leeds funding. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Ethical approval was granted by the Yorkshire and Humber Leeds West Research and Ethics Committee (Ref 17/YH/0263), on 19th October 2017 and Regulatory approval was granted by the Medicines and Healthcare products Regulatory Agency (MHRA), under The Medicines for Human Use (Clinical Trials) regulations on 29th August 2017.

The prognostic value of combined measures of the systemic inflammatory response in patients with colon cancer: an analysis of 1700 patients.

The pre-operative systemic inflammatory response (SIR) measured using an acute-phase-protein-based score (modified Glasgow Prognostic Score (mGPS)) or the differential white cell count (neutrophil-lymphocyte ratio (NLR)) demonstrates prognostic significance following curative resection of colon cancer. We investigate the complementary use of both measures to better stratify outcomes. The effect on survival of mGPS and NLR was examined using uni/multivariate analysis (UVA/MVA) in patients undergoing curative surgery for colon cancer. The synergistic effect of these scores in predicting OS/CSS was examined using a Systemic Inflammatory Grade (SIG). One thousand seven hundred and eight patients with TNM-I-III colon cancer were included. On MVA both mGPS and NLR were significant for OS (HR 1.16/1.21, respectively). Three-year survival stratified by mGPS was 83-58%(TNM-I-III), 87-65%(TNM-II) and 75-49%(TNM-III), and by NLR was 84-62%(TNM-I-III), 88-69%(TNM-II) and 77-49%(TNM-III). When mGPS and NLR were combined to form an overall SIG 0/1/2/3/4, this stratified 3-year OS 88%/84%/76%/65%/60% and CSS 93%/90%/82%/73%/70%, respectively (both p < 0.001). SIG stratified OS 93-68%/82-48% and CSS 97-80%/86-58% in TNM Stage II/III disease, respectively (all p < 0.001). The present study shows that the pre-operative SIR in patients undergoing curative surgery for colon cancer is best measured using a SIG utilising mGPS and NLR.