Comparing the efficacy of combined versus single immune cell adaptive therapy targeting colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is the most frequent cancer with limited therapeutic achievements. Recently, adoptive cellular immunotherapy has been developed as an antitumor therapy. However, its efficacy has not been tested in CRC. This study investigated the ability of an immune cell cocktail of dendritic cells (DCs), T cells, and natural killer (NK) cells to overcome immunological hurdles and improve the therapeutic efficacy of cell therapy for CRC. METHODS: CRC lysate-pulsed monocyte-derived DCs (Mo-DCs), CRC antigen-specifically expanded T cells (CTL), and in vitro-expanded NK cells were cultured from patient peripheral blood mononuclear cells (PBMC). The ability of the combined immune cells to kill autologous tumor cells was investigated by co-culturing the combined immune cells with patient-derived tumor cells. RESULTS: The Mo-DCs produced expressed T cell co-stimulating molecules like CD80, CD86, human leukocyte antigen (HLA)-DR and HLA-ABC, at high levels and were capable of activating naive T cells. The expanded T cells were predominantly CD8 T cells with high levels of CD8 effector memory cells and low levels of regulatory T cells. The NK cells expressed high levels of activating receptors and were capable of killing other cancer cell lines (K562 and HT29). The immune cell cocktail demonstrated a higher ability to kill autologous tumor cells than single types. An in vivo preclinical study confirmed the safety of the combined immune cell adaptive therapy showing no therapy-related death or general toxicity symptoms. CONCLUSION: The results suggested that combined immune cell adaptive therapy could overcome the limited efficacy of cell immunotherapy.

Long-term outcomes after endoscopic versus surgical resection of T1 colorectal carcinoma.

BACKGROUND: The long-term outcomes of patients with T1 colorectal cancer (CRC) who undergo endoscopic and/or surgical treatment are not well understood. Invasive CRC confined to the colonic submucosa (T1 CRC) is challenging in terms of clinical decision-making. We compared the long-term outcomes of T1 CRC by treatment method. METHODS: We examined 370 patients with pathological T1 CRC treated between 2000 and 2015 at Seoul St. Mary's Hospital. In total, 93 patients underwent endoscopic resection (ER) only, 82 underwent additional surgery after ER, and 175 underwent surgical resection only. Patients who did not meet the curative criteria were defined as "high-risk." High-risk patients were classified into three groups according to the treatment modalities: ER only (Group A: 35 patients), additional surgery after ER (Group B: 72 patients), and surgical resection only (Group C: 133 patients). The recurrence-free and overall survival (OS) rates, and factors associated with recurrence and mortality, were analyzed. Factors associated with lymph node metastasis (LNM) were subjected to multivariate analysis. RESULTS: Of the 370 patients, 7 experienced recurrence and 7 died. All recurrences occurred in the high-risk group and two deaths were in the low-risk group. In high-risk groups, there was no significant group difference in recurrence-free survival (P = 0.511) or OS (P =0.657). Poor histology (P =0.042) was associated with recurrence, and vascular invasion (P =0.044) with mortality. LNMs were observed in 30 of 277 patients who underwent surgery either initially or secondarily. Lymphatic invasion was significantly associated with the incidence of LNM (P < 0.001). CONCLUSIONS: ER prior to surgery did not affect the prognosis of high-risk T1 CRC patients, and did not worsen the clinical outcomes of patients who required additional surgery. Lymphatic invasion was the most important predictor of LNM.

The effect of probiotics supplementation in postoperative cancer patients: a prospective pilot study.

PURPOSE: Microbiota manipulation through selected probiotics may be a promising tool to prevent cancer development as well as onset, to improve clinical efficacy for cancer treatments. The purpose of this study was to evaluate change in microbiota composition after-probiotics supplementation and assessed the efficacy of probiotics in improving quality of life (QOL) in postoperative cancer patients. METHODS: Stool samples were collected from 30 cancer patients from February to October 2020 before (group I) and after (group II) 8 weeks of probiotics supplementation. We performed 16S ribosomal RNA gene sequencing to evaluate differences in gut microbiota between groups by comparing gut microbiota diversity, overall composition, and taxonomic signature abundance. The health-related QOL was evaluated through the EORTC Quality of life Questionnaire Core 30 questionnaire. RESULTS: Statistically significant differences were noted in group II; increase of Shannon and Simpson index (P = 0.004 and P = 0.001), decrease of Bacteroidetes and Fusobacteria at the phylum level (P = 0.032 and P = 0.014, retrospectively), increased of beneficial bacteria such as Weissella (0.096% vs. 0.361%, P < 0.004), Lactococcus (0.023% vs. 0.16%, P < 0.001), and Catenibacterium (0.0% vs. 0.005%, P < 0.042) at the genus level. There was a significant improvement in sleep disturbance (P = 0.039) in group II. CONCLUSION: Gut microbiota in cancer patients can be manipulated by specific probiotic strains, result in an altered microbiota. Microbiota modulation by probiotics can be considered as part of a supplement that helps to increase gut microbiota diversity and improve QOL in cancer patients after surgery.

Prognostic role of pre-sarcopenia and body composition with long-term outcomes in obstructive colorectal cancer: a retrospective cohort study.

BACKGROUND: The clinical significance of pre-sarcopenia in colorectal cancer obstruction has not yet been described. The present study aimed to determine the short- and long-term oncologic impacts of pre-sarcopenia in obstructive colorectal cancer. METHODS: We retrospectively analyzed 214 patients with obstructive colon cancer between January 2004 and December 2013. Initial staging computed tomography (CT) scans identified pre-sarcopenia and visceral obesity by measuring the muscle and visceral fat areas at the third lumbar vertebra level. Both short-term postoperative and long-term oncologic outcomes were analyzed. RESULTS: Among all 214 patients, 71 (33.2%) were diagnosed with pre-sarcopenia. Pre-sarcopenia had a negative oncologic impact in both disease-free survival (DFS) and overall survival (OS), (hazard ratio [HR] = 1.86, 95% confidence interval [CI] 1.04-3.13, p = 0.037, and HR = 1.92, CI 1.02-3.60, p = 0.043, respectively). Visceral adiposity, body mass index (BMI), and neutrophil-lymphocyte ratio (NLR) did not significantly impact DFS and OS. CONCLUSION: Pre-sarcopenia is a clinical factor significantly associated with OS and DFS but not with short-term complications in obstructive colorectal cancer. In future, prospective studies should incorporate body composition data in patient risk assessments and oncologic prediction tools.

Multifrequency Bioelectrical Impedance Analysis Compared With Computed Tomography for Assessment of Skeletal Muscle Mass in Primary Colorectal Malignancy: A Predictor of Short-Term Outcome After Surgery.

BACKGROUND: Herein, we evaluate the accuracy and reliability of multifrequency bioelectrical impedance analysis (BIA) to assess skeletal muscle mass (SMM) in the colorectal cancer patient compared with computed tomography (CT) scan and also analyze the association between SMM of BIA and postoperative outcomes. METHODS: From March to May 2017, the body composition of patients scheduled for elective surgery due to primary colorectal cancer in our institution was analyzed at the time of admission using BIA (InBody S20, Biospace Co Ltd, Seoul, South Korea). The relationship between the single cross-sectional area of skeletal muscle at the lumbar region using preoperative CT scan and the SMM determined via BIA were assessed. Postoperative outcomes were compared according to different status of SMM on BIA categorized into 3 groups (low, medium, or high). RESULTS: Fifty patients were analyzed, and the length of hospital stay was shorter and the initiation of oral diet was significantly earlier in the group with high SMM than in other groups (P = 0.001 and 0.038, respectively). The SMM on BIA showed a very significant correlation with skeletal muscle index using CT scan (0.705 of correlation coefficients, P < 0.001) and also strongly correlated with skeletal muscle index after adjusting for age, weight, and BMI on multivariate analysis (ß = 0.391 ± 0.057, P < 0.001). CONCLUSION: SMM determined by BIA is strongly correlated with SMM estimated by CT scan. Authors suppose that BIA could be an alternative to CT scan for the assessment of SMM in colorectal cancer patients.

Comparison of the effects of an ERAS program and a single-port laparoscopic surgery on postoperative outcomes of colon cancer patients.

Advancement of the surgical modality and perioperative care are the two main dimensions for the modern improvement of surgical outcome. The purpose of this study was to compare the effectiveness of the two by using the data from the single-port laparoscopic surgery and the early recovery after surgery (ERAS) program. Patients who underwent elective surgery for primary adenocarcinoma of the colon were divided into three groups and compared: ERAS (multi-port laparoscopic surgery with ERAS perioperative care), Conventional-SILS (single-port surgery with conventional perioperative care), or Conventional-Multi (multi-port laparoscopic surgery with conventional perioperative care). Ninety-one, 83, and 96 patients were registered, respectively. There were no differences among the three groups in baseline characteristics except pathological stage and operation site in colon. Although the ERAS group started a soft diet earlier and had earlier discharge, there were no differences in intra- and post-operative morbidity rate, readmission rate, or reoperation rate. The ERAS perioperative care was a significant factor for reducing length of hospital stay in the multivariate analysis, while single-port surgery was not. In modern laparoscopic colon cancer treatment, a systemic approach such as the ERAS program appears to be more effective than a technical approach for significantly improving short-term surgical outcomes.

Sarcopenia is negatively associated with long-term outcomes in locally advanced rectal cancer.

BACKGROUND: The association of sarcopenia and visceral obesity to treatment outcome is not clear for locally advanced rectal cancer. This study evaluates the influence of skeletal muscle and visceral fat on short-term and long-term outcomes in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation therapy followed by curative resection. METHODS: A total of 188 patients with locally advanced cancer were included between January 2009 and December 2013. Neoadjuvant chemoradiotherapy was followed by curative resection. Sarcopenia and visceral obesity were identified in initial staging CT by measuring the muscle and visceral fat area at the third lumbar vertebra level. RESULTS: Among the 188 included patients, 74 (39.4%) patients were sarcopenic and 97 (51.6%) patients were viscerally obese. Sarcopenia and high levels of preoperative carcinoembryonic antigen were significant prognostic factors for overall survival (P = 0.013, 0.014, respectively) in the Cox regression multivariate analysis. Visceral obesity was not associated with overall survival; however, it did tend to shorten disease-free survival (P = 0.079). CONCLUSIONS: Sarcopenia is negatively associated with overall survival in locally advanced rectal cancer patients who underwent neoadjuvant chemoradiation therapy and curative resection. Visceral obesity tended to shorten disease-free survival. Future studies should be directed to optimize patient conditions according to body composition status.

Effect of Adjuvant Chemotherapy on Stage II Colon Cancer: Analysis of Korean National Data.

PURPOSE: Debates exist regarding the effectiveness of adjuvant chemotherapy for stage II colon cancer. This study aimed to investigate the current status of adjuvant chemotherapy and its impact on survival for Korean stage II colon cancer patients by analyzing the National Quality Assessment data. MATERIALS AND METHODS: A total of 7,880 patientswho underwent curative resection for stage II colon adenocarcinoma between January 2011 andDecember 2014 in Koreawere selected randomly as evaluation subjects for the quality assessment. The factors that influenced overall survival were identified. The high-risk group was defined as having at least one of the following: perforation/ obstruction, lymph node harvest less than 12, lymphovascular/perineural invasion, positive resection margin, poor differentiation, or pathologic T4 stage. RESULTS: The median follow-up period was 38 months (range, 1 to 63 months). Chemotherapy was a favorable prognostic factor for either the high- (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.38 to 0.59; p < 0.001) or low-risk group (HR, 0.74; 95% CI, 0.61 to 0.89; p=0.002) in multivariate analysis. This was also the case in patients over 70 years of age. The hazard ratio was significantly increased as the number of involved risk factors was increased in patients who didn't receive chemotherapy. Adding oxaliplatin showed no difference in survival (HR, 1.36; 95% CI, 0.91 to 2.03; p=0.132). CONCLUSION: Adjuvant chemotherapy can be recommended for stage II colon cancer patients, but the addition of oxaliplatin to the regimen must be selective.

Novel predictors for lymph node metastasis in submucosal invasive colorectal carcinoma.

AIM: To evaluate a novel grading system to predict lymph node metastasis (LNM) in patients with submucosal invasive colorectal carcinoma (SICRC). METHODS: We analyzed the associations between LNM and various clinicopathological features in 252 patients with SICRC who had undergone radical surgery at the Seoul Saint Mary's hospital between 2000 and 2015. RESULTS: LNM was observed in 31 patients (12.3%). The depth and width of the submucosal invasion, lymphatic invasion, tumor budding, and the presence of poorly differentiated clusters (PDCs) were significantly associated with the incidence of LNM. Using multivariate analysis, the receiver operating characteristic curvewas calculated and the area under curve (AUC) was used to compare the ability of the different parameters to identify the risk of LNM. The most powerful clinicopathological parameter for predicting LNM was lymphatic invasion (difference AUC = 0.204), followed by the presence or absence of tumor budding (difference AUC = 0.190), presence of PDCs (difference AUC = 0.172) and tumor budding graded by the Ueno method (difference AUC = 0.128). CONCLUSION: Our results indicate that the tumor budding and the depth multiplied by the width measurements of submucosal invasion can provide important information for patients with SICRC.

The prognostic significance of KRAS and BRAF mutation status in Korean colorectal cancer patients.

BACKGROUND: BRAF and KRAS mutations are well-established biomarkers in anti-EGFR therapy. However, the prognostic significance of these mutations is still being examined. We determined the prognostic value of BRAF and KRAS mutations in Korean colorectal cancer (CRC) patients. METHODS: From July 2010 to September 2013, 1096 patients who underwent surgery for CRC at Seoul St. Mary's Hospital were included in the analysis. Resected specimens were examined for BRAF, KRAS, and microsatellite instability (MSI) status. All data were reviewed retrospectively. RESULTS: Among 1096 patients, 401 (36.7%) had KRAS mutations and 44 (4.0%) had BRAF mutations. Of 83 patients, 77 (92.8%) had microsatellite stable (MSS) or MSI low (MSI-L) status while 6 (7.2%) patients had MSI high (MSI-H) status. Patients with BRAF mutation demonstrated a worse disease-free survival (DFS, HR 1.990, CI 1.080-3.660, P = 0.02) and overall survival (OS, HR 3.470, CI 1.900-6.330, P < 0.0001). Regarding KRAS status, no significant difference was noted in DFS (P = 0.0548) or OS (P = 0.107). Comparing the MSS/MSI-L and MSI-H groups there were no significant differences in either DFS (P = 0.294) or OS (P = 0.557). CONCLUSIONS: BRAF mutation, rather than KRAS, was a significant prognostic factor in Korean CRC patients at both early and advanced stages. The subgroup analysis for MSI did not show significant differences in clinical outcome. BRAF should be included in future larger prospective biomarker studies on CRC.

The positive impact of surgical quality control on adequate lymph node harvest by standardized laparoscopic surgery and national quality assessment program in colorectal cancer.

PURPOSE: We aimed to present the factors associated with lymph node harvest (LNH) and seek whether surgical quality control measures can improve LNH. METHODS: From a prospectively collected data at a single institution, 874 CRC patients who underwent curative surgery between 2004 and 2013 were included. Factor and survival analyses were performed regarding LNH. Subgroup analysis was performed according to LNH group (LNH ≥ 12 vs LNH < 12) and year of surgery (2004-2008, 2009-2011, and 2012-2013 group). RESULTS: In the multivariate analysis, tumor location (OR 0.6, p < 0.001), stage (OR 1.95, p < 0.001), and year of surgery (OR 3.86, p < 0.001) showed an association with adequate LNH. In the subgroup analysis categorized by the year of surgery, surgical quality control measures by standardized laparoscopic surgery (OR 52.91, p < 0.001) showed notable association with adequate LNH. Comparing the 2009-2011 and 2012-2013 group, the national quality assessment program additionally improved adequate LNH percentage (83.9 vs 94.3%). In the survival analysis, disease-free survival (DFS) differed according to year of surgery, standardized laparoscopic surgery with high vascular ligation, and adequate LNH by stage. In the overall survival (OS) analysis, the LNH-related factors did not show significant difference. CONCLUSIONS: Through standardized laparoscopic surgery with high vascular ligation and national quality assessment program, surgical quality control had a positive impact on the increase of adequate LNH. Improving the modifiable LNH factors resulted in the enhancement of adequate LNH and related DFS.