Intratumour Fusobacterium nucleatum and immune response to oesophageal cancer.

BACKGROUND: Experimental evidence suggests a role of intratumour Fusobacterium nucleatum in the aggressive behaviour of gastrointestinal cancer through downregulating anti-tumour immunity. We investigated the relationship between intratumour F. nucleatum and immune response to oesophageal cancer. METHODS: Utilising an unbiased database of 300 resected oesophageal cancers, we measured F. nucleatum DNA in tumour tissue using a quantitative polymerase chain reaction assay, and evaluated the relationship between the abundance of F. nucleatum and the densities of T cells (CD8 + , FOXP3 + and PDCD1 + ), as well as lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoural lymphocytic reaction, stromal lymphocytic reaction and tumour-infiltrating lymphocytes) in oesophageal carcinoma tissue. RESULTS: F. nucleatum was significantly and inversely associated only with the peritumoural lymphocytic reaction (P = 0.0002). Compared with the F. nucleatum-absent group, the F. nucleatum-high group showed a much lower level of the peritumoural lymphocytic reaction (univariable odds ratio, 0.33; 95% confidence interval, 0.16-0.65; P = 0.0004). A multivariable model yielded a similar finding (multivariable odds ratio, 0.34; 95% confidence interval 0.16-0.69; P = 0.002). CONCLUSIONS: Intratumour F. nucleatum is associated with a diminished peritumoural lymphocytic reaction, providing a platform for further investigations on the potential interactive roles between intratumour F. nucleatum and host immunity.

Endoscopic Surgical Skill Qualification System: propensity-score matched cohort analysis of accredited supervisors in laparoscopic rectal cancer surgery.

BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). METHODS: We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. RESULTS: Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 - 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). CONCLUSION: This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.

The evaluation of postoperative bowel dysfunction in Japanese patients with rectal cancer.

PURPOSE: The present study assessed postoperative bowel dysfunction in Japanese patients with rectal cancer, including patients who underwent preoperative radiotherapy (RT). METHODS: A total of 277 rectal cancer patients who underwent primary resection were included in the analyses. A questionnaire survey was administered using the low anterior resection syndrome (LARS) score and Wexner score. Scores were determined one year after rectal surgery or diverting ileostomy closure. The LARS score was categorized as minor LARS (21-29) and major LARS (30-42). RESULTS: The proportions of patients with minor and major LARS were significantly larger and Wexner scores significantly higher in patients with distal tumors and a lower anastomosis level than in those with proximal tumors and a higher anastomosis level. Among the patients with lower rectal cancer, the proportions with minor and major LARS were similar between those with and without preoperative RT. The Wexner scores in patients with preoperative RT were significantly higher than in patients without RT. A distal tumor location and lower anastomosis level were independent risk factors of major LARS in multivariate analyses. CONCLUSION: A distal tumor location, low anastomosis level, and preoperative RT might be associated with postoperative bowel dysfunction in rectal cancer patients.

Preoperative iron status is a prognosis factor for stage II and III colorectal cancer.

BACKGROUND: Iron deficiency anemia is represented in colorectal cancer (CRC) patients. Iron surplus load to increase non-transferrin bound iron (NTBI), and NTBI promotes cancer progression and influences microbiota. This study investigated whether preoperative serum iron status was associated with prognosis after CRC resection. METHODS: We evaluated preoperative iron and transferrin saturation (TSAT), which was calculated as iron divided by total iron-binding capacity, in 327 patients who underwent surgery for Stage II-III CRC. Fe < 60 µg/dl and TSAT > 40% were defined as low and high iron, respectively. The associations between iron status and overall survival (OS) were evaluated in univariate and multivariate Cox proportional hazards analysis. RESULTS: Of the 327 patients, 179 (54.7%), 124 (37.9%) and 24 (7.3%) had low, normal and high iron, respectively. In univariate analysis, low iron was associated with shorter OS (hazard ratio [HR] 2.821, 95% confidence interval [CI] 1.451-5.485, P = 0.002). High iron was also associated with shorter OS (HR 3.396, 95% CI 1.359-8.489, P = 0.009). In multivariate analysis, high age (P = 0.002), depth of invasion pT4 (P = 0.012), lymph-node metastasis presence (P = 0.035), low albumin (P = 0.011), low iron (HR 2.282, 95% CI 1.163-4.478, P = 0.016) and high iron (HR 3.757, 95% CI 1.486-9.494 P = 0.005) were independently associated with shorter OS. High iron was associated with the amount of intratumoral Fusobacterium nucleatum compared with normal iron. CONCLUSION: Both low and high preoperative iron in Stage II-III CRC patients were associated with unfavorable OS in univariate and multivariate analyses.

Tumor Long-interspersed Nucleotide Element-1 Methylation Level and Immune Response to Esophageal Cancer.

OBJECTIVE: To examine the relationship between tumor long-interspersed nucleotide element-1 (LINE-1) methylation level and immune response to esophageal cancer. BACKGROUND: Evidence points to a correlation between the abundance of immune cells and a favorable prognosis in esophageal cancer patients. Accumulating evidence indicates a critical role of tumor LINE-1 hypomethylation in the aggressive behavior of esophageal cancer, which in turn leads to an unfavorable prognosis. METHODS: Utilizing a nonbiased database of 292 resected esophageal cancers, we measured tumor LINE-1 methylation level by pyrosequencing assay, and examined the relationship between LINE-1 methylation and the density of T cells (CD8 and FOXP3) and the lymphocytic reaction patterns (follicle lymphocytic reaction, peritumoral lymphocytic reaction, stromal lymphocytic reaction, and tumor-infiltrating lymphocytes) in esophageal carcinoma tissue. RESULTS: LINE-1 hypomethylation was associated with male gender and advanced stage cancer (P = 0.03 and P = 0.048, respectively). Tumor LINE-1 methylation level was significantly positively associated with peritumoral lymphocytic reaction (P = 0.004), but not with others. Compared with LINE-1 hypermethylation group, LINE-1 hypomethylation group showed much lower level of peritumoral lymphocytic reaction (univariable odds ratio 0.32, 95% confidence interval 0.16-0.64, P = 0.002). In multivariable model to control for potential confounders including disease stage, the similar finding was observed (multivariable odds ratio 0.31, 95% confidence interval 0.14-0.66, P = 0.004). CONCLUSIONS: Tumor LINE-1 hypomethylation level is associated with a diminished peritumoral lymphocytic reaction, providing impetus for further investigations on potential interactive roles of tumor LINE-1 hypomethylation and host immunity in esophageal cancer development.

Prognostic Nutritional Index, Tumor-infiltrating Lymphocytes, and Prognosis in Patients with Esophageal Cancer.

OBJECTIVE: To determine whether prognostic nutritional index (PNI) affects clinical outcome through local immunity in esophageal cancers. BACKGROUND: PNI is an indicator of nutritional status and systemic immune competence, and has attracted attention as a prognostic biomarker. Tumor-infiltrating lymphocytes (TILs) are a specific histological feature of human cancers, reflecting an individual's immunological tumor response. METHODS: Using a nonbiased database of 337 curatively resected esophageal cancers, we evaluated the relationship between PNI, TILs status, CD8 expression by immunohistochemical staining, and clinical outcome. RESULTS: Compared with PNI-high cases (n = 220), PNI-low cases (n = 117) showed significantly worse overall survival (log-rank P < 0.001; hazard ratio: 2.23; 95% confidence interval: 1.56-3.18; P < 0.001; multivariate hazard ratio: 1.67; 95% confidence interval: 1.14-2.44; P = 0.008). The TILs status was also significantly correlated with overall survival (P < 0.001). In addition, PNI was significantly associated with TILs status (P < 0.001) and the CD8-positive cell count (P = 0.041). A significant relationship between the peripheral blood lymphocyte count and TILs status was also observed (P < 0.001). CONCLUSIONS: PNI and TILs score expression were associated with clinical outcome in esophageal cancer, supporting their roles as prognostic biomarkers. Considering the relationship between PNI and TILs, nutritional status and systemic immune competence may influence patient prognosis through local immune response.

Fibrosis-4 Index, a Noninvasive Fibrosis Marker, Predicts Survival Outcomes After Hepatectomy for Colorectal Cancer Liver Metastases.

BACKGROUND: Liver fibrosis influences liver regeneration and surgical outcomes, and several noninvasive models based on laboratory data have been developed to predict liver fibrosis. This study was performed to determine whether the Fibrosis-4 (FIB-4) index, a noninvasive fibrosis marker, can predict the prognosis in patients with colorectal liver metastases (CRLM) undergoing hepatectomy. METHODS: This retrospective study involved 193 consecutive patients with CRLM who underwent hepatectomy. The FIB-4 index was calculated by laboratory data and age before hepatectomy and before preoperative chemotherapy. The FIB-4 cut-off was determined using survival classification and regression tree analysis. Patients were divided into two groups (high and low FIB-4 index), and post-hepatectomy overall survival (OS) and recurrence-free survival (RFS) were investigated. RESULTS: In total, 193 patients were evaluated. Chemotherapy before hepatectomy was performed in 105 (54.4%) patients. A high FIB-4 index (> 2.736) was found in 39 (20.2%) patients. OS was significantly shorter in patients with a high FIB-4 index than those with a low FIB-4 index in the univariate (45.9 vs. 74.4 months, log-rank p = 0.007) and multivariate analysis (hazard ratio 2.28, 95% confidence interval 1.39-3.74; p = 0.001). Among patients who received chemotherapy before hepatectomy, those with a high FIB-4 index had significantly shorter RFS (6.9 vs. 45.3 months, log-rank p = 0.047) and OS (23.9 vs. 55.0 months, log-rank p = 0.003) than those with a low FIB-4 index. This association was also confirmed by multivariate analysis (hazard ratio 4.28, 95% confidence interval 1.46-12.6; p = 0.008). CONCLUSION: Both the preoperative and prechemotherapy FIB-4 index can predict long-term outcomes after hepatectomy in patients with CRLM.

Risk factors and prognostic significance of lateral pelvic lymph node metastasis in advanced rectal cancer.

BACKGROUND: The aim of this study was to elucidate the risk factors for and prognostic value of lateral pelvic lymph node (LPLN) metastasis in advanced rectal cancer patients, including those with stage IV disease. METHODS: The treatment outcomes of 78 patients with advanced rectal cancer, the lower margin of which was located at or below the peritoneal reflection, who underwent curative-intent surgery with bilateral LPLN dissection from 2005 to 2018 were retrospectively analyzed. RESULTS: In total, 78 rectal cancer patients, including 13 patients with stage IV tumors, 9 patients (11.5%) had LPLN metastasis. A multivariate analysis to identify preoperative clinical factors associated with LPLN metastasis showed that tumor location (below the peritoneal reflection: Rb), LPLN metastasis on preoperative imaging and distant metastasis were independent predictors of LPLN metastasis. In addition, metastasis at the regional lymph nodes in the mesorectum was significantly associated with LPLN metastasis. Both the disease-free survival (DFS) and cancer-specific survival (CSS) of patients with LPLN metastasis were significantly worse in comparison to patients without LPLN metastasis, and the CSS of stage IV patients with LPLN metastasis was significantly worse in comparison to stage IV patients without LPLN metastasis. CONCLUSIONS: Tumor location (Rb), LPLN metastasis on preoperative imaging and distant metastasis were risk factors for LPLN metastasis. The prognosis of rectal cancer patients with LPLN metastasis is poor. There may not be the indication of LPLN dissection in stage IV lower rectal cancer except cases having complaints due to LPLN metastasis.

Indoleamine 2, 3-dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune-based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5-azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin-fixed, paraffin-embedded samples resected from esophageal cancer patients. We treated cell lines with 5-azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = -0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.

Can PD-L1 expression evaluated by biopsy sample accurately reflect its expression in the whole tumour in gastric cancer?

Programmed death ligand 1 (PD-L1) expression as a predictive biomarker for programmed cell death 1 (PD-1) inhibitor efficacy in gastric cancer (GC) remains controversial. We hypothesised that the conflicting results may be due to the inaccurate assessment of PD-L1 expression using biopsy samples. A total of 191 patients with GC who received radical resection were enrolled. PD-L1 expressions in biopsy and paired resected samples by immunohistochemistry staining were compared according to the number of biopsies. The numbers of PD-L1-positive patients determined by biopsy and resected samples were 89 (46.6%) and 135 (70.1%), respectively. The accordance rate was 64.4% (κ = 0.31). Single biopsy showed a lower accordance rate compared with multiple biopsies. Our study revealed that single biopsy cannot fully reflect PD-L1 expression in the whole tumour in GC. Multiple biopsies are recommended for accurate diagnosis of PD-L1 expression in GC.

IDO1 Expression Is Associated With Immune Tolerance and Poor Prognosis in Patients With Surgically Resected Esophageal Cancer.

OBJECTIVES: To evaluate the relationship between indoleamine 2, 3-dioxygenase (IDO1) expression and tumoral immune status and clinical outcome in esophageal cancer. SUMMARY BACKGROUND DATA: IDO1 is a primary enzyme that generates immunosuppressive metabolites such as tryptophan and kynurenine. Like the PD-1/PD-L1 pathway, IDO1 plays a major role in tumor immunology and is a potential immune-based therapeutic target. METHODS: The expressions of IDO1, CD8 (a marker of cytotoxic T cells), FOXP3 [a marker of regulatory T cells (Treg)], and PD-L1 in 305 curatively resected esophageal cancers were evaluated by immunostaining. RESULTS: Overall survival was significantly better in the IDO1 negative cases (n = 234) than in the IDO1 positive cases (n = 71) [log-rank P = 0.0041; hazard ratio (HR): 1.75; 95% confidence interval (CI): 1.12-2.67; P = 0.015]. CD8 high expression was significantly positively correlated with overall survival (log-rank P = 0.025) and low IDO1 expression (P = 0.044). The inverse correlation between CD8 and IDO1 expressions was confirmed by double immunostaining for IDO1 and CD8. Stratification based on IDO1 and CD8 expressions was also significantly associated with overall survival (log-rank P = 0.0024). In addition, the IDO1-positive group was correlated with high counts of FOXP3-positive cells (P = 0.020), but not with PD-L1 expression status (P = 0.19). CONCLUSIONS: IDO1 expression was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. Combining the IDO1 and CD8 statuses enabled further classification of the clinical outcomes of patients.

Effect of Resection of the Thoracic Duct and Surrounding Lymph Nodes on Short- and Long-Term and Nutritional Outcomes After Esophagectomy for Esophageal Cancer.

BACKGROUND: The effect of resection of the thoracic duct (TD) along with surrounding lymph nodes (LN) on short- and long-term outcomes of esophagectomy in esophageal cancer patients is not well defined. METHODS: A total of 537 consecutive patients suffering from esophageal cancer who underwent three-incision esophagectomy between April 2005 and August 2018 were eligible for short-term outcome analysis. Among them, 487 patients who underwent surgery before August 2017 were eligible for analysis of long-term outcomes. Moreover, 164 patients who underwent esophagectomy after August 2012 and had no recurrence at 1-year postoperative follow-up were prospectively investigated for postoperative nutritional status. RESULTS: A total of 145 patients (27.0%) underwent TD resection with surrounding LN. Since the clinical stage was significantly more advanced in the removal group, preoperative treatment was more frequently performed in them. The operative time was significantly longer in the removal group. Intraoperative bleeding was higher in the removal group. Morbidity of Clavien-Dindo classification (CDc) ≥ II and pulmonary morbidities were frequently observed in the removal group. Multivariate analysis suggested that TD resection was an independent risk factor for pulmonary morbidities. Moreover, it may be associated with the incidence of CDc ≥ II morbidity. Greater numbers of LN were dissected in the thorax of patients in the removal group. However, overall survival was equivalent irrespective of the TD procedure in each stage. Nutritional status at 1-year follow-up was equivalent between the groups. CONCLUSIONS: On the basis of the present results, routine removal of the TD during esophagectomy is not recommended.

Clinical Importance of Sputum in the Respiratory Tract as a Predictive Marker of Postoperative Morbidity After Esophagectomy for Esophageal Cancer.

BACKGROUND: Respiratory morbidity is common after esophagectomy and can be a major cause of surgery-related mortality. Thus, it is important to identify novel predictors that can preoperatively estimate the incidence of postoperative respiratory morbidity. Asymptomatic sputum in the respiratory tract is sometimes observed on preoperative computed tomography (CT). This study aimed to determine the clinical importance of sputum in the respiratory tract as a predictor of postoperative morbidity after esophagectomy for esophageal cancer. PATIENTS AND METHODS: The study included 609 consecutive patients who underwent three-incisional esophagectomy for esophageal cancer between April 2005 and November 2018. RESULTS: Among the patients, 76 (12.5%) had sputum in the respiratory tract on preoperative CT. This finding was significantly associated with older age, more extreme smoking habit, worse performance status, lower forced expiratory volume 1%, and more frequent pulmonary comorbidities. Additionally, the incidence of postoperative pneumonia was higher in these patients than in those without sputum (16 vs 8%, p = 0.028). Sputum in the main bronchus was associated with higher frequencies of morbidity of Clavien-Dindo classification (CDc) ≥ II (p = 0.019), severe morbidity of CDc ≥ IIIb (p = 0.058), pneumonia (p = 0.10), and pulmonary morbidity (p = 0.19) compared with the finding of sputum in the trachea alone. On multivariate analysis, sputum in the respiratory tract was an independent risk factor (hazard ratio, 2.07; 95% confidence interval, 1.019-4.207; p = 0.044) for postoperative pneumonia. CONCLUSIONS: Sputum in the respiratory tract is a novel predictor of postesophagectomy pneumonia. Patients with sputum in the more distal respiratory tract might have high risk of postoperative morbidities.

The role of FBXW7, a cell-cycle regulator, as a predictive marker of recurrence of gastrointestinal stromal tumors.

BACKGROUND: Few reliable prognostic markers have been established despite elucidation of the molecular mechanisms of gastrointestinal stromal tumor (GIST) development. We evaluated F-box and WD repeat domain-containing 7 (FBXW7), a cell-cycle-regulating and tumor suppressor, in GISTs. We aimed to determine the clinical relevance of FBXW7 in GISTs and characterize the molecular mechanism of FBXW7 in a GIST cell line. METHODS: We measured FBXW7 expression in 182 GIST cases, correlated the expression levels with clinicopathological features, and characterized the molecular mechanism underlying suppressed FBXW7 expression in GIST cells in vitro. RESULTS: Of the 182 GISTs, 98 (53.8%) and 84 (46.2%) were categorized in the high and low FBXW7 expression groups, respectively. Compared with the high FBXW7 expression group, the low expression group showed a significantly poorer prognosis in terms of recurrence-free (P = 0.01) and overall (P = 0.03) survival. FBXW7 expression was a significant independent factor affecting the 10-year recurrence-free survival rate (P = 0.04). In vitro, FBXW7-specific siRNAs enhanced c-myc and Notch 1 protein expression and upregulated cell proliferation, invasion, and migration. CONCLUSION: FBXW7 is a potential predictive marker of recurrence after curative resection of GISTs. FBXW7 expression may help identify patients benefitting from adjuvant therapy more precisely compared with a conventional risk stratification model.

Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression.

RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Low Skeletal Muscle Mass before Salvage-Line Chemotherapy Is a Poor Prognostic Factor in Patients with Refractory Metastatic Colorectal Cancer.

BACKGROUND: Regorafenib and TAS-102 are standard salvage-line treatment options for patients with chemorefractory metastatic colorectal cancer (mCRC). We aimed to evaluate the prognostic significance of skeletal muscle mass in mCRC patients receiving these salvage-line therapies. METHODS: We conducted a retrospective analysis of 52 patients with mCRC who received regorafenib or TAS-102 as salvage-line treatment. Skeletal muscle cross-sectional area was measured by pretreatment CT to obtain the skeletal muscle index (SMI, cm2/m2). We divided patients into 2 groups (low-SM/high-SMI) based on the median value of SMI. RESULT: The median SMI was 51.8 cm2/m2 in males and 39.2 cm2/m2 in females. In Kaplan-Meier analysis, patients in the low-SMI group showed significantly shorter overall survival (3.7 vs. 7.3 months, log-rank p = 0.002) and progression-free survival (1.9 vs. 2.8 months, log-rank test p = 0.009) than those in the high-SMI group. Subsequent multivariate analysis revealed that the SMI was an independent prognostic factor (hazard ratio = 2.381, 95% CI 1.189-4.944, p = 0.014). Patients in the low-SMI group had significantly more grade 3 or 4 adverse events than those in the high-SMI group (46 vs.12%, p = 0.013). CONCLUSION: Low skeletal muscle mass is a negative factor for survival outcomes in mCRC patients treated with salvage-line chemotherapy.

CT-guided percutaneous radiofrequency ablation for lung metastases from colorectal cancer.

BACKGROUND: Radiofrequency ablation (RFA) can be a minimally invasive therapeutic option in patients with lung metastasis from colorectal caner. We aimed to elucidate the safety and survival benefit of computed tomography (CT)-guided percutaneous RFA for lung metastasis from colorectal cancer. METHODS: A total 188 lesions were ablated in 43 patients from 2005 to 2017. The clinicopathological and survival data of patients were collected retrospectively. The short- and long-term outcomes and prognostic factors were analyzed. RESULTS: Eight patients (18.6%) had viable extrapulmonary metastasis at RFA treatment. The median number of treated lung tumors was 2, and the median maximum diameter was 12 mm. Complications, such as pneumothorax, pleural effusion and subcutaneous emphysema, occurred in 24 (55.8%) patients. Although chest tube drainage for pneumothorax was needed in 6 patients (14.0%), there were no mortalities. Repeated RFA for lung recurrence after primary RFA was performed in 14 patients (32.6%). In a median follow-up of 24.3 months, the median progression-free and overall survival (OS) were 6.8 months and 52.7 months, respectively. The presence of extrapulmonary metastasis and a maximum tumors size of > 15 mm were independently associated with a worse disease-free survival and OS. The OS of patients who underwent repeated RFA was significantly better than that of patients who underwent RFA only once. CONCLUSION: CT-guided percutaneous RFA for lung metastasis from colorectal cancer is a safe and effective procedure in patients not eligible for surgery, particularly for lesions smaller than 1.5 cm without extrapulmonary metastasis.

Preservation of physiological passage through the remnant stomach prevents postoperative malnutrition after proximal gastrectomy with double tract reconstruction.

PURPOSE: Double tract reconstruction (DT) after proximal gastrectomy (PG) is considered beneficial for postoperative nutrition status by preserving the physiological passage of food. We conducted this study to assess postoperative nutrition status based on food passage after this operation. METHODS: The subjects of this retrospective study were 63 patients who underwent PG with DT. The patients were divided into two groups according to whether they had postoperative malnutrition (PM) 1 year postoperatively (PM group) or not (non-PM group). PM was defined by both weight loss > 10% and a low body mass index of < 20 or < 22 kg/m2 for patients younger and older than 70 years, respectively. We then evaluated the predictors of PM. RESULTS: There were 33 patients in the PM group. These patients were predominantly female (p < 0.01) and lacked physiological passage through the remnant stomach (PRS) on postoperative fluoroscopy (defined as non-PRS, p = 0.03). Multivariate logistic regression analysis revealed that female gender and non-PRS status were independent predictors of PM (odds ratio [95% CI]; 7.42 [1.33-41.4]; p = 0.02, 6.77 [1.01-45.4]; p = 0.04, respectively). CONCLUSION: Preservation of the physiological passage of food through the remnant stomach prevents PM after PG with DT.

PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer.

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.

Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc.

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5+ human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs. Stem Cells 2017;35:2027-2036.