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Background and aimsDistant metastasis is a major cause of deaths in patients with colorectal cancer (CRC), which is partly due to lack of robust metastasis-predictive biomarkers. In spite of the important function of microRNA (miR)-203 in cancer metastasis, its clinical significance in CRC metastasis remains unknown. Here, we evaluated the potential role of serum miR-203 as a non-invasive biomarker for CRC metastasis.MethodsMiR-203 expression was quantified by quantitative reverse-transcription PCR in 58 pairs of primary CRC (pCRC) and corresponding matched liver metastasis (LM), as well as 186 serum and 154 matched tissue specimens from patients with CRC in cohort 1. Next, we performed validation of miR-203 levels in serum from 144 patients with CRC in an independent cohort (cohort 2). Mouse models of CRC-associated metastases were established to identify the source of circulating miR-203. Expression patterns of miR-203 in tissues were determined by in situ hybridisation.ResultsMiR-203 expression was significantly upregulated in LM compared with matched pCRC tissues. Serum miR-203 levels were significantly upregulated in a stage-dependent manner, and high miR-203 expression was associated with poor survival in patients with CRC in both patient cohorts. Increased miR-203 levels in serum indicated high risk for poor prognosis (HR=2.1), as well as metastasis to lymph nodes (OR=2.5), liver (OR=6.2), peritoneum (OR=7.2) and distant organs (OR=4.4). Serum miR-203 levels were significantly higher in animals with liver or systemic metastasis compared with controls.ConclusionsHigh levels of serum miR-203 associate with poor survival and metastasis, suggesting it to be a promising non-invasive prognostic and metastasis-predictive biomarker in patients with CRC.

Neutrophil extracellular traps (NETs) represent extracellular microbial trapping and killing. Recently, it has been implicated in thrombogenesis, autoimmune disease, and cancer progression. The aim of this study was to characterize NETs in various organs of a murine sepsis model in vivo and to investigate their associations with platelets, leukocytes, or vascular endothelium. NETs were classified as two distinct forms; cell-free NETs that were released away from neutrophils and anchored NETs that were anchored to neutrophils. Circulating cell-free NETs were characterized as fragmented or cotton-like structures, while anchored NETs were characterized as linear, reticular, membranous, or spot-like structures. In septic mice, both anchored and cell-free NETs were significantly increased in postcapillary venules of the cecum and hepatic sinusoids with increased leukocyte-endothelial interactions. NETs were also observed in both alveolar space and pulmonary capillaries of the lung. The interactions of NETs with platelet aggregates, leukocyte-platelet aggregates or vascular endothelium of arterioles and venules were observed in the microcirculation of septic mice. Microvessel occlusions which may be caused by platelet aggregates or leukocyte-platelet aggregates and heterogeneously decreased blood flow were also observed in septic mice. NETs appeared to be associated with the formation of platelet aggregates or leukocyte-platelet aggregates. These observational findings may suggest the adverse effect of intravascular NETs on the host during a sepsis.

Background This study assessed programmed cell death ligand 1 (PD-L1) expression in primary tissues and soluble PD-L1 (sPD-L1) concentration in matched preoperative serum in gastric cancer (GC) patients to perform direct comparison between tissue and serum PD-L1 expression and to clarify the prognostic implication in GC. Methods The study enrolled 180 GC patients who underwent surgery for GC at the authors’ institution. The study evaluated tissue PD-L1 expression using immunohistochemistry and quantified sPD-L1 concentration in preoperative serum using enzyme-linked immunosorbent assay in GC patients. Results The findings showed that PD-L1 was overexpressed in GC tissues compared with normal mucosa. Tissue PD-L1 expression was significantly higher in the GC patients with advanced T stage, presence of lympho-vascular invasion, lymph node metastasis, and peritoneal metastasis. Furthermore, elevated tissue PD-L1 expression was significantly associated with poor prognosis for overall survival (OS) and disease-free survival (DFS). Serum sPD-L1 was significantly higher in the GC patients than in the healthy volunteers. Although serum sPD-L1 was not correlated with any clinicopathologic factors, the patients with high serum sPD-L1 showed poorer OS and DFS than those with low sPD-L1. Multivariate analyses showed that both elevated tissue PD-L1 and serum sPD-L1 were independent prognostic factors for poor OS [tissue PD-L1: hazard ratio (HR), 4.28; 95% confidence interval (CI), 1.43–12.8; P  = 0.0094 vs. serum sPD-L1: HR, 11.2; 95% CI, 3.44–36.7; P  = 0.0001] and poor DFS (tissue PD-L1: HR, 6.96; 95% CI, 2.48–19.6; P  = 0.0002 vs. serum sPD-L1: HR, 8.7; 95% CI, 3.16–23.9; P  < 0.0001) for the GC patients. Furthermore, infiltrative CD8- and Foxp3-positive T cells were significantly increased in the GC patients with elevated tissue PD-L1 expression. Conclusion Both serum sPD-L1 and tissue PD-L1 expression may serve as predictive biomarkers for recurrence and prognosis in GC patients.

BackgroundProgrammed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) play a pivotal role in cancer immunotherapy. Each of these molecules has a membrane-bound receptor form (mPD-L1/mCTLA-4) and a soluble form (sPD-L1/sCTLA-4). However, these prognostic impacts in colorectal cancer (CRC) remain unclear.MethodsWe immunohistochemically scored tumoral mPD-L1/mCTLA-4 expression and quantified preoperative circulating sPD-L1/sCTLA-4 levels using matched serum specimens from 131 patients with pStage I–III CRC. We also examined the association between these statuses and tumor infiltrating lymphocytes (TILs) in these patients.ResultsElevated levels of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 were significantly correlated with poor overall survival (OS) and disease-free survival (DFS). Co-high expression of tumoral mPD-L1 and mCTLA-4 or co-elevated levels of serum sPD-L1 and sCTLA-4 were strongly correlated with poor OS and DFS. Multivariate analysis revealed that both statuses were negative independent prognostic factors for OS [hazard ratio (HR) 3.86, 95% confidence interval (95% CI) 1.71–8.51, p = 0.001; HR 5.72, 95% CI 1.87–14.54, p = 0.004, respectively] and DFS (HR 2.53, 95% CI 1.23–4.95, p = 0.01; HR 6.88, 95% CI 2.42–17.13, p = 0.0008, respectively). Although low expression of tumoral mCTLA-4 was significantly correlated with increased CD8(+) TILs, there was no correlation in any other combination.ConclusionsWe verified the prognostic impacts of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 in pStage I–III CRC patients. Dual evaluation of immune checkpoint molecules in primary tissues or preoperative serum could identify a patient population with poor prognosis in these patients.

PurposeThe clinical significance of the platelet count × C-reactive protein level multiplier (P-CRP) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy followed by curative surgery has not been fully evaluated.MethodsIn this retrospective study, the correlation between the P-CRP and prognosis was evaluated in 135 patients with LARC. We also performed a subgroup analysis limited to patients with pathological TNM stage III [ypN(+)] LARC.ResultsThe cut-off value of the P-CRP for prognosis was set at 4.11. The high and low P-CRP groups comprised 39 (28.89%) and 96 (71.11%) patients, respectively. Among the investigated clinicopathological factors, the serum carcinoembryonic antigen level and presence of recurrence were significantly associated with the P-CRP value. In the Kaplan–Meier analysis, both overall survival (OS) and disease-free survival (DFS) were shorter in the high P-CRP group (p < 0.0001 and p = 0.0002, respectively; log-rank test). Multivariate analysis using a Cox proportional hazards model showed that a high P-CRP was an independent prognostic factor for OS [hazard ratio (HR) 29.20; 95% confidence interval (CI), 3.42–294.44; p = 0.0024] and DFS (HR 5.89; 95%CI 1.31–22.69; p = 0.023) in patients with LARC. In addition, a high P-CRP predicted poor OS and DFS in patients with pathological TNM stage III [ypN(+)] LARC (p = 0.0001 and p = 0.0012, respectively; log-rank test).ConclusionsThe P-CRP is a promising predictor of survival and recurrence in patients with LARC treated by neoadjuvant chemoradiotherapy followed by curative surgery.

Purpose The systemic inflammatory response is attracting increasing attention as a predictive biomarker for oncological outcome in patients with colorectal cancer. This study is aimed at verifying if the lymphocyte–C-reactive protein (CRP) ratio (LCR) could be used as a predictor of oncological outcome in patients with rectal cancer (RC) receiving preoperative chemoradiotherapy (CRT). Methods We analyzed data for 86 patients with RC who received preoperative CRT followed by total mesorectal excision at our institution. A ratio of 6000 was used as the cut-off value for LCR for further analysis. Results The post-CRT LCR was significantly lower than the pre-CRT LCR in patients with RC. Although post-CRT LCR status was not significantly correlated with overall survival (OS), low pre-CRT LCR was significantly associated with shorter recurrence-free survival (RFS: p  = 0.02) and OS ( p  = 0.017) in this population and was an independent prognostic factor for both RFS and OS (hazard ratio (HR) 3.19, 95% confidence interval (CI) 1.33–7.66, p  = 0.009; HR 2.83, 95%CI 1.14–7.01, p  = 0.025, respectively). Furthermore, low pre-CRT LCR was a stronger indicator of early recurrence ( p  = 0.001) and poor prognosis ( p  = 0.025) in RC patients without pathological lymph node metastasis compared with patients with pathological lymph node metastasis, and prognostic potential of pre-CRT LCR was clearly revealed especially RC patients receiving long-course CRT. Conclusions Assessment of pretreatment LCR status might aid decision-making regarding postoperative treatment strategies in patients with RC receiving CRT followed by potentially curative resection.

Aim The clinical significance of the geriatric nutritional risk index (GNRI) in locally advanced rectal cancer (LARC) patients undergoing preoperative chemoradiotherapy (CRT) followed by curative surgery has not been comprehensively evaluated. Methods This retrospective study enrolled 93 LARC patients diagnosed with clinical lymph node metastasis. The GNRI formula was as follows: 1.489 × albumin (g/l) + 41.7 × current weight/ideal weight. Patients were categorized as GNRI low (GNRI < 104.25) or high (GNRI > 104.25) according to the receiver operating characteristic (ROC) curve for survival analysis. The impact of GNRI status on the prognostic outcomes of curative surgery for LARC was examined. Results There were 55 (59.14%) and 38 (40.86%) patients in the GNRI high and low groups, respectively. Of the investigated demographic factors, age, pathological tumor invasion, and presence of recurrence were significantly associated with the GNRI value. In Kaplan–Meier analysis, overall survival (OS) and disease-free survival (DFS) were significantly shorter in the GNRI low group (OS: p  = 0.00020, DFS: p  = 0.0044, log-rank test). Multivariate analysis using a Cox proportional hazards model showed that a low GNRI was an independent risk factor for poor OS (hazard ratio (HR) = 3.22; 95% confidence interval (CI), 1.37–8.23; p  = 0.0068) and DFS (HR = 2.32; 95%CI = 1.15–4.79; p  = 0.018). Although use of adjuvant therapy has no impact on prognosis (OS: p  = 0.26, DFS: p  = 0.29), low GNRI showed shorter OS and DFS in patients with pathological lymph node metastasis [ypN(+)] (OS: p  = 0.033, DFS: p  = 0.032, log-rank test). Conclusions GNRI is a useful marker for LARC patients diagnosed with clinical lymph node metastasis and treated by preoperative CRT followed by curative surgery. GNRI is a useful tool to identify high risk of recurrence for improving the survival in LARC patients.

Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well‐established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P < 0.0001; log‐rank test) and disease‐free survival (IMAC: P = 0.0003; PMI: P = 0.0002; log‐rank test), multivariate Cox's regression analysis revealed that low PMI was an independent prognostic factor for both overall survival (hazard ratio: 4.69, 95% confidence interval (CI): 2.19–10, P = 0.0001) and disease‐free survival (hazard ratio: 2.33, 95% CI: 1.14–4.77, P = 0.021) in CRC patients. Serum miR‐203 expression negatively correlated with pre‐operative PMI level (P = 0.0001, ρ = −0.25), and multivariate logistic regression analysis revealed that elevated serum miR‐203 was an independent risk factor for myopenia (low PMI) in CRC patients (odds ratio: 5.16, 95% CI: 1.8–14.8, P = 0.002). Overexpression of miR‐203 inhibited cell proliferation and induced apoptosis via down‐regulation of BIRC5 (survivin) expression in human SkMC line. Conclusions Assessment of serum miR‐203 expression could be used for risk assessment of myopenia, and miR‐203 might be a novel therapeutic target for inhibition of myopenia in CRC.

Background Programmed cell death ligand 1 (PD-L1) regulates immune responses through interaction with its receptor. PD-L1 is not only a predictor of poor prognosis but also a new therapeutic target in several malignancies. Neoadjuvant chemoradiotherapy (CRT) is an effective tool for local control of rectal cancer, but the disease recurrence rate remains high. The aim of this study was to retrospectively evaluate the correlation between PD-L1 expression and clinicopathological variables in rectal cancer after neoadjuvant CRT. Materials and methods A total of 90 rectal cancer patients who underwent neoadjuvant CRT were enrolled in this study. We evaluated PD-L1 expression using immunohistochemistry. Moreover, we investigated the correlation between PD-L1 expression and tumor-infiltrating T cells, and between CD8- and Foxp3-positive cells. Results Patients with high PD-L1 expression more frequently had vascular invasion and tumor recurrence compared to patients with low PD-L1 expression ( P  = 0.0225 and P  = 0.0051). High PD-L1 expression was significantly associated with poor recurrence-free and overall survival ( P  = 0.0027 and P  = 0.0357). Multivariate analysis revealed lymph node metastasis and high PD-L1 expression as independent risk factors for tumor recurrence ( P  = 0.0102 and P  = 0.0374). Numbers of infiltrating CD8-positive cells in patients with high PD-L1 expression were significantly lower than in patients with low PD-L1 expression ( P  = 0.0322). Conclusion Our data suggest that inhibition of PD-L1 may be a new immunotherapeutic strategy to reduce tumor recurrence and improve prognosis in patients with rectal cancer after neoadjuvant CRT.

Background Intrapelvic aberrant needles are rare in clinical practice. Long-term foreign bodies in the abdominal cavity may form granulation tissue or an abscess, and may cause organ injury. Therefore, such foreign bodies need prompt removal. Case presentation A 26-year-old male athlete was referred to our hospital for investigation of an aberrant acupuncture needle in the gluteus. The needle was unable to be removed during acupuncture treatment, and the end broke off and remained in the gluteus. Abdominal X-ray examination showed a thin, 40-mm-long, metallic foreign body resembling an acupuncture needle. Abdominal computed tomography showed an abnormal shadow in the gluteus. However, it was unclear whether the tip of the needle reached the pelvic cavity. Thus, it was decided to surgically extract the needle via laparoscopic surgery under X-ray guidance as a safe and minimally invasive method. Although X-ray fluoroscopy confirmed that the aberrant needle was located in the gluteus, the needle could not be felt with the forceps, as the peritoneum surrounding the needle had granulomatous changes due to inflammation. Therefore, the retroperitoneum was further dissected to search for the needle. Once the needle was identified, its flexibility enabled it to be easily removed by grasping it directly with a needle holder. The length of the aberrant needle was 40 mm. The postoperative course was uneventful, and the patient was discharged from hospital on postoperative day 2. Conclusions When a foreign body remains in the gluteus and its tip touches intrapelvic organs, such as the rectum, it is critical to determine the best approach for its safe removal. Given the anatomical location of the foreign body and the patient background, laparoscopic removal was considered the best approach in the present case.