Expression of Immune-Related and Inflammatory Markers and Their Prognostic Impact in Colorectal Cancer Patients.

The tumor microenvironment of colorectal cancer (CRC) is heterogenous; thus, it is likely that multiple immune-related and inflammatory markers are simultaneously expressed in the tumor. The aim of this study was to identify immune-related and inflammatory markers expressed in freshly frozen CRC tissues and to investigate whether they are related to the clinicopathological features and prognosis of CRC. Seventy patients with CRC who underwent curative surgical resection between December 2014 and January 2017 were included in this study. Tissue samples were obtained from tumor and non-tumor areas in the patients' colons. The concentrations of immune-related markers (APRIL/TNFSF13, BAFF, LAG-3, PD-1, PD-L1, and CTLA-4) and inflammatory markers (CHIT, MMP-3, osteocalcin, pentraxin-3, sTNF-R1, and sTNF-R2) in the samples were measured using the Bio-plex Multiplex Immunoassay system. The concentrations of APRIL/TNFSF13, BAFF, and MMP-3 in the samples were significantly high; thus, we conducted analyses based on the cut-off values for these three markers. The high-APRIL/TNFSH13-expression group showed a significantly higher rate of metastatic lesions than the low-expression group, whereas the high-MMP-3-expression group had higher CEA levels, more lymph node metastases, and more advanced disease stages than the low-expression group. The five-year disease-free survival of the high-MMP-3-expression group was significantly shorter than that of the low-expression group (65.1% vs. 90.2%, p = 0.033). This study provides evidence that the APRIL/TNFSF13, BAFF, and MMP-3 pathway is overexpressed in CRC tissues and is associated with unfavorable clinicopathological features and poor prognosis in CRC patients. These markers could serve as diagnostic or prognostic biomarkers for CRC.

Role of TGF-ß and p38 MAPK in TSG-6 Expression in Adipose Tissue-Derived Stem Cells In Vitro and In Vivo.

Mesenchymal stem cells (MSCs) regulate immune cell activity by expressing tumor necrosis factor-α (TNF-α)-stimulated gene 6 (TSG-6) in inflammatory environments; however, whether anti-inflammatory responses affect TSG-6 expression in MSCs is not well understood. Therefore, we investigated whether transforming growth factor-ß (TGF-ß) regulates TSG-6 expression in adipose tissue-derived stem cells (ASCs) and whether effective immunosuppression can be achieved using ASCs and TGF-ß signaling inhibitor A83-01. TGF-ß significantly decreased TSG-6 expression in ASCs, but A83-01 and the p38 inhibitor SB202190 significantly increased it. However, in septic C57BL/6 mice, A83-01 further reduced the survival rate of the lipopolysaccharide (LPS)-treated group and ASC transplantation did not improve the severity induced by LPS. ASC transplantation alleviated the severity of sepsis induced by LPS+A83-01. In co-culture of macrophages and ASCs, A83-01 decreased TSG-6 expression whereas A83-01 and SB202190 reduced Cox-2 and IDO-2 expression in ASCs. These results suggest that TSG-6 expression in ASCs can be regulated by high concentrations of pro-inflammatory cytokines in vitro and in vivo, and that A83-01 and SB202190 can reduce the expression of immunomodulators in ASCs. Therefore, our data suggest that co-treatment of ASCs with TGF-ß or p38 inhibitors is not adequate to modulate inflammation.

Differences in clinical features and oncologic outcomes between metastatic right and left colon cancer.

Approximately 20% to 25% of patients with colorectal cancer (CRC) have distant organ metastasis at the time of initial diagnosis. The primary tumor location has been suggested as a prognostic factor for patients with metastatic CRC. In recent years, the distinction between right colon cancer (RCC) and left colon cancer (LCC) has been brought into focus due to their different outcomes, prognoses, and clinical responses to chemotherapy. In this article we aimed to review the underlying differences between metastatic RCC and LCC in terms of epidemiology, clinical features, and oncologic outcomes. The outcomes of patients with left-sided tumors were better than those of patients with right-sided tumors in terms of overall survival (OS) and objective response rate (ORR) after treatment with chemotherapy + panitumumab in the PRIME and 20050181 trials. The outcomes of patients with LCC were better than those of patients with RCC in terms of OS, progression-free survival (PFS) and ORR after treatment with FOLFIRI + cetuximab in the CRYSTAL and CALGB 80405 trials. In the FIRE-3 trial, the OS and PFS, but not the ORR, of patients with LCC were superior to those of patients with RCC. LCC and RCC exhibit distinctive clinical features and epidemiology. However, we must further investigate the impact of these distinctive features and how they influence the differential oncologic outcomes.

The Expression Patterns of Immune Checkpoint Molecules in Colorectal Cancer: An Analysis Based on Microsatellite Status.

Recently, immunotherapy has arisen as a novel treatment approach for patients with colorectal cancer (CRC), but the effectiveness of immunotherapy varies in these patients. We hypothesized that immune checkpoint molecules (ICMs), which are the targets of immunotherapy, are often exhibited concomitantly. Our objective was to investigate the patterns of ICM expression in patients with CRC and the differences in ICM expression based on microsatellite instability status. The immunohistochemical expression of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG-3) in the tumor center and periphery was assessed in patients with non-metastatic colorectal cancer. We enrolled 83 patients with CRC: a total of 40 microsatellite-stable (MSS) and 43 microsatellite-instability-high (MSI-H) cancer patients. PD-L1 was more frequently expressed in the tumor center in the MSI-H patients with than that in the MSS patients (18 [41.9%] vs. 3 [7.5%], respectively; p < 0.001), and the same trend was observed for TIM-3 expression (30 [69.8%] vs. 19 [47.5%], respectively; p = 0.047). The concomitant expression of two or more ICMs was more frequently observed than no expression or the expression of a single molecule in both the MSS and MSI-H groups; a total of 34 (79.7%) patients with MSI-H cancer and 23 (57.5%) with MSS cancer showed ICM expression at the tumor center, whereas 34 (79.7%) patients with MSI-H cancer and 22 (55%) with MSS cancer showed expression at the tumor periphery. Patients with the genetic characteristics of MSI-H cancer showed higher expression levels of ICMs than those in patients with MSS cancer, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC.

EMR1/ADGRE1 Expression in Cancer Cells Upregulated by Tumor-Associated Macrophages Is Related to Poor Prognosis in Colorectal Cancer.

EMR1, a member of the adhesion G protein-coupled receptor family (ADGRE1), is a macrophage marker that is abnormally expressed in cancer cells. However, its clinical significance in colorectal cancer (CRC) is not well-known. In this investigation, EMR1 expression in tumor cells (EMR1-TC) was found in 91 (22.8%) of the 399 CRC samples tested by immunohistochemical staining and showed a significant relationship with lymph node metastasis. Furthermore, EMR1-TC was significantly associated with CD68+ CD163+ tumor-associated macrophages (TAMs), and CRC with a high combined EMR1-TC+CD68+CD163+ score showed worse recurrence-free survival prognosis. In an in vitro co-culture assay of colon cancer cells with myeloid cells, we found that EMR1 expression significantly upregulated in cancer cells was induced by macrophages. In addition, there was increased expression of M2 markers (CD163 and interleukin-6 & 10) in myeloid portion, while that of M1 markers (CD86 and iNOS) remained unchanged. Accordingly, upon treatment with M2 macrophage polarization inhibitors (O-ATP, trametinib, bardoxolone methyl), EMR1 expression reduced significantly, along with M2 markers (CD163 and interleukin-6 & 10). In conclusion, EMR1-TC was a high-risk factor for lymph node metastasis and correlated with poor recurrence free survival, particularly in patients with TAM-rich CRC. Furthermore, EMR1 expression in colon cancer cells may be related to M2 macrophage polarization and vice versa.

Risk Factors for Mortality Associated With Pelvic Fractures at a Level I Trauma Center.

Pelvic bone fractures are usually caused by high-energy trauma and are often accompanied by organ injuries. For hemodynamically unstable patients with pelvic bone fractures, knowing the anatomic type of fracture-whether it is a pelvic ring injury or an acetabular fracture-might be helpful in prioritizing treatment. A total of 302 patients with pelvic bone fractures who received treatment at the authors' level I trauma center between March 1, 2015, and February 28, 2017, were included in this study. Patients with pelvic bone fractures were enrolled in the Korea Trauma Data Bank and classified by anatomic type of pelvic bone fracture: pelvic ring injury, acetabular fracture, or combined fractures. The authors used t tests to analyze survival and death groups and multivariate regression to analyze mortality factors. Different types of pelvic bone fractures had significantly different mortality rates (P<.001). Forty-four (22.6%) of 195 patients with pelvic ring injuries and 6 (18.8%) of 32 patients with combined fractures died. Meanwhile, only 1 of 75 patients with isolated acetabular fractures died (1.3%). The mortality rate was lowest for type A pelvic ring injuries (8.2%) and highest for type C pelvic ring injuries (68.2%). The difference was statistically significant (P<.001). It is commonly acknowledged that age, combined injuries, higher Injury Severity Score, and lower initial systolic blood pressure are risk factors for mortality, but research has shown that classification and anatomic type of pelvic bone fracture are also highly related. [Orthopedics. 2021;44(6):e724-e728.].

Robotic versus laparoscopic low anterior resection of rectal cancer: short-term outcome of a prospective comparative study.

BACKGROUND: The aim of this study is to compare the short-term results between robotic-assisted low anterior resection (R-LAR), using the da Vinci Surgical System, and standard laparoscopic low anterior resection (L-LAR) in rectal cancer patients. METHODS: 113 patients were assigned to receive either R-LAR (n = 56) or L-LAR (n = 57) between April 2006 and September 2007. Patient characteristics, perioperative clinical results, complications, and pathologic details were compared between the groups. Moreover, macroscopic grading of the specimen was evaluated. RESULTS: Patient characteristics were not significantly different between the groups. The mean operation time was 190.1 +/- 45.0 min in the R-LAR group and 191.1 +/- 65.3 min in the L-LAR group (P = 0.924). The conversion rate was 0.0% in the R-LAR groups and 10.5% in the L-LAR group (P = 0.013). The serious complication rate was 5.4% in the R-LAR group and 19.3% in the L-LAR group (P = 0.025). The specimen quality was acceptable in both groups. However, the mesorectal grade was complete (n = 52) and nearly complete (n = 4) in the R-LAR group and complete (n = 43), nearly complete (n = 12), and incomplete (n = 2) in the L-LAR group (P = 0.033). CONCLUSION: R-LAR was performed safely and effectively, using the da Vinci Surgical System. The use of the system resulted in acceptable perioperative outcomes compared to L-LAR.

Improvement of outcomes in patients with pelvic fractures and hemodynamic instability after the establishment of a Korean regional trauma center.

PURPOSE: Despite using a multidisciplinary treatment approach, the mortality rate of patients with hemodynamic instability from severe pelvic fractures is still 40-60%. We evaluated the improvement of outcomes in this patient population after the establishment of a regional trauma center in Korea. METHODS: We retrospectively reviewed the medical charts of 50 patients with hemodynamic instability due to pelvic fractures between March 2011 and November 2016. Patients were divided into two groups: the pre-trauma center (PTC) group (n = 23) and trauma center (TC) group (n = 27). RESULTS: Sixteen (32.0%) patients died of exsanguination. Patients in the TC group had shorter trauma resuscitation room stay (101 vs 273 min, p < 0.001) and underwent preperitoneal pelvic packing (PPP) more frequently (88.9 vs 8.7%, p < 0.001) than those in the PTC group. During the TC period, emergent procedures such as PPP and pelvic angiography were performed more frequently (92.6 vs 39.1%, p < 0.001). Although there was no statistical difference in the overall mortality rate between groups, patients in the TC group had less mortality due to hemorrhage (18.5 vs 47.8%, p = 0.027). Logistic regression analysis demonstrated that initial systolic blood pressure and establishment of trauma center were independent protective factors of mortality from hemorrhage [odds ratio (OR) 0.957, 95% confidence interval (CI) 0.926-0.988, p = 0.007; OR 0.134, 95% CI 0.028-0.633, p = 0.011]. CONCLUSIONS: Since the regional trauma center was established, emergent procedures such as pelvic angiography and PPP were performed more frequently, and mortality due to exsanguination was significantly decreased.

Effectiveness and postoperative wound infection of preperitoneal pelvic packing in patients with hemodynamic instability caused by pelvic fracture.

INTRODUCTION: Despite the use of a multidisciplinary treatment approach, the mortality rate of hemodynamic instability due to severe pelvic fracture remains 40-60%. Several recent studies have shown that preperitoneal pelvic packing (PPP) was useful for achieving hemostasis in these patients in the acute phase. However, few studies have examined postoperative complications. The purpose of the present study was to evaluate clinical outcomes and wound infections of PPP in these patients. MATERIALS AND METHODS: We retrospectively reviewed the medical charts of 62 patients with hemorrhagic shock due to pelvic fracture between March 2011 and May 2017. Excluding four patients (two with other major hemorrhage sites and two who experienced cardiac arrest in the emergency room), the patients were divided into PPP (n = 30) and non-PPP (n = 28) groups according to PPP application. Clinical outcomes including early-stage mortality, transfusion amount, and surgical site infection (SSI) were compared between the two groups. RESULTS: The overall mortality rate was 48.3% and the mean Injury Severity Score (ISS) was 39 ± 9. The 30 patients in the PPP group had a significantly lower hemorrhage-induced mortality rate than the 28 patients in the non-PPP group (16.7% vs 50%, p = 0.019), although both groups had similar patient characteristics (age, ISS, and initial serum lactate level). Independent factors associated with hemorrhage-induced mortality were PPP and the requirement of packed red blood cells for 4 h. In the PPP group, SSI occurred in 5 of 25 (20%) patients. CONCLUSIONS: PPP may be considered as a hemostatic modality for hemodynamic instability due to pelvic fracture because it reduces the hemorrhage-induced mortality rate. However, wound infections after the procedure should be considered.

Efficacy and toxicity of high-dose nebulized colistin for critically ill surgical patients with ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii.

PURPOSE: Few studies have compared nebulized and intravenous (IV) colistin for multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa pneumonia. This study compared the nephrotoxicity and clinical outcomes for these two delivery routes. METHODS: This study retrospectively compared 95 critically ill surgical patients who were diagnosed with Acinetobacter baumannii ventilator associated pneumonia and received colistin between March 2013 and January 2016. RESULTS: The most common diagnoses were brain hemorrhage (27.4%), traumatic brain injury (20%), traumatic thoracic injury (15.8%), and secondary peritonitis (11.6%). Compared to the IV group, the nebulizer group was significantly older (60.0 vs. 67.5years, p=0.010), had higher APACHE II scores (16.3 vs. 19.9, p=0.001), and more frequently had diabetes mellitus (6.8% vs. 21.6%, p=0.043). Nephrotoxicity was more common in the IV group (60.5% vs. 15.7%, p<0.0001). Both groups had similar microbiological and clinical outcomes (p=0.921 and p=0.719, respectively). Patients with nephrotoxicity exhibited prolonged IV or nebulized colistin treatment and more frequent combination with vancomycin. Nephrotoxicity was independently associated with IV delivery (odds ratio: 8.48, 95% confidence interval: 2.95-24.39, p<0.0001). CONCLUSIONS: Nebulized colistin may have less nephrotoxicity and provide similar clinical results, compared to IV colistin.

Diagnostic and therapeutic role of endoscopic retrograde pancreatography in the management of traumatic pancreatic duct injury patients: Single center experience for 34 years.

BACKGROUND: Traumatic pancreatic injuries are rare and present diagnostic and therapeutic difficulties. We evaluated the usefulness of endoscopic retrograde pancreatography and transpapillary pancreatic stent in the diagnosis and treatment of pancreatic trauma patients. METHODS: We reviewed medical records of 83 pancreas trauma patients who underwent endoscopic retrograde pancreatography for the suspicion of pancreas duct injury between January 1983 and December 2016. Patient notes, radiologic findings, laboratory investigations, operative records, and endoscopic retrograde pancreatography reports were reviewed. RESULTS: Pre-endoscopic retrograde pancreatography abdominal computed tomography was performed in 52 patients. Twenty-seven patients of them were diagnosed with a major pancreatic duct injury by subsequent endoscopic retrograde pancreatography. Eleven major pancreatic duct injuries (40.7%) were missed by the pre-endoscopic retrograde pancreatography abdominal CT. Major pancreatic duct injury was confirmed by endoscopic retrograde pancreatography in 43 patients. These 43 major pancreatic duct injury patients were classified into the Operative (n = 21), Stent (n = 15), and Conservative (n = 7) groups according to the first treatment modality which was chosen by attending surgeon. Age, initial white blood cell count, initial serum amylase, associated injury, and major pancreatic duct injury site were similar among groups, while the rate of parenchymal leakage (Dye leakage confined to pancreatic capsule) on endoscopic retrograde pancreatography findings differed. Parenchymal leakage was most common in the Conservative group. Pancreas related mortality occurred in 1 (4.76%) Operative group, 2 (13.33%) Stent group, and 0 (0%) Conservative group. Pancreas related complication occurred in 16 (76.19%) Operative group, 10 (66.67%), Stent group and 5 (71.43%) Conservative group. There were no statistically significant differences in the occurrence rate of pancreas related complications and mortalities among three groups. CONCLUSION: Endoscopic retrograde pancreatography helps clinicians choose a treatment modality for major pancreatic duct injury since it provides information about the precise condition of the major pancreatic duct injury. Endoscopic retrograde pancreatography with transpapillary pancreatic stenting also shows promise as a substitute for laparotomy or pancreatic resection in selected patients.

In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer.

PURPOSE: We evaluated the usefulness of the in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) for prediction of clinical response to fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer. MATERIALS AND METHODS: Tumor specimens of 86 patients with pathologically confirmed stage II colorectal adenocarcinoma were tested for chemosensitivity to fluorouracil. Chemosensitivity was determined by cell death rate (CDR) of drug-exposed cells, calculated by comparing the intracellular ATP level with that of untreated controls. RESULTS: Among the 86 enrolled patients who underwent radical surgery followed by fluorouracil-based adjuvant chemotherapy, recurrence was found in 11 patients (12.7%). The CDR ≥ 20% group was associated with better disease-free survival than the CDR < 20% group (89.4% vs. 70.1%, p=0.027). Multivariate analysis showed that CDR < 20% and T4 stage were poor prognostic factors for disease-free survival after fluorouracil-based adjuvant chemotherapy. CONCLUSION: In stage II colorectal cancer, the in vitro ATP-CRA may be useful in identifying patients likely to benefit from fluorouracil-based adjuvant chemotherapy.

Contributing factors on lymph node yield after surgery for mid-low rectal cancer.

PURPOSE: The purpose of the present study was to evaluate the contributing factors to the lymph node status as well as to define the impact of preoperative concurrent chemoradiotherapy (CCRT) on the number of lymph nodes retrieved in mid-low rectal cancer. MATERIALS AND METHODS: We retrospectively analyzed 277 patients who underwent curative surgical resection for mid-low rectal cancer between 1998 and 2007. Eighty-two patients received long course preoperative CCRT followed by surgery. RESULTS: A mean of 13.12±9.28 lymph nodes was retrieved. In a univariate analysis, distance from the anal verge, pT stage, pN stage, lymphovascular invasion, preoperative CCRT had significant influence on the number of lymph nodes retrieved. In a multivariate model, patients in the CCRT group had fewer retrieved lymph nodes than the non-CCRT group (p<0.001). Both univariate and multivariate analyses showed that the ypN0 group had fewer retrieved lymph nodes than the ypN1-2 group (p=0.027) in the CCRT group. CONCLUSION: Preoperative CCRT was an independent risk factor for failure to harvest an appropriate number of lymph nodes, and node-negative patients who received CCRT had fewer lymph nodes harvested.

Outcomes of laparoscopic gastrectomy after endoscopic treatment for gastric cancer: a comparison with open gastrectomy.

PURPOSE: Additional gastrectomy is needed after endoscopic resection for early gastric cancer when pathology confirms any possibility of lymph node metastasis or margin involvement. No studies depicted the optimal type of surgery to apply in these patients. We compared the short-term and long-term outcomes of laparoscopic gastrectomy with those of open gastrectomy after endoscopic resection to identify the optimal type of surgery. MATERIALS AND METHODS: From 2003 to 2010, 110 consecutive patients who underwent gastrectomy with lymphadenectomy either by laparoscopic (n=74) or by open (n=36) for gastric cancer after endoscopic resection were retrospectively analyzed. Postoperative and oncological outcomes were compared according to types of surgical approach. RESULTS: Clinicopathological characteristics were comparable between the two groups. Laparoscopic group showed significantly shorter time to gas passing and soft diet and hospital day than open group while operation time and rate of postoperative complications were comparable between the two groups. All specimens had negative margins regardless of types of approach. Mean number of retrieved lymph nodes did not differ significantly between the two groups. During the median follow-up of 47 months, there were no statistical differences in recurrence rate (1.4% for laparoscopic and 5.6% for open, P=0.25) and in overall (P=0.22) and disease-free survival (P=0.19) between the two groups. Type of approach was not an independent risk factor for recurrence and survival. CONCLUSIONS: Laparoscopic gastrectomy after endoscopic resection showed comparable oncologic outcomes to open approach while maintaining benefits of minimally invasive surgery. Thus, laparoscopic gastrectomy can be a treatment of choice for patients previously treated by endoscopic resection.