Clinical burden of preoperative albumin-globulin ratio in esophageal cancer patients.

BACKGROUND: Lower albumin-globulin ratio (AGR) is associated with increased mortality in several cancers. However, no studies have evaluated the relationship between the AGR and prognostic outcome in esophageal cancer (EC) patients. METHODS: To identify indicators of early recurrence and poor prognosis, we assessed the clinicopathological findings and preoperative laboratory data (carcinoembryonic antigen [CEA], squamous cell carcinoma antigen, total protein, and albumin) of 112 EC patients who underwent surgery. The AGR was calculated as albumin/(total protein-albumin). RESULTS: A lower AGR was significantly associated with tumor progression. The CEA level was an independent predictor for overall survival (OS) and disease-free survival (DFS). The AGR and CEA combination was identified as a feasible indicator of poor prognosis and early recurrence. Among EC patients without lymph node metastasis, those with lower AGR had poorer DFS and OS than those with higher AGR. CONCLUSION: AGR was identified as a significant predictor of OS and DFS in EC patients. Among EC patients without lymph node metastasis, AGR may help identify candidates who might benefit from more intensive adjuvant therapy.

Prognostic Impact of Preoperative Albumin-to-Globulin Ratio in Patients with Colon Cancer Undergoing Surgery with Curative Intent.

AIM: To identify predictors of poor prognosis of patients with colon cancer (CC) who underwent surgery with curative intent, we investigated the association between the albumin to globulin ratio (AGR) with clinicopathological findings such as overall (OS) and disease-free (DFS) survival. PATIENTS AND METHODS: We conducted a retrospective study of clinicopathological findings, including preoperative laboratory data, for 248 patients with stage I-III CC. RESULTS: Patients with low AGR had shorter DFS and OS compared to those with high AGR. Multivariate analyses identified low AGR as an independent variable independently associated with recurrence and poor prognosis of patients with CC who underwent surgery with curative intent regardless of lymphnode metastasis. CONCLUSION: The preoperative AGR was an independent predictor of recurrence and poor prognosis of patients with CC who underwent surgery with curative intent. The AGR indicates that these patients may benefit from intensive adjuvant therapy.

Inflammation-based prognostic scores as indicators to select candidates for primary site resection followed by multimodal therapy among colorectal cancer patients with multiple metastases.

BACKGROUND: Although patients with metastatic colorectal cancer (CRC) are often unable to undergo treatment after resection of primary tumors, identifying such patients before surgery is not easy. In this study, we evaluated the association among clinicopathological findings, survival outcomes, and ability to undergo multimodal therapy after primary tumor resection in patients with Stage IV CRC. METHODS: We collected clinicopathological findings and preoperative laboratory data, including carcinoembryonic antigen (CEA) and systemic inflammatory response markers for 92 patients who were treated for Stage IV CRC between 2005 and 2014. We used multivariate analysis on factors that affect prognosis and ability to undergo postoperative treatment. RESULTS: Postoperative multimodal therapy improved overall survival (OS) significantly. Among serum markers, elevated CEA, neutrophil-to-lymphocyte ratio, and modified Glasgow prognosis score (mGPS) were significant indicators of shorter OS. In multivariate analysis, low performance status (P = 0.003), undifferentiated histology type (P = 0.019), and elevated mGPS (P = 0.042) were independent predictors of worse prognosis; and older age (P = 0.016), right-sided colon cancer (P = 0.043), and elevated mGPS (P = 0.031) were independent risk factors for difficulty of introducing postoperative multimodal therapy. CONCLUSIONS: Preoperative mGPS is a useful objective indicator for CRC patients with multiple metastases who are able to undergo primary site resection followed by postoperative multimodal therapy.

Successful identification of a predictive biomarker for lymph node metastasis in colorectal cancer using a proteomic approach.

Colorectal cancer (CRC)-associated mortality is primarily caused by lymph node (LN) and distant metastasis, highlighting the need for biomarkers that predict LN metastasis and facilitate better therapeutic strategies. We used an Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-based comparative proteomics approach to identify novel biomarkers for predicting LN metastasis in CRC patients. We analyzed five paired samples of CRC with or without LN metastasis, adjacent normal mucosa, and normal colon mucosa, and differentially expressed proteins were identified and subsequently validated at the protein and/or mRNA levels by immunohistochemistry and qRT-PCR, respectively. We identified 55 proteins specifically associated with LN metastasis, from which we selected ezrin for further analysis and functional assessment. Expression of ezrin at both the protein and mRNA levels was significantly higher in CRC tissues than in adjacent normal colonic mucosa. In univariate analysis, high ezrin expression was significantly associated with tumor progression and poor prognosis, which was consistent with our in vitro findings that ezrin promotes the metastatic capacity of CRC cells by enabling cell invasion and migration. In multivariate analysis, high levels of ezrin protein and mRNA in CRC samples were independent predictors of LN metastasis. Our data thus identify ezrin as a novel protein and mRNA biomarker for predicting LN metastasis in CRC patients.

Esophageal Cancer with Bone Marrow Hyperplasia Mimicking Bone Metastasis: Report of a Case.

A 63-year-old man visited the clinic with numbness in the right hand. Magnetic resonance imaging demonstrated multiple low-intensity lesions in the cervical vertebrae and sacrum, which was suspicious of cervical bone metastasis. Fluorodeoxyglucose positron emission tomography/computed tomography revealed areas of increased fluorodeoxyglucose uptake in the thoracic esophagus, sternum and sacrum. A flat, elevated esophageal cancer was identified by upper gastrointestinal endoscopy, and the macroscopic appearance indicated early-stage disease. From the cervical, thoracic and abdominal computed tomography images, there were no metastatic lesions except for the bone lesions. To confirm whether the bone lesions were metastatic, we performed bone biopsy. The histopathological diagnosis was bone marrow hyperplasia. It was crucial for treatment planning to establish whether the lesions were distant metastases. Here, we report a case of esophageal cancer with bone marrow hyperplasia mimicking bone metastasis.

Intravital imaging of the effects of 5-fluorouracil on the murine liver microenvironment using 2-photon laser scanning microscopy.

5-fluorouracil (5FU) is often used in the treatment of colorectal cancer. 5FU improves the median overall and disease-free survival rates and reduces recurrence rates in patients who have undergone curative surgical resection. However, in the adjuvant setting, whether 5FU eradicates clinically undetectable micrometastases in target organs such as the liver, or whether 5-FU inhibits the adhesion of circulating tumor cells has not yet been established. In the present study, 5FU was administered following the inoculation of red fluorescent protein-expressing HT29 cells into green fluorescent protein (GFP)-transgenic nude mice to examine its inhibitory effect. 2-photon laser scanning microscopy was performed at selected time points for time-series imaging of liver metastasis of GFP-transgenic mice. The cell number in vessels was quantified to evaluate the response of the tumor microenvironment to chemotherapy. HT29 cells were visualized in hepatic sinusoids at the single-cell level. A total of 2 hours after the injection (early stage), time-series imaging revealed that the number of caught tumor cells gradually reduced over time. In the 5FU treatment group, no significant difference was observed in the cell number in the early stage. One week after the injection (late stage), a difference in morphology was observed. The results of the present study indicated that 5FU eradicated clinically undetectable micrometastases in liver tissues by acting as a cytotoxic agent opposed to preventing adhesion. The present study indicated that time-series intravital 2-photon laser scanning microscopic imaging of metastatic tumor xenografts may facilitate the screening and evaluation of novel chemotherapeutic agents with less interindividual variability.

Circulating microRNA-203 predicts metastases, early recurrence, and poor prognosis in human gastric cancer.

BACKGROUND: Metastasis is a major cause of death in patients with gastric cancer (GC). MicroRNAs (miRNAs) relating to the epithelial-mesenchymal transition (EMT) control GC progression and metastasis. The aim of this study was to evaluate serum EMT-associated miRNAs for metastatic and prognostic noninvasive biomarkers in GC. METHODS: In the first step of this study (preliminary experiments), we selected candidate miRNAs associated with metastasis by analyzing the expression of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141, and miR-429) and miR-203 in serum samples from stage I (n = 12) and stage IV (n = 12) GC patients. The second phase involved the independent validation of candidate miRNAs in serum specimens from 130 patients with GC and 22 controls. RESULTS: Based on the preliminary experiments, miR-203 was selected as the candidate serum miRNA that was most closely associated with metastasis. Validation analysis revealed that serum miR-203 levels were significantly lower in stage IV than stage I-III GC patients. Serum miR-203 expression was significantly lower in GC patients with a higher T stage, vessel invasion, and lymph node, peritoneal, and distant metastases. Low expression of serum miR-203 was significantly associated with poor disease-free and overall survival. Multivariate analysis revealed that low serum miR-203 expression was an independent predictive marker for lymph node, peritoneal, and distant metastases and a poor prognosis in patients with GC. CONCLUSIONS: Serum miR-203 has the potential to serve as a noninvasive biomarker for prognosis and to predict metastasis in patients with GC.

Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.

Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients.

Angiopoietin-like Protein 2 as a Predictor of Early Recurrence in Patients After Curative Surgery for Gastric Cancer.

BACKGROUND: Angiopoietin-like protein-2 (ANGPTL2) mediates chronic inflammation. Tumor cell-derived ANGPTL2 promotes tumor invasion and angiogenesis. ANGPTL2 expression has not been fully investigated in gastric cancer (GC). MATERIALS AND METHODS: ANGPTL2 expression in 354 patients with GC was assessed by immunohistochemistry (IHC). IHC scores were calculated, and the association of ANGPTL2 with clinicopathological factors and patient outcomes was evaluated. RESULTS: Immunoreactive ANGPTL2 protein was expressed mainly in GC cell cytoplasm. Kaplan-Meier analysis showed that high expression of ANGPTL2 indicated significantly poorer overall disease-free survival (DFS). Among patients with curatively resected GC, multivariate analysis for DFS revealed that high ANGPTL2 expression (p<0.01), advanced T-stage (p=0.015), lymph node metastasis (p<0.01), and advanced Unio Internationalis Contra Cancrum (UICC) stage (p<0.01) were independent risk factors for poor DFS. CONCLUSION: High cytoplasmic ANGPTL2 expression in GC tissue was associated with tumor progression, invasion, metastasis, and poor prognosis. ANGPTL2 may be a useful marker for detecting early postoperative recurrence in patients with GC.

Preoperative prediction of peritoneal metastasis in gastric cancer as an indicator for neoadjuvant treatment.

AIM: The aim of the present study was to investigate whether serum markers and clinical factors could be used for preoperative prediction of peritoneal metastasis in gastric cancer (GC) as an indicator for neoadjuvant treatment. PATIENTS AND METHODS: We enrolled 493 patients with GC for whom preoperative serum tumor markers [carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9], systemic inflammatory marker C-reactive protein (CRP), host immune markers [neutrophil and lymphocyte counts and their ratio (NLR)], albumin as a nutritional marker, and objective preoperative clinical factors were available as indicators of postoperative peritoneal metastasis. RESULTS: Specific clinical factors, including tumor size, histopathology of biopsy sample, and tumor morphology, were significantly correlated with peritoneal metastasis. CA19-9, lymphocyte count and NLR were also predictive factors for peritoneal metastasis. Multivariate analysis identified the clinical factors tumor morphology and histopathology, and laboratory markers CA19-9 and lymphocyte count as independent factors predictive for peritoneal metastasis. A combination of independent predictive factors achieved high predictive accuracy (0.882) for peritoneal metastasis preoperatively. CONCLUSION: A combination of specific factors is an alternative method to preoperatively discriminate patients with GC with peritoneal metastasis from those without.

Development of acute pancreatitis after Nissen fundoplication.

Acute pancreatitis subsequent to Nissen fundoplication for gastroesophageal reflux disease (GERD) is an extremely rare adverse event. We describe a pediatric case of acute pancreatitis resulting from superior mesenteric artery syndrome (SMAS) and gas bloat after fundoplication. Gas bloat is one of the known postoperative complications after Nissen fundoplication. Poor nutrition status, which is often associated with severe pediatric GERD, is a risk factor for SMAS. In this case, development of gas bloat and SMAS led to the formation of a closed loop and increased intraluminal pressure of the duodenum and pancreatic duct. Many pediatric patients who need anti-reflux surgery face the risk of developing this entity. Preventive measures, such as treatment with prokinetics and frequent small-volume meals, should be considered until improvement of nutritional status after fundoplication.

Visualization of in vivo thromboprophylactic and thrombolytic efficacy of enoxaparin in laser-induced vascular endothelial injury model using multiphoton microscopy.

Enoxaparin is used postoperatively for the prevention of venous thromboembolism. In vitro studies and clinical trials have demonstrated the anticoagulant and antithrombotic efficacy of enoxaparin. In this study, we visualised thromboprophylactic and thrombolytic efficacy of enoxaparin in a laser-induced thrombus formation model in vivo using two-photon laser-scanning microscopy (TPLSM). Thrombus was induced by the selective irradiation of vascular endothelium in arterioles of the cecum of green fluorescent protein transgenic mice. The thromboprophylactic and thrombolytic efficacy of enoxaparin was visualised in vivo real-time using TPLSM. Platelet adhesion, aggregation, and platelet-dependent thrombus formation were observed in the laser-induced thrombus formation model with reproducibility. Laser-induced thrombus formation was significantly inhibited by enoxaparin pretreatment as the thromboprophylactic agent, as compared with control. The mean thrombus volumes were 652 microcubic meters in mice pretreated with enoxaparin and 8906 microcubic meter in control mice. Enoxaparin reduced the volume of laser-induced thrombus when using it as a thrombolytic agent. The mean rate of reduction was 59 percent. In a lipopolysaccharide-induced sepsis model, thromboprophylactic efficacy of enoxaparin was also observed in vivo in real-time. In vivo thromboprophylactic and thrombolytic efficacy of enoxaparin can be visualised at the single platelet level in the laser-induced endothelium injury model using TPLSM.

Preoperative assessment of vascular anatomy by multidetector computed tomography before laparoscopic colectomy for transverse colon cancer: report of a case.

Although the safety of laparoscopic surgery for colon cancer has been reported in many randomized controlled trials, concerns about the difficulty of surgery for transverse colon cancer has not been fully resolved, mainly because of the variation in the vascular anatomy of mesenteric vessels, which leads to difficulty in determining the optimal operative procedure and the extent of lymph node dissection. We present the case of a patient with transverse colon cancer who underwent laparoscopic surgery after preoperative assessment using a combination of endoscopic clipping and three-dimensional computed tomography angiography (3DCTA). A 68-year-old man was diagnosed with transverse colon cancer, and laparoscopic surgery has been planned. 3DCTA showed right-middle and left-middle colic arteries arising independently from the superior mesenteric artery. The relationship between the clip and vessels showed that the right-middle colic artery was the feeding artery of the tumor. Operative findings were consistent with 3DCTA findings, and transverse colectomy with lymph node dissection was successfully performed.

Short- and long-term outcomes of laparoscopic gastrectomy in elderly patients with gastric cancer.

BACKGROUND: Elderly patients are regarded as being at increased risk during major abdominal surgery because of a lack of functional reserve and an increased number of comorbidities. The aim of this study was to compare short- and long-term outcomes of laparoscopic gastrectomy between elderly and young gastric cancer patients. METHODS: Two-hundred ten patients who underwent laparoscopic gastrectomy for gastric cancer at our institution between January 2001 and December 2011 were included in this retrospective study. Patients were divided into two age groups (younger than 70 years and older than 70 years) and were evaluated with respect to postoperative morbidity, quality of life (QOL), and survival. RESULTS: Postoperative morbidity was similar in elderly and young groups (18.3 vs. 21.6 %; P = 0.718). Overall survival of the elderly group was significantly worse than that of the young group (P < 0.001). However, disease-specific survival was not significantly different between the two groups. Longitudinal postoperative change in QOL in the elderly group showed a recovery similar to that in the young group. CONCLUSIONS: Laparoscopic gastrectomy can be performed as safely in elderly patients as in young patients, with comparable postoperative results and long-term outcomes, including QOL, although the life expectancy of elderly patients is shorter.

In vivo optical pathology of paclitaxel efficacy on the peritoneal metastatic xenograft model of gastric cancer using two-photon laser scanning microscopy.

BACKGROUND: We previously visualized in vivo responses to chemotherapy in a colorectal liver metastatic xenograft model using in vivo real-time and time-series intravital two-photon laser scanning microscopy (TPLSM). In this study, we established the method for evaluating the response of peritoneal xenografts to chemotherapy of metastatic gastric cancer using intravital TPLSM. METHODS: Red fluorescent protein-expressing gastric cancer cells (NUGC4) were inoculated into the peritoneal cavity of green fluorescent protein nude mice. RESULTS: Laparotomy revealed that 2 weeks after inoculation, macroscopic peritoneal metastatic nodules were formed. The first intravital TPLSM session revealed that they were composed of red tumor cell clusters and green surrounding stroma. Paclitaxel was administered intraperitoneally after the first TPLSM three times a week for 7 days in the treatment group. At the second laparotomy, there were significantly fewer and smaller nodules in the treated mice than in the controls. The second intravital TPLSM session showed tumor cell fragmentation, swelling, and nuclear condensation in the metastatic nodules--a response to chemotherapy. There were multinuclear tumor cells in the paclitaxel-treated living mice. CONCLUSIONS: Our method may become a powerful tool for evaluating the efficacy of novel anti-gastric cancer drugs in a preclinical murine model with minimum interindividual variation.

Puborectal sling interposition combined with seton drainage for pouch-vaginal fistula after rectal cancer surgery with colonic J pouch-anal reconstruction: report of a case.

The management of postoperative rectovaginal fistula (RVF) after rectal cancer surgery is difficult and requires reconstruction of the anastomotic site and fistula. Though various surgical procedures have been reported for the repair of RVFs, the results of surgical repair are often unsatisfactory, and failure of the initial repair leads to difficulty in the later operations. Furthermore, it has been reported that cases associated with local infection result in low success rates. We report a case of an 80-year-old woman with a recurrent colonic J pouch-vaginal fistula after anoabdominal rectal resection with partial internal sphincteric resection, who achieved a good outcome following a repair using a puborectal sling interposition combined with seton drainage. It may be a useful option for RVF management in repair of such pouch-vaginal fistula after coloanal anastomosis with intersphincteric resection.

Conversion Therapy Using mFOLFOX6 With Panitumumab for Unresectable Liver Metastases From Multiple Colorectal Cancers With Familial Adenomatous Polyposis.

A 39-year-old man received a diagnosis of unresectable multiple liver metastases from multiple colorectal cancers with familial adenomatous polyposis. After construction of an ileostomy, modified FOLFOX6 (mFOLFOX6) with panitumumab was administrated because rectal cancer and sigmoid colon cancer are KRAS wild type. The 13 courses of chemotherapy resulted in a marked reduction in the size of liver metastases and sigmoid colon cancer. Consequently, curative resection with total colectomy, ileal pouch anal anastomosis, and liver metastasis resection with radiofrequency ablation was performed. Progression of KRAS wild-type rectal cancer after chemotherapy suggested that each clone from rectal and sigmoid colon cancer might have a different sensitivity to epidermal growth factor receptor antibody. Immunohistochemical analysis revealed loss of PTEN expression in rectal cancer compared with liver metastases from sigmoid colon cancer, showing that the difference of mFOLFOX6 with panitumumab might be related to activation of the PI3K-AKT pathway.

In vivo characterization of neutrophil extracellular traps in various organs of a murine sepsis model.

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.

Clinical significance of tartrate-resistant acid phosphatase type-5 expression in human gastric cancer.

AIM: The present study investigated the clinical significance of tartrate-resistant acid phosphatase type-5 (ACP5) expression in gastric cancer. MATERIALS AND METHODS: In 150 specimens of gastric cancer and adjacent normal mucosa, expression of ACP5 protein and mRNA and was determined by immunohistochemical staining and quantitative real-time polymerase chain reaction, respectively. RESULTS: Expression of ACP5 mRNA was significantly higher in cancer tissues than in adjacent normal mucosa. Elevated ACP5 mRNA was associated with lymph node metastasis and peritoneal dissemination. Logistic regression analysis revealed that elevated ACP5 expression was an independent risk factor for peritoneal dissemination and was associated with shorter survival. Immunohistochemical staining of primary carcinomas showed ACP5 to be expressed mainly in the cytoplasm. CONCLUSION: ACP5 is predictive of peritoneal dissemination in patients with gastric cancer, and might play a crucial role in the establishment of peritoneal dissemination.

In vivo optical imaging of cancer metastasis using multiphoton microscopy: a short review.

Intravital (in vivo) microscopy using fluorescently-tagged proteins is a valuable tool for imaging the expression of a specific protein, its subcellular location and the dynamics of specific cell populations in living animals. Recently, multiphoton microscopy including two-photon laser scanning microscopy (TPLSM) has been used in the field of tumor biology due to its ability to image target organs at higher magnification and at deeper depths from the tissue surface for longer time periods. We developed a method of in vivo real-time imaging for tumor metastasis using TPLSM with an organ stabilizing system, which allow us to observe not only a single tumor cell and its microenvironment for a long time, but also to observe the same organ of the same mouse at multiple time points in preclinical models. Here, we presented in vivo real-time images of 1) tumor cell arrest, 2) tumor cell-platelet interaction, 3) tumor cell-leukocyte interaction, and 4) metastatic colonization at the secondary organs as representative steps of metastatic process of experimental liver metastasis models using TPLSM.