The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

[Usefulness of Mohs Paste Against Breast Cancer with Skin Invasion].

We report with the addition of literature because we have experienced 3 cases of locally advanced breast cancer with skin invasion that have alleviated symptoms and improved quality of life by using Mohs paste. In Case 1, Mohs paste reduced exposed tumors, exudation, and bleeding. In Case 2, bleeding, which had been the cause of the marked anemia, was controlled, and tumor shrinkage and epithelialization were observed. Case 3 had a poor prognosis due to systemic metastasis, but the QOL improved for a certain period of time as exudation, bleeding, and foul odor were controlled. From the viewpoint of palliative care, Mohs paste is a safe and effective treatment method against various symptoms such as large amounts of exudation, bleeding, and foul odor caused by breast cancer skin invasion, and depending on the case, prognosis can be expected to be extended by shrinking the tumor. The cooperation of not only doctors but also palliative care teams including pharmacists and nurses is essential for use.

Effects of electrical muscle stimulation on cerebral blood flow.

BACKGROUND: Electrical muscle stimulation (EMS) induces involuntary muscle contraction. Several studies have suggested that EMS has the potential to be an alternative method of voluntary exercise; however, its effects on cerebral blood flow (CBF) when applied to large lower limb muscles are poorly understood. Thus, the purpose of this study was to examine the effects of EMS on CBF, focusing on whether the effects differ between the internal carotid (ICA) and vertebral (VA) arteries. METHODS: The participants performed the experiments under EMS and control (rest) conditions in a randomized crossover design. The ICA and VA blood flow were measured before and during EMS or control. Heart rate, blood pressure, minute ventilation, oxygen uptake, and end-tidal partial pressure of carbon dioxide (PETCO2) were monitored and measured as well. RESULTS: The ICA blood flow increased during EMS [Pre: 330 ± 69 mL min-1; EMS: 371 ± 81 mL min-1, P = 0.001, effect size (Cohen's d) = 0.55]. In contrast, the VA blood flow did not change during EMS (Pre: 125 ± 47 mL min-1; EMS: 130 ± 45 mL min-1, P = 0.26, effect size = 0.12). In the EMS condition, there was a significant positive linear correlation between ΔPETCO2 and ΔICA blood flow (R = 0.74, P = 0.02). No relationships were observed between ΔPETCO2 and ΔVA blood flow (linear: R = - 0.17, P = 0.66; quadratic: R = 0.43, P = 0.55). CONCLUSIONS: The present results indicate that EMS increased ICA blood flow but not VA blood flow, suggesting that the effects of EMS on cerebral perfusion differ between anterior and posterior cerebral circulation, primarily due to the differences in cerebrovascular response to CO2.

Clinical characteristics of Campylobacter enteritis after pediatric renal transplantation: A retrospective analysis from single center.

BACKGROUND: There are few reports of patients with Campylobacter enteritis after renal transplantation, and only a few case reports of bacteremia have been published. Although antibiotic therapy for 3-5 days has been recommended for immunocompromised patients, the optimal treatment for Campylobacter enteritis after renal transplantation has not been established. This study aimed to clarify the clinical characteristics and treatment outcomes of Campylobacter enteritis after pediatric renal transplantation. METHODS: This retrospective study included patients who underwent pediatric renal transplantation and were found to have Campylobacter species in stool cultures between January 2014 and May 2017. RESULTS: This study included eight patients who underwent pediatric renal transplantation. The median age at the time of renal transplantation was 14 years, and the median period between transplantation and disease occurrence was 4.6 years. Clinical symptoms were abdominal pain for eight patients, diarrhea for eight patients, fever for seven patients, vomiting for three patients, and headache for three patients. Campylobacter jejuni was isolated from the stool cultures of all patients. The median administration period of antibiotics as initial therapy was 7 days (range, 4-11 days). However, clinical relapse was observed in four patients after completing antibiotic therapy. Patients who experienced clinical relapse required a second course of antibiotic therapy for a median duration of 7 days (range, 5-10 days). CONCLUSIONS: Patients with Campylobacter enteritis after pediatric renal transplantation are at high risk for clinical relapse and may require a longer duration of antibiotic therapy than that generally described.

High expression of EphA3 (erythropoietin-producing hepatocellular A3) in gastric cancer is associated with metastasis and poor survival.

BACKGROUND: As the major subfamily of receptor tyrosine, erythropoietin-producing hepatocellular (Eph) receptor has been related to progression and prognosis in different types of tumors. However, the role and mechanism of EPHA3 in gastric cancer is still not well understood. METHODS: Specimen were collected from 202 patients who underwent gastric resection for gastric adenocarcinoma. The expression of EphA3 was studied using immunohistochemistry. We analyzed the clinicopathological factors and prognostic relevance of EphA3 expression in gastric cancer. RESULTS: High expression of EphA3 was associated with male predominance (p = 0.031), differentiated histology (p < 0.001), depth of tumor (p = 0.002), lymph node metastasis (p = 0.001), distant metastasis (p = 0.021), liver metastasis (p = 0.024), advanced stage (p < 0.001), and high HER2 expression (p = 0.017). Relapse-free survival (RFS) was significantly worse in patients with high expression of EphA3 than in those with low expression of EphA3 (p = 0.014). Multivariate analysis for RFS showed that depth of tumor [hazard ratio (HR) 9.333, 95% confidence interval (CI) 2.183-39.911, p = 0.003] and lymph node metastasis [hazard ratio (HR) 5.734, 95% confidence interval (CI) 2.349-13.997, p < 0.001] were independent prognostic factors. CONCLUSIONS: These findings suggest that high expression EphA3 may participate in metastasis and worse survival.

TPX2 expression is associated with poor survival in gastric cancer.

BACKGROUND: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated protein required for microtubule formation in human cells. Several studies have demonstrated that TPX2 is overexpressed in multiple tumor types and promotes tumor growth and metastasis. However, there have been few reports regarding its role in gastric cancer. In this study, we evaluated TPX2 expression and investigated its correlations with gastric cancer clinicopathological features and prognosis. METHODS: Tumor samples were obtained from 290 patients with gastric adenocarcinoma who had undergone gastrectomy. The expression of TPX2 protein was examined using immunohistochemical staining. TPX2 messenger RNA (mRNA) levels were evaluated using real-time quantitative reverse transcription PCR in 19 of the gastric cancer tumors and adjacent normal tissues. RESULTS: The mRNA levels of TPX2 were significantly higher in gastric cancer tissues than in matched adjacent normal tissues (p = 0.004). In the immunohistochemical analysis, TPX2 overexpression was found in 123 (42.4%) of 290 patients. High TPX2 expression was positively associated with age, type of histology, depth of tumor, lymph node metastasis, stage, and remote metastasis or recurrence. High TPX2 expression was significantly associated with poorer disease-specific survival (p = 0.004) and relapse-free interval (p = 0.013). CONCLUSIONS: Our results indicated that high TPX2 expression was associated with tumor progression and poor survival in gastric cancer.

Erythropoietin-Producing Hepatocellular A1 is an Independent Prognostic Factor for Gastric Cancer.

BACKGROUND: Erythropoietin-producing hepatocellular (Eph) receptors are the largest subfamily of receptor tyrosine kinases that have been investigated as a possible target for molecular targeted therapy of various cancers. METHODS: Patients (n = 222) who underwent gastrectomy for primary gastric cancer were enrolled in this study. Tumor protein expression of EphA1 and EphB6 in surgically resected specimen was investigated using immunohistochemistry. The associations between expression of EphA1 and EphB6 and clinicopathological factors and prognosis were analyzed. RESULTS: High expression of EphA1 was associated with undifferentiated histology (P = 0.002), depth of tumor (P < 0.001), lymph node metastasis (P = 0.001), venous invasion (P = 0.015), stage (P = 0.001), and remote metastasis or recurrence (P < 0.001). In univariate analysis, patients with high expression of EphA1 had significantly poorer overall survival and relapse-free survival compared with patients with low EphA1 expression. The expression level of EphB6 was not associated with any clinicopathological factors and patient survival. Multivariate analysis indicated that depth of tumor [hazard ratio (HR) 9.26, 95 % confidence interval (CI) 0.03-0.46, P = 0.003], lymph node metastasis (HR 9.26, 95 % CI 0.07-0.39, P < 0.001), and high expression of EphA1 (HR 1.86, 95 % CI 0.29-0.99, P = 0.048) are independent prognostic factors for relapse-free survival. CONCLUSIONS: EphA1 is a possible target of molecular targeted therapy of gastric cancer.

Miniaturized antibodies for imaging membrane type-1 matrix metalloproteinase in cancers.

Since membrane type-1 matrix metalloproteinase (MT1-MMP) plays pivotal roles in tumor progression and metastasis and holds great promise as an early biomarker for malignant tumors, a method of evaluating MT1-MMP expression levels would be valuable for molecular biological and clinical studies. Although we have previously developed a (99m) Tc-labeled anti-MT1-MMP monoclonal IgG ((99m) Tc-MT1-mAb) as an MT1-MMP imaging probe by nuclear medical techniques for this purpose, slow pharmacokinetics were a problem due to its large molecular size. Thus, in this study, our aim was to develop miniaturized antibodies, a single chain antibody fragment (MT1-scFv) and a dimer of two molecules of scFv (MT1-diabody), as the basic structures of MT1-MMP imaging probes followed by in vitro and in vivo evaluation with an (111) In radiolabel. Phage display screening successfully provided MT1-scFv and MT1-diabody, which had sufficiently high affinity for MT1-MMP (KD  = 29.8 and 17.1 nM). Both (111) In labeled miniaturized antibodies showed higher uptake in MT1-MMP expressing HT1080 cells than in non-expressing MCF7 cells. An in vivo biodistribution study showed rapid pharmacokinetics for both probes, which exhibited >20-fold higher tumor to blood radioactivity ratios (T/B ratio), an index for in vivo imaging, than (99m) Tc-MT1-mAb 6 h post-administration, and significantly higher tumor accumulation in HT1080 than MCF7 cells. SPECT images showed heterogeneous distribution and ex vivo autoradiographic analysis revealed that the radioactivity distribution profiles in tumors corresponded to MT1-MMP-positive areas. These findings suggest that the newly developed miniaturized antibodies are promising probes for detection of MT1-MMP in cancer cells.

EphA4 is a prognostic factor in gastric cancer.

BACKGROUND: Erythropoietin-producing hepatocellular (Eph) receptor, consisting of a family of receptor tyrosine kinases, plays critical roles in tumour development and is considered an attractive target for cancer therapy. METHODS: Tumour samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy. The expressions of EphA2, EphA4, and ephrinA1 were evaluated immunohistochemically. RESULTS: High expressions of EphA2, EphA4, and ephrinA1 significantly correlated with variables related to tumour progression, including the depth of invasion, metastatic lymph nodes, pathological stage, and distant metastasis or recurrent disease. High expressions of EphA2, EphA4, and ephrinA1 were significantly associated with poorer disease-specific survival (DSS; p < 0.001, p < 0.001, p = 0.026). On multivariate analysis, EphA4 was an independent prognostic factor of DSS (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.1-4.8; p = 0.028), and EphA2 tended to be a prognostic factor (HR, 2.4; 95% CI, 1.0-5.8; p = 0.050). In stage II and III cancer, EphA4 and EphA2 were both significantly associated with shorter survival (p = 0.007 and 0.019), but only EphA2 was an independent prognostic factor (HR, 2.6; 95% CI, 1.1-6.3; p = 0.039). CONCLUSION: EphA4 may play important roles in tumor progression and outcomes in patients with gastric cancer.

Systemic Lupus Erythematosus Presenting With Thrombotic Thrombocytopenic Purpura at Onset: A Case Report.

Background: Thrombotic microangiopathy (TMA) is a syndrome associated with hemolytic anemia, thrombocytopenia, and various organ disorders. Thrombotic thrombocytopenic purpura (TTP) is a disease that develops when a disintegrin-like and metalloproteinase with thrombospondin type l motif 13 (ADAMTS13) activity decreases to < 10% of that in normal plasma, causing platelet thrombosis in microvessels throughout the body. Currently, ADAMTS13-deficient TMA is diagnosed as TTP. Systemic lupus erythematosus (SLE)-related TMA includes both acquired TTP, in which ADAMTS13 activity is significantly reduced, and secondary TMA, in which ADAMTS13 activity is not reduced. Both diseases have different prognoses. Case Presentation: An 11-year-old girl was admitted to our hospital on suspicion of TMA with thrombocytopenia and hemolytic anemia. Because the patient had hypocomplementemia, SLE-related TMA or complement-related TMA was considered. Therefore, we initiated plasma exchange (PE) for the patient. Subsequently, she fulfilled the pediatric SLE diagnostic criteria, and ADAMTS13 activity was shown to be decreased and the anti-ADAMTS13 antibody titer increased. She was thus diagnosed with acquired TTP caused by SLE. Treatment response was good as a platelet count and ADAMTS13 activity improved with three times of PE, followed by methylprednisolone pulse therapy and administration of mycophenolate mofetil. Renal pathology showed thrombus formation in glomerular arterioles and lupus nephritis categorized as Class III (A) of the International Society of Nephrology and the Renal Pathology Society classification. Because the patient was thought to be in the high-risk group of SLE, three courses of intravenous cyclophosphamide pulse therapy were administered as an additional induction therapy. No recurrence of TTP was observed. Conclusion: In SLE-related TMA, measurement of ADAMTS13 activity and the anti-ADAMTS13 antibody titer are necessary for diagnosis, and for predicting prognosis and recurrence of the disease; however, in the acute phase of immune-mediated TMA, it is important to initiate proper treatments even before knowing the results to improve prognosis.

Any modality of renal replacement therapy can be a treatment option for Joubert syndrome.

Joubert syndrome (JS) is an inherited ciliopathy characterized by a distinctive cerebellar and brain stem malformation which is known as the "molar tooth sign" on axial brain images, hypotonia, and developmental delay. Approximately 25-30% of patients with JS have kidney disease and many of them progress to end-stage kidney disease (ESKD). However, there are few reports on the outcomes of renal replacement therapy (RRT) in patients with JS and ESKD. In this study, we clarified the clinical features, treatment, and outcomes of patients with JS who underwent RRT. We retrospectively analyzed the medical records and clinical characteristics of 11 patients with JS who underwent RRT between June 1994 and July 2019. Data are shown as the median (range). Gene analysis was performed in 8 of the 11 cases, and CEP290 mutations were found in four patients, two had TMEM67 mutations, one had a RPGRIP1L mutation, and one patient showed no mutation with the panel exome analysis. Complications in other organs included hydrocephalus in two cases, retinal degeneration in eight cases, coloboma in one case, liver diseases in four cases, and polydactyly in one case. Peritoneal dialysis (PD) was introduced in seven cases, with a median treatment duration of 5.4 (3.4-10.7) years. Hemodialysis was performed using arteriovenous fistula in two cases, and kidney transplantation was performed 9 times in eight cases. Only one of the grafts failed during the observation period of 25.6 (8.2-134.2) months. The glomerular filtration rate at the final observation was 78.1 (41.4-107.7) mL/min/1.73 m2. The median age at the final observation was 13.4 (5.6-25.1) years, and all patients were alive except one who died of hepatic failure while on PD. Any type of RRT modality can be a treatment option for patients with JS and ESKD.

High expression of HER3 is associated with a decreased survival in gastric cancer.

BACKGROUND: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers. EXPERIMENTAL DESIGN: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. RESULTS: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). CONCLUSIONS: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

IGFBP1 Is a Predictive Factor for Haematogenous Metastasis in Patients With Gastric Cancer.

BACKGROUND/AIM: The clinicopathological significance and prognostic value of insulin-like growth factor binding protein 1 (IGFBP1) in gastric cancer have not been investigated to date. This study aimed to investigate the relationship of IGFBP1 expression with clinicopathological variables and prognosis. MATERIALS AND METHODS: The correlation of IGFBP1 expression with the clinicopathological factors and the correlation of clinicopathogical factors with haematogenous metastasis in 219 gastric cancer patients who underwent surgery was examined. RESULTS: High IGFBP1 expression was significantly associated with a poorer disease-specific survival (p<0.001) and relapse-free survival (p<0.001) in univariable analysis although IGFBP1 was not an independent prognostic factor. High IGFBP1 expression was the only independent risk factor of haematogenous metastasis. CONCLUSION: High IGFBP1 expression was associated with haematogenous metastasis and poor survival. IGFBP1 might become a new prognostic factor and a target of molecular targeted therapy of gastric cancer.

Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer.

Gastric cancer is the second most common cause of cancer deaths worldwide. The identification of molecular genetic parameters that are associated with response to chemotherapy and prognosis is of utmost interest. We examined methylation of the apoptosis-related genes, TMS1 and DAPK, in 81 primary gastric cancers using methylation-specific PCR and compared their methylation status with clinicopathological findings. Aberrant methylation of TMS1 and DAPK genes was detected in 26 (32.1%) tumors and in 18 (22.2%) tumors, respectively. The overall survival of patients with both methylated genes was significantly shorter compared with those with only one methylated gene or no methylated genes (p = 0.0003). Neither gene methylation had any relation to other clinicopathological findings. Next, we examined 43 patients treated by 5-fluorouracil-based chemotherapy, who had distant metastasis or recurrence after radical resection, to determine the relation between chemosensitivity and methylation. The response rate was lower in patients with either methylation than without (TMS1: 22.2% vs. 48.0%; DAPK: 21.4% vs. 44.8%). Overall survival tended to be shorter in the patients with both methylations compared with either or no methylations (p = 0.0806). The time to progression of patients with methylation of TMS1 or DAPK was significantly shorter than patients without methylation (TMS1: p = 0.0123; DAPK: p = 0.0464). Furthermore, the time to progression of patients with both methylated genes was significantly shorter than patients with one methylation or no methylation (p = 0.0082). In conclusion, TMS1 and DAPK methylation might predict the prognosis and response to chemotherapy in gastric cancer.

Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis.

BACKGROUND: Lactate-dehydrogenase-5 (LDH-5) is an important isoenzyme converting pyruvate to lactate under hypoxic conditions and might play an important role in the development and progression of malignancies. However, the role of LDH-5 in gastric cancer is still unclear. In this study, we investigated the clinical significance of LDH-5 expression in gastric carcinoma. METHODS: LDH-5 expression in 152 patients with different grade and stage gastric carcinoma was analyzed by immunohistochemistry. In addition, hypoxia-inducible factor 1alpha (HIF-1alpha) as a marker of tumor hypoxia, as well as vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) as angiogenesis parameters were also assessed in this study. Correlations between the expression of investigated proteins and various clinicopathological factors including survival were determined. RESULTS: There were 94 cases (61.8%) showing high LDH-5 expression, and 95 patients (62.5%) had high HIF-1alpha expression. Positive correlation was found between LDH-5 expression and HIF-1alpha, VEGF, and COX-2. The overexpression of LDH-5 was more prevalent in advanced tumors having positive vessel invasion. Patients with overexpression of LDH-5 showed far lower disease-free (63.5% vs 82.7%) and overall (56.3% vs 78.4%) survival rates compared with patients with low LDH-5 expression. HIF-1alpha expression was shown to have no significance on survival. In multivariate analysis, high LDH-5 expression kept its independence as a negative prognostic indicator. CONCLUSION: The results of the current study show that LDH-5 expression may be a useful prognostic factor for patients with gastric carcinoma.

MDM2 mRNA expression in the p53 pathway may predict the potential of invasion and liver metastasis in colorectal cancer.

PURPOSE: The p53/MDM2/p14ARF pathway is one of the major signaling cascades involved in the regulation of apoptosis. Although many tumors have been reported to show disruption of the p53/MDM2/p14ARF pathway, few studies have examined p53, MDM2, and p14ARF simultaneously in colorectal carcinoma. The present study was undertaken to clarify whether correlations exist among MDM2, p53, and p14ARF in colorectal cancer. METHODS: We determined the presence of mutations in the p53 gene, MDM2 expression, and methylation status of the p14ARF in 97 primary colorectal carcinoma specimens. Associations with survival and clinicopathologic factors were investigated. RESULTS: At least one abnormality of these three molecules was found in 82 (84 percent) tumors. We observed a significant inverse association between MDM2 expression and tumor invasion (P = 0.01). Furthermore, the presence of liver metastasis was also significantly associated with low MDM2 expression (P = 0.02). CONCLUSIONS: The results suggest that disruption of the p53/MDM2/p14ARF pathway may frequently participate in colonic carcinogenesis and that MDM2 expression status may be a factor in the prediction of potential invasion and liver metastasis of colorectal carcinomas.

Decreased expression of SOCS-3 mRNA in breast cancer with lymph node metastasis.

Signal transducers and activators of transcription (STATs) play a pleomorphic role in signal transduction, similarly to an oncogene. Suppressors of cytokine signaling (SOCS) inhibit STAT pathways. In breast cancer, little is known about the correlation among STATs, SOCS, and clinicopathological/biological features. Therefore, we investigated p-STAT3 (activated form of STAT3) and SOCS-1/3 expression, and clarified their correlation. Immunohistochemical staining for p-STAT3 antigen was performed in 74 surgically resected primary breast cancers. Real-time RT-PCR was used to measure mRNA expression of SOCS-1 and SOCS-3. There were no significant correlations between p-STAT3 expression and clinicopathological/biological features. SOCS-3 mRNA expression in the lymph node-positive group was significantly lower than that in the negative group (p=0.013). Among three groups divided based on the number of involved lymph nodes (node-negative group, 1-3 involved nodes group, 4 or more involved nodes group), the group with 4 or more involved nodes had the lowest expression of SOCS-3 (p=0.043). Correlations were not seen between SOCS-1 and SOCS-3 expression and other clinicopathological/biological features, except for blood vessel invasion. There were no statistical correlations between either SOCS-1 or SOCS-3 mRNA expression and p-STAT3 expression. Reduced expression of SOCS-3 is closely related to lymph node metastasis. Therefore, SOCS-3 may be a good predictor for lymph node metastasis.

Prognostic Significance of High EphA1-4 Expression Levels in Locally Advanced Gastric Cancer.

BACKGROUND/AIM: Erythropoietin-producing hepatocellular carcinoma receptor A (EphA) is associated with angiogenesis and invasive tumor progression. In this study, we evaluated the EphA1-4 expression levels in advanced gastric cancer. PATIENTS AND METHODS: Tumor tissues obtained from 114 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. In addition, the impact of EPHA 1-4 mRNA expression on survival was analyzed using the Kaplan-Meier plotter database on the website. RESULTS: High EphA 1, 2, and 4 expression levels were significantly related to recurrence (p<0.01, p=0.04, and p<0.01). Both high EphA 1 and 4 expression levels were independent predictors of relapse-free interval (hazard ratio [HR]=2.0, p=0.03; HR=2.4, p=0.03) and disease-specific survival (HR=2.0, 95% p=0.03; HR=2.5, p=0.02) on multivariate analysis. In the Kaplan-Meier plotter database, high EPHA2 mRNA expression was significantly associated with poor survival in patients with gastric cancer (p=0.0098), and high expression levels of EPHA1 and 4 tended to be associated with poor survival (p=0.050, p=0.052). CONCLUSION: EphA 1, 2, and 4 may play key roles in recurrence and survival in patients with advanced gastric cancer.

Correlations between cyclooxygenase-2 expression and angiogenic factors in primary tumors and liver metastases in colorectal cancer.

BACKGROUND: Angiogenesis is required for growth and metastasis of colorectal cancer (CRC), and several positive regulators of tumor angiogenesis have been identified. Cyclooxygenase-2 (COX-2), known to be elevated in several human cancers, regulates angiogenesis by inducing angiogenic factors. The aim of this study was to clarify the levels and evaluate the relationships of COX-2, vascular endothelial growth factor A and C, thymidine phosphorylase (TP) and microvascular density (MVD) in paired tissue specimens between primary CRC and corresponding metastatic liver cancer. METHODS: Tissue samples from pairs of primary tumors and corresponding metastatic liver tumors from 44 patients with CRC were immunohistochemically evaluated for COX-2, VEGF-A, VEGF-C, TP and MVD. RESULTS: The primary and corresponding metastatic liver tumors tended to show concordant immunoreactivity for COX-2 (P = 0.005, rs = 0.428), VEGF-A (P = 0.039, rs = 0.314), TP (P = 0.005, rs = 0.422) and MVD (P = 0.046, rs = 0.304) by Spearman rank test. The rate of COX-2 immunoreactivity was higher in liver metastases than in primary tumors (P = 0.002), while the rate of VEGF-A was higher in primary tumors than in liver metastases (P = 0.0004). The incidence of TP immunoreactivity and the level of MVD did not differ between primary and metastatic liver tumors (P = 0.247; P = 0.229). Significant correlations were found between COX-2 immunoreactivity and VEGF-A immunoreactivity in metastatic liver tumors (P = 0.033) as well as in primary tumors (P = 0.008). CONCLUSION: The positive correlations between COX-2, VEGF-A, TP and MVD in primary CRC and liver metastasis as demonstrated here will help to predict the angiogenic activity of liver metastasis by analyzing primary tumors, allowing for individualized cancer treatment options.

Cadherin 5 Is a Significant Risk Factor for Hematogenous Recurrence and a Prognostic Factor in Locally Advanced Gastric Cancer.

BACKGROUND/AIM: Cadherin 5 (CDH5) is important for adhesion in epithelial cells, and expressed in tumor cells in several malignancies. In the present study, we evaluated the clinical significance of CDH5 protein expression in locally advanced gastric cancer. MATERIALS AND METHODS: Tumor tissues obtained from 113 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. RESULTS: High CDH5 expression was significantly associated with recurrence (p=0.017), especially hematological recurrence (p=0.022). High CDH5 expression was a significant risk factor for hematogenous recurrence on multivariate analysis (odds ratio[OR]=3.9, confidential interval [CI] 1.0-15, p=0.043). Patients with high CDH5 expression had a significantly shorter progression-free interval (RFI, p=0.010) than patients with low CDH5 expression. High CDH5 expression was an independent prognostic factor on multivariate analysis of RFI (hazard ratio[HR]=2.2, 95% CI 1.1-4.3, p=0.021). CONCLUSION: CDH5 may play a key role in hematogenous recurrence of advanced gastric cancer and may be a viable treatment target.