The advanced lung cancer inflammation index predicts outcomes in patients with Crohn's disease after surgical resection.

AIM: Precise biomarkers for predicting prognosis could help to identify high-risk Crohn's disease (CD) patients to facilitate better follow-up during the postoperative course. In this study, the primary aim is the identification of the most reliable nutrition marker that predicts surgical relapse in CD patients. METHOD: We first evaluated the predictive value of various nutrition markers for postoperative surgical relapse in CD patients and identified the advanced lung cancer inflammation index (ALI) as a promising biomarker. Then, we assessed the clinical significance of preoperative ALI in CD patients using two cohorts. RESULTS: Preoperative ALI showed the highest correlation with reoperation rate compared with other nutritional parameters in CD patients receiving surgical resection (sensitivity 53%, specificity 86%, area under the curve 0.71). Lower levels of preoperative ALI were significantly correlated with the presence of perianal disease. A lower level of preoperative ALI was an independent prognostic factor for reoperation rate after an intestinal resection (hazard ratio 3.37, 95% CI 1.38-10.12, P = 0.006), and the prognostic impact of preoperative ALI was successfully validated in an independent cohort using the same cut-off value. CONCLUSION: Preoperative ALI might be useful for postoperative management of CD patients.

Tropomyosin-related receptor kinase B at the invasive front and tumour cell dedifferentiation in gastric cancer.

BACKGROUND: Tropomyosin-related receptor kinase B (TrkB) promotes proliferation and invasion, relating to poor prognosis of various malignancies. We examined the role of TrkB at the invasive front of gastric cancer (GC) and its association with tumour cell dedifferentiation and tumour budding. METHODS: Immunoreactive TrkB was evaluated at the tumour centre and margin using whole-tissue sections of 320 GC patients. Tumour cell dedifferentiation was defined as higher histologic grade at the tumour margin than the surface or tumour centre. Tumour budding was also scored on cytokeratin-stained sections. RESULTS: Sixty-five patients (20%) showed higher TrkB expression at the invasive front (TrkB expression was higher at the tumour margin than tumour centre). It was significantly associated with several aggressive phenotypes in the full cohort (n=320). It showed a prognostic significance in test subgroup (n=98) and was identified as an independent prognostic factor (HR=2.09; 95% CI: 1.26-3.53) by multivariate analysis in validation subgroup (n=222). Twenty-one patients showed tumour cell dedifferentiation. In predominantly differentiated tumour, higher TrkB at the invasive front was significantly associated with tumour budding rather than tumour cell dedifferentiation. CONCLUSIONS: Assessment of immunoreactive TrkB at the invasive front by whole-tissue sections provides prognostic information for GC patients.

Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer.

BACKGROUND: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. METHODS: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. RESULTS: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. CONCLUSION: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression.

Clinical significance of CD133 and hypoxia inducible factor-1α gene expression in rectal cancer after preoperative chemoradiotherapy.

AIMS: The mechanism of distant recurrence in rectal cancer after preoperative chemoradiotherapy (CRT) has yet to be fully elucidated. Further improvements in survival rates cannot be achieved without decreasing distant recurrence after preoperative CRT. Recently, it was reported that hypoxic conditions were correlated with cancer stem cell generation. Therefore, we investigated the correlation between the expression of CD133 and hypoxia inducible factor-1α (HIF-1α), and their association with clinical outcome. MATERIALS AND METHODS: Fifty-two patients with rectal cancer underwent preoperative CRT. Residual cancer cells after CRT were obtained from formalin-fixed paraffin-embedded specimens using micro-dissection. The expression levels of CD133 (PROM1) and HIF-1α genes were measured using real-time reverse transcription polymerase chain reaction. The correlation between expression and irradiation was evaluated using colon cancer cell lines. Immunohistochemical staining of these proteins after CRT was also investigated. RESULTS: We observed a significant inverse correlation between the gene expression of CD133 (PROM1) and HIF-1α genes in residual cancer cells after CRT. Elevated CD133 gene expression was associated with distant recurrence and poor recurrence-free survival. Elevated HIF-1α gene expression was associated with poor overall survival. In vitro, the change in gene expression levels after irradiation showed inverse patterns. Immunohistochemical analyses showed that residual cancer cells strongly expressed CD133 and lacked HIF-1α expression. CONCLUSION: Our results suggest that CD133 and HIF-1α expression is associated with tumour re-growth and distant recurrence after CRT. These results may assist in clarifying the development of future cancer therapeutics in rectal cancer patients undergoing preoperative CRT.

Loss of tumoral expression of soluble IL-6 receptor is associated with disease progression in colorectal cancer.

BACKGROUND: Interleukin-6 (IL-6) binds both the membrane and soluble forms of the IL-6 receptor (sIL-6R), which induces a complex with gp130, and proliferation of tumour cells. The aim of this study is to clarify the relationship between tumoral sIL-6R expression and disease progression in colorectal cancer patients. METHODS: We measured tissue concentrations of sIL-6R in tumour and normal mucosa from 161 colorectal cancer patients undergoing surgery, and in supernatants from colon cancer cell lines. The expression of IL-6, IL-6R and gp130 was evaluated by immunohistochemical analysis. RESULTS: Loss of tumour expression of sIL-6R as defined by sIL-6R Ca/N ratio <1.0 was significantly associated with factors reflecting disease progression, and was an independent prognostic factor not only in all the patients in this study, but also in the patients with curative intent. Colon cancer cell lines produced sIL-6R in vitro, and the production of sIL-6R in cancer cell lines was stimulated by cytokine stimulation. Immunohistochemistry revealed that loss of tumour expression of sIL-6R was significantly inversely correlated with intense IL-6 expression in the cytoplasm of cancer cells. In addition, tumoral IL-1beta expression was significantly correlated with sIL-6R expression. CONCLUSION: Loss of tumour expression of sIL-6R is associated with colorectal cancer disease progression.

Gene expression profiles of epidermal growth factor receptor, vascular endothelial growth factor and hypoxia-inducible factor-1 with special reference to local responsiveness to neoadjuvant chemoradiotherapy and disease recurrence after rectal cancer surgery.

AIMS: To establish a causal relationship between the gene expression profiles of angiogenetic molecular markers, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF-1), in rectal cancer and the local responsiveness to neoadjuvant chemoradiotherapy and subsequent disease recurrence. MATERIALS AND METHODS: We examined the pre-treatment tumour biopsies (n=40) obtained from patients with rectal adenocarcinoma (clinical International Union Against Cancer stage ll/III) who were scheduled to receive neoadjuvant 5-fluorouracil-based chemoradiotherapy for EGFR, VEGF and HIF-1 expression by quantitative real-time polymerase chain reaction. RESULTS: Responders (patients with significant tumour regression, i.e. pathological grades 2/3) showed significantly lower VEGF, HIF-1 and EGFR gene expression levels than the non-responders (patients with insignificant tumour regression, i.e. pathological grades 0/1) in the pre-treatment tumour biopsies. The elevated expression level of each gene could predict patients with a low response to chemoradiation. During the median follow-up of all patients (41 months; 95% confidence interval 28-60 months), 6/40 (15%) developed disease recurrence. Although local responsiveness to neoadjuvant chemoradiotherapy was associated with neither local nor systemic disease recurrence, lymph node metastasis and an elevated VEGF gene expression level were independent predictors of systemic disease recurrence. The 3-year disease-free survival rates of the patients with lower VEGF or EGFR expression levels were significantly lower than those of patients with higher VEGF or EGFR expression levels. CONCLUSIONS: Analysing VEGF expression levels in rectal cancer may be of benefit in estimating the effects of neoadjuvant chemoradiotherapy and in predicting systemic recurrence after rectal cancer surgery.

Evaluation and treatment for spinal cord tethering in patients with anorectal malformations.

BACKGROUND: It has recently been recognized that there is a close relationship between spinal cord tethering (SCT) and congenital anorectal malformation (ARM). PATIENTS AND METHODS: We evaluated spinal MRI examinations of 28 patients with ARM (14 boys and 14 girls) aged 5 months to 9 years. All patients diagnosed with SCT subsequently underwent operation. Patients were divided into high and low type ARM groups. We reviewed the relationship between SCT and ARM, and evaluated the untethering surgery. RESULTS: We evaluated 14 boys (high, 9; low, 5) and 14 girls (high, 4; low, 10). Of these 28 patients, 13 had SCT on MRI. Five out of 13 patients with high type ARM and 8 out of 15 patients with low type ARM had SCT. Seven out of 10 girls with low type ARM had SCT. Ten of these 13 patients with SCT experienced bowel/urological/orthopedic symptoms. SCT symptoms progressed prior to operation in the 2 patients who underwent untethering surgery a few years after their initial MRI examination. Postoperatively, orthopedic symptoms disappeared completely in all patients, but other symptoms did not. CONCLUSIONS: Based on the results of this study, we recommend routine MRI examination of patients with ARM and early untethering surgery in cases with SCT.

Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.

In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure. The plasma levels of total PAI-1 and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-I, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.

Increased plasma thrombomodulin as a vascular endothelial cell marker in patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

Several hemostatic and vascular endothelial cell markers were measured in 39 patients with thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) and in 20 healthy volunteers to examine the relationship between the occurrence of hemostatic abnormality or vascular endothelial cell injury and patient outcome. The plasma levels of von Willebrand factor, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI-1), and the TPA-PAI-1 complex were significantly increased in TTP/HUS patients; however, the levels of these markers were not significantly different between TTP/HUS patients who survived and those who died, suggesting that these markers might not be directly related to outcome. The plasma levels of soluble granule membrane protein (GMP)-140 were significantly higher in TTP/HUS patients than in healthy volunteers, suggesting that platelets and vascular endothelial cells are activated or injured in TTP/HUS. There was no significant difference in GMP-140 levels between TTP/HUS patients with good and poor prognoses; this may be owing to the release of GMP-140 from platelets. The plasma thrombomodulin (TM) levels in TTP/HUS patients were significantly higher than in healthy volunteers; the plasma TM levels were significantly higher in patients who died than in patients who survived. These findings showed that TM levels reflect the outcome and that the outcome of TTP/HUS depends on the presence vascular endothelial cell injury. The plasma protein C and antithrombin levels were markedly reduced in TTP/HUS patients who died compared with those who survived. These findings suggest that reduced plasma antithrombin and protein C may be useful markers of systemic vascular endothelial injury. In conclusion, the results of this study showed that the outcome of TTP/HUS is related to vascular endothelial cell injury and that plasma TM, antithrombin, and protein C levels may be useful markers of systemic vascular endothelial cell injury.

Increased plasma levels of tissue factor pathway inhibitor-activated factor X complex in patients with disseminated intravascular coagulation.

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.

Plasma levels of activated protein C-protein C inhibitor complex in patients with hypercoagulable states.

Plasma levels of activated protein C (APC)-protein C inhibitor (PCI) were significantly increased in patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), acute myocardial infarction (AMI), pulmonary embolism (PE), or deep vein thrombosis (DVT) and in patients undergoing hemodialysis (HD). Plasma levels of APC-alpha(1)-antitrypsin (AT) complex were significantly increased in patients with DIC and in those with TTP. Plasma levels of PCI were significantly decreased in patients with DIC, non-DIC, or TTP and in those undergoing HD. In the pre-DIC stage, the plasma levels of APC-PCI complex were significantly increased but not those of APC-alpha(1)-AT complex. These data suggest that measurements of APC-PCI complex and APC-alpha(1)-AT complex may be useful for the diagnosis of DIC. After treatment of DIC, the plasma levels of APC-PCI complex and APC-alpha(1)-AT complex were significantly decreased, but not those of PCI. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-alpha(2)-plasmin complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were markedly increased in patients with DIC or pre-DIC and were moderately increased in patients with non-DIC, TTP, AMI, PE, or DVT and in those undergoing HD. The receiving operating characteristic (ROC) analysis showed that SFM and the APC-PCT complex are useful markers for diagnosis of DIC. The specificity of plasma TAT and PPIC levels was low. The positive rate of APC-PCI complex was higher than 90% with DIC, TTP, AMI, PE, and it was higher than 60% with DVT and HD. Since the APC-PCI complex was elevated not only in patients with venous thrombosis but also in those with arterial thrombosis, components of the protein C pathway might be useful markers for the diagnosis of arterial thrombosis.

Coagulation tests and anti-phospholipid antibodies in patients positive for lupus anticoagulant.

We examined activated partial thromboplastin time, kaolin clotting time, mixing with normal plasma in kaolin clotting time, dilute Russell's viper venom time, dilute Russell's viper venom time at high lipid concentrations, anti-phospholipid antibodies, and anti-cardiolipin-beta2-glycoprotein I complex antibody in 135 patients with prolongation of activated partial thromboplastin time and diagnosed 86 patients positive for lupus anticoagulant. The sensitivity of activated partial thromboplastin time and dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio for lupus anticoagulant were markedly high, but the specificity of activated partial thromboplastin time for lupus anticoagulant was not markedly high. The specificity, but not the sensitivity, of kaolin clotting time-mixing with normal plasma in kaolin clotting time was markedly high. In summary, dilute Russell's viper venom time to dilute Russell's viper venom time-high lipid concentrations ratio gave high sensitivity as well as specificity, being the only assay to confirm this. Of the patients positive for lupus anticoagulant, 25% were positive for anti-phospholipid antibodies and 17% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody. Of the lupus anticoagulant-positive patients with thrombosis, 45% were positive for anti-phospholipid antibodies, 35% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody, 60% were positive for both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody, and only 17% were negative for anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. These findings suggest that lupus anticoagulant can be diagnosed by dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio, and that thrombosis in lupus anticoagulant-positive may be predictable from both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. Plasma tissue type plasminogen activator level in lupus anticoagulant patients was significantly increased, and plasma tissue type plasminogen activator and fibrin-D-dimer levels in lupus anticoagulant-positive patients with thrombosis were significantly higher than in those without thrombosis, suggesting that the diagnosis of thrombosis by hemostatic markers might be important in lupus anticoagulant.

Decreased tissue factor and tissue-plasminogen activator antigen in relapsed acute promyelocytic leukemia.

This study evaluated hemostatic data in 28 patients with newly diagnosed acute promyelocytic leukemia (APL) and 15 patients with relapsed APL. Activated partial thromboplastin time and prothrombin time were prolonged at initial onset of APL. Plasma level of fibrinogen was significantly decreased in patients with initial disease of APL, but it was not decreased significantly during the relapse of APL. Plasma fibrin and fibrinogen degradation products levels were significantly increased and platelet counts significantly decreased in both groups. Plasma levels of antiplasmin significantly decreased at initial onset but not during relapse. Plasma levels of antithrombin were within normal range in patients with initial disease but significantly decreased in those with relapse. Plasma levels of D-dimer, soluble fibrin monomer (sFM), plasmin-plasmin inhibitor complex (PPIC), and thrombin antithrombin complex (TAT) levels were significantly high in both groups. Plasma levels of PPIC, sFM, and D-dimer were significantly higher at initial onset of APL than during relapse. However, there was no significant difference in DIC score between patients with initial onset and those with relapse; plasma levels of tissue factor (TF) significantly increased in both groups, but they were significantly higher at initial onset of APL than during relapse. TF and tissue type plasminogen activator (t-PA) antigen levels in leukemic cell lysate were significantly increased in both groups, and they were significantly lower during relapse than at initial onset. Hemostatic abnormalities occurring in patients with relapsed APL might be the result of the decrease of TF and t-PA in leukemic cells. These findings suggest that DIC in APL patients with relapse might not be caused only by TF and t-PA and thus should be treated with different therapy from patients with initial onset of APL.