Preoperative evaluation of mammographic microcalcifications after neoadjuvant chemotherapy for breast cancer.

AIM: To assess the predictive value of preoperative residual mammographic microcalcifications for residual tumours after neoadjuvant chemotherapy (NAC) for breast cancer. MATERIALS AND METHODS: This single-centre retrospective study included breast cancer patients who underwent NAC and demonstrated suspicious microcalcifications within or near the tumour bed on mammography from June 2015 to August 2018. The residual microcalcifications and remnant lesion on magnetic resonance imaging (MRI) were correlated with histopathological findings of residual tumours and immunohistochemical markers. RESULTS: A total of 96 patients were included. Ten patients achieved pathological complete response (pCR) and previous suspicious microcalcifications were associated with benign pathology in 10.4% (10/96) of the patients. In the remaining 86 patients who did not achieve pCR, 61.5% (59/96) of the residual microcalcifications were associated with invasive or in situ carcinoma and 28.1% (27/96) with benign pathology. Hormone receptor-positive (HR+) patients had the highest proportion of residual malignant microcalcifications compared to HR- patients (48.9% versus 13.5%, respectively; p=0.019). MRI correlated better than residual microcalcifications on mammography in predicting residual tumour extent in all subtypes (ICC=0.709 versus 0.365). MRI also showed higher correlation with residual tumour size for the HR-/HER2+ and HR-/HER2- subtype (ICC=0.925 and 0.876, respectively). CONCLUSION: The extent of microcalcifications on mammography after NAC did not correlate with the extent of residual cancer in 38.5% of women. Regardless of the extent of microcalcifications, residual tumour extent on MRI after NAC and molecular subtype could be an accurate tool in evaluating residual cancer after NAC.

Relationship between smoking and spontaneously healed pulmonary TB on chest radiography in a South Korean population.

SETTING: The Korea National Health and Nutrition Examination Survey is a national, population-based, cross-sectional surveillance programme.OBJECTIVE: 1) To investigate the prevalence of spontaneously healed pulmonary tuberculosis (SHPTB) on chest radiographs (CXRs) in South Korea, as well as its demographic and clinical associations, and 2) to determine the relationship between SHPTB and smoking.DESIGN: People with normal findings on CXRs (n = 24 190) and those with SHPTB (n = 1863) were compared in univariate, bivariate and multivariate analyses with respect to smoking and demographic and clinical factors.RESULTS: The prevalence of SHPTB was 7.2%. The proportion of patients with SHPTB tended to be higher in males, people of older age, ever smokers, as well as people with low body mass index and low education level. In bivariate analysis, after adjustments for age and sex, SHPTB was found more often among ex-smokers (P = 0.005) and current smokers (P = 0.024) than in non-smokers. Multivariate analyses revealed increased relative odds for SHPTB with increased age (P < 0.001), male sex (P < 0.001) and ex-smoker status (P = 0.016). Passive smoking was also significantly associated with SHPTB (P = 0.022).CONCLUSION: In addition to increasing the risk of active TB and negatively affecting the outcome of TB treatment, smoking is also associated with SHPTB, as detected on CXRs.

Prognostic significance of cachexia score assessed by CT in male patients with small cell lung cancer.

To determine the prognostic significance of CT-determined cachexia scores (CSs) in 127 consecutive male small cell lung cancer (SCLC) patients, cross-sectional areas of muscle and fat tissues at the third lumbar vertebra (L3) were retrospectively measured on baseline CT images. CSs were determined based on the presence of sarcopenia and/or adipopenia. According to the presence of sarcopenia (L3 muscle index <55 cm2 /m2 , 86.8%) and adipopenia (L3 fat index <22 cm2 /m2 , 11.8%), CSs were defined as follows: CS2 (sarcopenia and adipopenia, 11.8%), CS1 (sarcopenia only, 74.8%) and CS0 (13.4%). CS2 was significantly related to lower body mass index (p < .001) and poor performance status (p = .002), and patients with CS2 had shorter OS than patients with CS1 or CS0 (median OS, 5.0 months vs. 8.9 months vs. 18.3 months; p = .007). Multivariable analysis revealed that CS was an independent prognostic factor of poor survival (HR, 1.99 for CS1 and 2.59 for CS2, p = .036 and .023, CS0 as a reference), along with extensive stage (p < .001), supportive care only (p < .001) and an elevated lactate dehydrogenase (p = .005). CT-determined CSs, based on the presence of sarcopenia and/or adipopenia, could be used to predict prognosis in male SCLC.

Preoperative Computed Tomography-Determined Sarcopenia and Postoperative Outcome After Surgery for Non-Small Cell Lung Cancer.

BACKGROUND: Sarcopenia, reduced skeletal muscle mass, is associated with frailty, injuries, and mortality. The purpose of this study was to evaluate the impact of computed tomography-determined sarcopenia on surgical complications and outcomes after resection of non-small cell lung cancer. METHODS: For a total 272 non-small cell lung cancer patients that underwent surgery between 2011 and 2016, cross-sectional area of muscle at the third lumbar vertebra (L3) was retrospectively measured using preoperative chest computed tomography images. Sarcopenia was defined as an L3 muscle index of <55 cm2/m2 for men and of <39 cm2/m2 for women. Clinical characteristics, postoperative complications, disease-free survival, and overall survival of patients with or without sarcopenia were compared. RESULTS: A total of 60.3% ( n = 164) were male, and mean patient age was 62.9 ± 9.6 years. The prevalence of sarcopenia was 22.4% for all study subjects, 32.9% for men, and 6.5% for women. No significant difference was observed between patients with or without sarcopenia in terms of intensive care unit or hospital stay ( p = 0.502 and p = 0.378, respectively), and the presence of sarcopenia was not associated with postoperative complications. Furthermore, no significant difference was observed between the 3-year disease-free survival rate (74.3% vs 66.7%, p = 0.639) or 3-year overall survival rate (83.9% vs 87.7%, p = 0.563) of patients with or without sarcopenia. CONCLUSION: Sarcopenia as determined by preoperative computed tomography does not appear to have a negative impact on surgical outcome or overall survival for resected non-small cell lung cancer patients.

Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Magnesium sulphate attenuates acute postoperative pain and increased pain intensity after surgical injury in staged bilateral total knee arthroplasty: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: We evaluated the effect of magnesium sulphate on increased pain in 44 patients undergoing staged bilateral total knee arthroplasty (TKA). METHODS: The magnesium group (n=22) and the control group (n=22) received magnesium sulphate and isotonic saline, respectively, throughout the surgery. Postoperative pain (visual analogue scale, VAS) at rest and the amounts of patient-controlled analgesia (PCA, fentanyl) and rescue analgesia (ketoprofen) administered during the first 48 h were compared between the two groups and within each group between the first and second TKA. RESULTS: The VAS scores were significantly higher in the control group than in the magnesium group not only after the first TKA [29 (11) vs 19 (9) at 24 h and 33 (8) vs 24 (10) at 48 h; P=0.001] but also after the second TKA [44 (17) vs 20 (10) at 24 h and 43 (14) vs 25 (10) at 48 h; P<0.001]. In the control group, VAS scores were significantly higher for the second than for the first operated knee [44 (17) vs 29 (11) at 24 h and 43 (14) vs 33 (8) at 48 h; P<0.001 and P=0.006, respectively]. In the magnesium group, there were no significant differences in VAS scores between the first and second TKA. Magnesium significantly reduced the amounts of rescue analgesics and fentanyl administered over the first 48 h postoperatively. CONCLUSIONS: Magnesium sulphate administration significantly reduced postoperative pain and minimized the difference in pain intensity between the first and second operations. CLINICAL TRIAL REGISTRATION: KCT0001361.

Performing a Right Hemihepatectomy Sequentially After Deceased Donor Liver Transplantation--The Solution for a Large-for-size Graft: A Case Report.

BACKGROUND: Large-for-size (LFS) is a serious problem that can develop during liver transplantation (LT) and is related to morbidities such as insufficient blood supply causing graft dysfunction or impractical closure of the abdominal wall leading to graft compression. LFS is usually discussed in pediatric LT and is often managed by reducing the size of the graft before implantation. In contrast, only a few cases about managing unexpected LFS during adult LT have been reported, and no case after the vascular anastomosis has been completed has been reported. CASE REPORT: A 36-year-old, 43-kg woman underwent an emergency LT using a deceased donor, although the estimated graft/recipient weight ratio was 3.98%. After completing the vascular anastomosis, a severe hepatic venous outflow obstruction from the graft developed due to compression of the inferior vena cava from the hypertrophied right posterior lobe of the graft. We performed a right hemihepatectomy sequentially after LT, and hepatic blood flow recovered sufficiently based on a Doppler sonogram. The postoperative clinical course was uneventful without vascular or ductal complications, and the primary abdominal wall closure was successfully achieved without wound complications. CONCLUSIONS: Performing a right hemihepatectomy sequentially after completing the vascular anastomosis during LT could be a very simple and effective solution for unexpected LFS during LT.

Angioplasty of communicating veins to the brachial vein in haemodialysis patients with obliterated superficial veins of the upper arm.

AIM: To evaluate the outcomes of angioplasty of the communicating veins when superficial veins of the upper arm were almost totally obliterated in haemodialysis patients. MATERIALS AND METHODS: Twenty-one angioplasties of the communicating veins that were performed for failing haemodialysis fistulas in patients with almost totally obliterated superficial veins of the upper arm from December 2006 to March 2011 were retrospectively reviewed. Fistulas were of the following types: native radiocephalic fistulas (n = 20) and radio-antecubital fistulas (n = 1). All angioplasties were performed using 5-8 mm conventional balloons. Cutting balloon angioplasty was additionally performed in five patients. The primary, secondary, and target lesion patency rate was calculated using Kaplan-Meier analysis. RESULTS: The communicating vein was located in the antecubital fossa. Technical and clinical success rates were 100% and 95.2%, respectively. Follow-up duration was 1-52 months (mean 20 months). The primary patency rates were 76%, 43%, and 29% at 3, 6, and 12 months, respectively, and target lesion patency rates were 81%, 62%, and 43% at 3, 6, and 12 months, respectively. The secondary patency rates were 81%, 76%, and 57% at 3, 6, and 12 months, respectively. There were no major or minor complications. CONCLUSION: Angioplasty of the communicating vein is effective in restoring function in failing haemodialysis fistula in patients with obliterated superficial veins of the upper arm.

Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin.

Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.

Validation of a scoring tool to predict drug-resistant pathogens in hospitalised pneumonia patients.

BACKGROUND: Health care-associated pneumonia (HCAP) affects a heterogeneous group of patients in frequent contact with health care systems. However, HCAP criteria poorly predict infection with drug-resistant (DR) pathogens. OBJECTIVE: To validate our previously reported risk-scoring model (predictive of DR pathogen infection) in patients admitted to hospital with pneumonia. DESIGN: We evaluated 580 patients admitted with culture-positive bacterial pneumonia. We identified risk factors, evaluated the risk-scoring model's capacity to predict infection by DR pathogens and compared the model's diagnostic accuracy with that of current HCAP criteria. RESULTS: DR pathogens were observed in 227/580 patients (39.1%). Of 269 HCAP patients, 153 (56.9%) were infected with DR pathogens. Overtreatment was more common in HCAP than in community-acquired pneumonia (58.7% vs. 41.2%, P < 0.001). Recent hospitalisation, admission from a long-term care facility, recent antibiotic treatment and tube feeding were independently associated with DR pathogens. For pathogen prediction, the risk-scoring model showed better diagnostic accuracy than HCAP criteria (area under receiver operating-characteristic curve = 0.723 vs. 0.673, P < 0.001). CONCLUSION: According to current HCAP criteria, half of the HCAP patients were treated unnecessarily with broad-spectrum antibiotics. Risk scoring by stratifying risk factors could improve the identification of patients likely to be infected with DR pathogens.

Histologically benign but clinically malignant neoplasms in the thorax: CT-pathological overview.

The purpose of this article is to review the computed tomography (CT) and histopathological features of uncommon primary neoplasms of the thorax that can manifest clinically malignant features (multiplicity of pulmonary nodules, an invasive nature, and metastases or recurrence after surgery) with little evidence of histological malignancy.

Randomised clinical trial: a comparative study of 10-day sequential therapy with 7-day standard triple therapy for Helicobacter pylori infection in naïve patients.

BACKGROUND: The eradication rates following standard triple therapy for Helicobacter pylori infection are declining worldwide. Recent studies have shown that sequential therapy for H. pylori infection yields high cure rates. AIM: To compare the efficacy and tolerability of a sequential regimen as first-line treatment of H. pylori infection with a standard triple regimen. METHODS: A total of 348 naïve H. pylori-infected patients from six hospitals in Korea were assigned randomly to standard triple or sequential therapy groups. Standard triple therapy consisted of 20 mg of rabeprazole, 1 g of amoxicillin and 500 mg of clarithromycin, twice daily for 7 days. Sequential therapy consisted of a 5-day dual therapy (20 mg of rabeprazole and 1 g of amoxicillin, twice daily) followed by a 5-day triple therapy (20 mg of rabeprazole, 500 mg of clarithromycin, and 500 mg of metronidazole, twice daily). RESULTS: The intention-to-treat (ITT) and per-protocol (PP) eradication rates were 62.2% (95% CI 54.8-69.6%) and 76.0% (95% CI 68.5-83.5%) in the standard triple group, and 77.8% (95% CI 71.4-84.2%) and 87.9% (95% CI 82.3-93.5%) in the sequential group, respectively. The eradication rate was significantly higher in the sequential group compared with the standard triple group in both the ITT and PP populations (P = 0.002 and P = 0.013 respectively), whereas the incidence of adverse events was similar. CONCLUSIONS: Ten-day sequential therapy is more effective and equally tolerated for eradication of H. pylori infection compared with standard triple therapy. Sequential therapy may have a role as first-line treatment for H. pylori infection.

Persistent or recurrent varicocoele after failed varicocoelectomy: outcome in patients treated using percutaneous transcatheter embolization.

AIM: To determine the efficacy of percutaneous transcatheter embolization in the management of patients with spermatic varicocoeles persisting or recurring after surgery. MATERIALS AND METHODS: Over a period of 10 years, 28 patients (age range 13-55 years) were referred for percutaneous transcatheter embolization of postsurgical, recurrent varicocoeles. Medical documents were retrospectively reviewed to evaluate past surgical history, subjective symptoms, and results of scrotal examination, ultrasound, and semen parameters. Pre-embolization venograms were analysed to assess the anatomy of the testicular vein. The technical and clinical outcomes of embolization were then determined. RESULTS: The 28 patients included in the study had undergone laparoscopic varicocoelectomy (39.3%), high retroperitoneal ligation (25%), or inguinal ligation (25%). Subjective symptoms were scrotal pain (60.7%) and a palpable scrotal mass (50%) exclusively on the left side. Venograms revealed abnormalities of the left testicular vein in all cases. Embolization was technically successful in all but two cases, thus yielding an occlusion rate of 93%; a single case of suspected thrombophlebitis was the only complication. After excluding two, technically unsuccessful cases and one patient who was lost to follow-up, 25 patients underwent scrotal examination after embolization, which revealed complete resolution in 20 cases (80%), partial improvement in four cases (16%), and no improvement in a single case (4%). Among the follow-up group of patients, of the 12 who initially presented with scrotal pain, six (50%) were symptom-free and four (33.3%) had partial improvement. CONCLUSION: Percutaneous transcatheter embolization of the testicular vein is technically feasible and effective for managing postsurgical recurrent varicocoeles.

Basal STAT3 activities are negatively correlated with tumor size in papillary thyroid carcinomas.

BACKGROUNDS: Signal transducer and activators of transcription-3 (STAT3) plays a critical role in promoting survival and cell growth as well as facilitating angiogenesis and metastasis in several cancers. AIM: This investigation focused on evaluation of STAT3 activities in human papillary thyroid cancers (PTC). METHODS: STAT3 activities of nuclear extracts of tumor tissue were measured from 35 PTC patients using enzyme- linked immunosorbent assay-based kits. RESULTS: STAT3 activities of PTC tissues were significantly lower than those of surrounding normal thyroid tissues [0.36 (interquartile range 0.24-0.72) vs 0.50 (0.29-1.11) arbitrary units, p<0.01]. We further analyzed the association between STAT3 activity and clinicopathologic factors in PTC tissue. Tumors with size ≥2 cm displayed significantly lower STAT3 activities than those <2 cm [0.25 (0.21-0.37) vs 0.53 (0.37-0.61) arbitrary units, p<0.01]. Notably, tumor size was inversely correlated with STAT3 activities in T1799A BRAF mutation-positive cases (Rs=-0.58, p<0.05), but not mutation-negative cases. CONCLUSIONS: STAT3 activities of PTC measured via DNA binding are suppressed in contrast to other human cancers. Tumor size larger than 2 cm is the only clinicopathologic parameter associated with low STAT3 activity. Moreover, tumor size appears inversely correlated with STAT3 activity, specifically in T1799A BRAF mutation-positive cases.

Prognostic factors for idiopathic pulmonary fibrosis: clinical, physiologic, pathologic, and molecular aspects.

BACKGROUND: Previous studies identified clinical and physiologic factors of idiopathic pulmonary fibrosis (IPF) that are related to an increased risk of mortality. But there are few studies about histologic and molecular approach. OBJECTIVE: We investigated whether the C-reactive protein (CRP), fibroblastic foci, phosphorylated Smad2/3 (p-Smad2/3), tumor growth factor-beta (TGF-beta), TGF-beta receptor II (TbetaRII), and the polymorphism of the TGF-beta1 codon 10 are associated with the progression of IPF patients. DESIGN: Eighty-six IPF patients who underwent surgical lung biopsies were examined. For each patient, clinical and physiologic parameters were investigated, and we performed immunohistochemical staining for p-Smad2/3 and TbetaRII, and genotyping of the TGF-beta1 codon 10 polymorphism. RESULTS: Age at diagnosis, gender, symptom duration, and smoking status did not show a significant association. However, the amount of smoking (p = 0.002), severe reduction in the percentages of predicted forced vital capacity (p = 0.013) and diffusion lung capacity of carbon monoxide (p = 0.023), CRP (p = 0.009) at diagnosis, and fibroblastic foci (p = 0.026) were associated with a poor prognosis. Cellularity, fibrosis, expression level of p-Smad2/3 and TbetaRII, and genotype of the TGF-beta1 codon 10 polymorphism did not have a statistically significant association with the prognosis. CONCLUSION: This study confirmed the amount of smoking, abrupt decrease in follow-up pulmonary function parameters, fibroblastic foci, and increased levels of CRP concentration at diagnosis were significantly associated with poor survival. Larger studies are required to confirm all prognostic factors including CRP.

Patients with unresectable hepatocellular carcinoma beyond Milan criteria: should we perform transarterial chemoembolization or liver transplantation?

Patients with unresectable, beyond Milan criteria, hepatocellular carcinoma (HCC) invariably undergo palliative transarterial chemoembolization (TACE). The aim of this study was to compare the outcomes of conventional TACE versus liver transplantation (LT) in unresectable (beyond Milan criteria) HCC. Twelve patients underwent LT and 86 TACE for unresectable, beyond Milan criteria HCC. The inclusion criteria were a single tumor60 years, vascular invasion, or extrahepatic spread. Survival rates were calculated using the Kaplan-Meier method. Multivariate analysis showed that TACE was a prognostic factor for survival (hazard ratio, 16.66, P=.000). The LT group showed significantly better survival than the TACE cohort. Two cases (16.7%) in the LT group recurred at a median time of 13.5 months. Survival rates at 1, 3, and 5 years were 100%, 88.9%, and 76.2% in the LT group, and 85.6%, 45.6%, and 21.4% in the TACE group, respectively. Patients with unresectable, beyond Milan criteria HCC should be given the option to receive LDLT, because LT offers a significantly better likelihood of survival than TACE.

Early and delayed onset cytomegalovirus infection of liver transplant recipients in endemic areas.

BACKGROUND: The delayed onset of cytomegalovirus (CMV) infection after liver transplantation can place patients at risk for graft failure and mortality. METHODS: We compared early versus delayed onset of CMV infection to identify risk factors for mortality among liver transplant recipients in an endemic area. RESULTS: Among 710 consecutive adult liver transplant recipients, incidence of CMV infection was 47.5% (337/710). Male gender, biliary complications, acute rejection episodes, antilymphocyte antibodies high hemoglobin, and high total bilirubin were significantly different among patients with delayed versus early onset CMV infections. The overall incidence of early versus delayed CMV infections was 43.1% (306/710) versus 4.4% (31/710). Among them, 11.1% (34/306) and 25.8% (8/31) of patients developed CMV disease. CONCLUSION: These results showed that a higher proportion of patients developed disease among delayed CMV infected patients (P=.039). The overall and graft survival curves for patients with early onset CMV infections were better than those of patients who had delayed onset CMV infections (P=.026 and P=.014). Recurrence of hepatitis B virus, hepatic dysfunction, and retransplantation were associated with increased mortality among patients who had a delayed CMV infection.

Risk factors for posttransplant lymphoproliferative disorder in pediatric liver transplant recipients with cytomegalovirus antigenemia.

Epstein-Barr virus (EBV) infections, associated with posttransplant lymphoproliferative disorder (PTLD) are known to develop in cytomegalovirus (CMV)-infected transplant recipients due to the indirect effects of CMV. This study evaluated risk factors for PTLD among pediatric liver transplant recipients with CMV infections. We reviewed the medical records of 119 patients

Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway.

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B(4) receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappaB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.