TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment.

The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.

The absolute lymphocyte to monocyte ratio is associated with poor prognosis in classical Hodgkin lymphoma patients younger than 60 years of age.

Recent studies suggest that absolute lymphocyte count, absolute monocyte count and their ratio [lymphocyte/monocyte ratio (LMR)] at diagnosis may predict survival in classical Hodgkin lymphoma (cHL). Here, we investigated the prognostic significance of LMR in cHL patients in relation to age of patients. Subjects included 351 cHL patients (age range from 4 to 84 years, median age 34 years, sex ratio 1.58) who had been followed-up for a median period of 59 months (range, 0.1-245 months). The estimated 5-year overall survival (OS) rate was 86.8%. Subgroup analysis was performed according to patients' age; non-elderly group (<60 years of age) versus elderly group (≥60 years of age). There was no significant difference in the level of absolute lymphocyte count, absolute monocyte count or LMR between the age groups. Using receiver operating characteristic curve analysis, the optimal cut-off value of LMR for the entire cohort was determined at 2.8, whereas the optimal cut-off for the elderly group was 2.2. In the non-elderly group (<60 years old), patients with LMR <2.8 had significantly lower OS or lymphoma-specific survival compared with those with LMR ≥2.8 (p < 0.001, both). In contrast, neither the LMR value of 2.8 or 2.2 predicted survival in the elderly group. In multivariate analysis, LMR remained a significant prognostic factor for OS (p = 0.049). The results of our analysis suggest that low LMR is associated with poor OS in patients of <60 years old.

LGALS3 as a prognostic factor for classical Hodgkin's lymphoma.

LGALS3, a member of the lectin family, has an important role in tumor progression through inhibition of apoptosis. LGALS3 shares several significant structural properties with BCL2. In this study, we examined the prognostic significance of LGALS3 and BCL2 in uniformly treated classical Hodgkin's lymphoma. Diagnostic tissues from 110 patients with uniformly treated classical Hodgkin's lymphoma were evaluated retrospectively by immunohistochemical analysis of LGALS3 and BCL2 expression. The median follow-up time was 6.2 years (range, 0.2-17.3 years). Twenty-seven patients (25%) expressed LGALS3 protein in Hodgkin/Reed-Sternberg cells, which was associated with poor overall survival and event-free survival (P=0.007 and P<0.001). Fifteen patients (14%) expressed BCL2 protein in Hodgkin/Reed-Sternberg cells, which was not associated with overall survival and event-free survival (P=0.928 and P=0.900).There was no correlation between LGALS3 and BCL2 expression (P=0.193). Multivariate analysis identified LGALS3 protein as an independent prognostic factor for event-free survival (P=0.007). Subgroup analysis according to the Ann Arbor stage of classical Hodgkin's lymphoma showed that LGALS3 protein expression had a prognostic value in limited-stage classical Hodgkin's lymphoma (P<0.001). The results of this study suggest that LGALS3 is an independent prognostic factor in classical Hodgkin's lymphoma, and may allow the identification of a subgroup of patients with limited-stage classical Hodgkin's lymphoma who require more intensive therapy.

Epigallocatechin gallate protects against fat and muscle atrophy in B16BL6 melanoma-bearing mice on a high-fat diet.

AIMS: Epidemiological evidence indicates that there is a substantial association between body mass index (BMI) and at least ten forms of cancer, including melanoma, and BMI imbalance contributes to the poor survival rate of cancer patients before and after therapy. Nevertheless, few pharmacological studies on models of obesity and cancer have been reported. In this study, we administered epigallocatechin gallate (EGCG) to B16BL6 tumor-bearing mice that received a high-fat diet (HFD) to examine its impact. METHODS: B16BL6 tumor-bearing mice were fed a HFD. Body weight and food intake were documented every week. We conducted a Western blot analysis to examine the protein levels in the tumor, gastrocnemius (GAS), and tibialis anterior (TA) muscles, as well as the inguinal and epididymal white adipose tissues (iWAT and eWAT). KEY FINDINGS: EGCG has been shown to have anti-cancer effects equivalent to those of cisplatin, a chemotherapy drug. Furthermore, EGCG protected against the loss of epidydimal white adipose tissue by regulating protein levels of lipolysis factors of adipose triglyceride lipase and hormone-sensitive lipase as well as WAT browning factors of uncoupling protein 1, as opposed to cisplatin. EGCG was shown to reduce the protein levels of muscular atrophy factors of muscle RING-finger protein-1, whereas cisplatin did not contribute to rescuing the atrophy of TA and GAS muscles. CONCLUSION: Taken together, our findings indicate that EGCG has a preventive effect against cachexia symptoms and has anti-cancer effects similar to those of cisplatin in tumor-bearing mice fed a high-fat diet.

Moderating AKT signaling with baicalein protects against weight loss by preventing muscle atrophy in a cachexia model caused by CT26 colon cancer.

Cancer cachexia is a type of energy-wasting syndrome characterized by fatigue, anorexia, muscle weakness, fat loss, and systemic inflammation. Baicalein, a flavonoid with bioactive properties, has demonstrated the ability to mitigate cardiac and skeletal muscle atrophy in different experimental settings. This effect is achieved through the inhibition of muscle proteolysis, suggesting its potential in preserving skeletal muscle homeostasis. In this study, we investigated the anti-cancer cachexia effects of baicalein in the regulation of muscle and fat wasting, both in vivo and in vitro. Baicalein attenuated body weight loss, including skeletal muscle and white adipose tissue (WAT), in CT26-induced cachectic mice. Moreover, baicalein increased muscle fiber thickness and suppressed the muscle-specific ubiquitin-protease system, including F-box only protein 32 and muscle RING-finger protein-1, by activating AKT phosphorylation both in vivo and in vitro. The use of LY294002, a particular inhibitor of AKT, eliminated the observed impact of baicalein on the improvement of muscle atrophy. In conclusion, baicalein inhibits muscle proteolysis and enhances AKT phosphorylation, indicating its potential role in cancer cachexia-associated muscle atrophy.

Receptor tyrosine kinases MET and RON as prognostic factors in diffuse large B-cell lymphoma patients receiving R-CHOP.

Receptor tyrosine kinases MET and RON (MST1R) form non-covalent complexes on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role for MET expression in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to examine the impact of MET and RON expression in uniformly treated DLBCL patients. The expression of MET and RON was retrospectively examined by immunohistochemistry in 120 DLBCL patients treated with rituximab combined with a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). The median follow-up time was 42.5 months (range, 1-89 months). Thirty-two (26%) and 30 patients (25%) expressed MET or RON, respectively. Seventy-five patients (62.5%) were negative for both MET and RON (MET(-) RON(-) ). MET negativity was associated with worse overall survival (P = 0.029). In multivariate analysis, negativity for both MET and RON (MET(-) RON(-) ) was strongly associated with inferior overall survival (P = 0.008). Interestingly, the MET(-) RON(-) phenotype retained its prognostic impact after subgroup analysis according to the international prognostic index or by the cell of origin by immunohistochemical algorithm by Choi et al. This study suggests that the MET(-) RON(-) phenotype is an independent prognostic factor in DLBCL patients receiving R-CHOP, and may identify a subgroup of DLBCL patients who require more intensive therapy.

The role of (18) F-fluorodeoxyglucose-positron emission tomography in the assessment of disease activity in patients with takayasu arteritis.

OBJECTIVE: The assessment of disease activity in Takayasu arteritis (TA) is difficult in clinical situations because clinical symptoms and laboratory parameters do not always reflect the actual inflammation of the arterial wall. We undertook this study to comprehensively investigate the role of (18) F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in the assessment of disease activity in patients with TA. METHODS: We performed a retrospective chart review of 53 FDG-PET scans in 38 patients with TA. We measured (18) F-fluorodeoxyglucose ((18) F-FDG) accumulation in the vascular wall of the large vessel using semiquantitative (visual grade) and quantitative (standard uptake value intensity) analyses. Clinical disease activity was evaluated based on the National Institutes of Health criteria for active TA, and erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels were measured. RESULTS: At baseline, active vascular (18) F-FDG uptake (visual grade ≥2) was observed in 18 of 24 patients with active disease and in 5 of 14 patients with inactive disease. There was a significant association between clinical disease activity and disease activity judged by FDG-PET (P = 0.008). Visual grade, standard uptake value intensity, and the number of vascular lesions with active (18) F-FDG uptake were significantly higher in patients with active disease and correlated well with the ESR and CRP levels. In 15 followup FDG-PET scans, the changes in visual grade, areas of active vascular (18) F-FDG uptake, and standard uptake value intensity reflected changes in clinical disease activity. CONCLUSION: (18) F-FDG uptake was associated with clinical disease activity and markers of inflammation, and FDG-PET reflected changes in clinical disease activity in patients with TA. FDG-PET may be a useful tool for aiding in the assessment of disease activity in patients with TA.

Argon plasma coagulation is safe and effective for treating smaller gastric lesions with low-grade dysplasia: a comparison with endoscopic submucosal dissection.

BACKGROUND AND AIMS: The best therapeutic modality has not been established for gastric low-grade adenomas or dysplasia (LGD), which can progress to invasive carcinoma despite a low risk. This study aims to investigate the clinical efficacy, safety, and local recurrence after argon plasma coagulation (APC) treatment of gastric LGD compared with endoscopic submucosal dissection (ESD). PATIENTS AND METHODS: A total of 320 patients with gastric LGD ≤ 2.0 cm treated with APC or ESD between 2004 and 2011 were retrospectively analyzed. We compared local recurrence rate, complication rate, procedure time, and admission to hospital between APC and ESD groups. RESULTS: Of the 320 patients, 116 patients were treated with APC and 204 with ESD. During follow-up, local recurrence was more common in the APC group (3.8 %, 4/106) than the ESD group (0.5 %, 1/188; log-rank test P = 0.036). However, all patients with local recurrence (n = 5) were treated by additional APC, and followed up without further recurrences. ESD was complicated by two perforations (1.0 %, 2/204) compared with no perforations in the APC group (0 %, 0/116). Bleeding complications were not different between the APC (1.7 %, 2/116) and ESD (2.0 %, 4/204) groups. Procedure time was shorter in the APC (7.8 ± 5.1 min) than the ESD (53.1 ± 38.1 min) group (P < 0.001). The proportion of hospitalization was less in the APC group (31.0 %, 36/116) than the ESD group (100.0 %, 204/204) (P < 0.001). CONCLUSIONS: APC can be a good treatment option for patients with LGD ≤ 2.0 cm.

Panax ginseng C.A. meyer alleviates benign prostatic hyperplasia while preventing finasteride-induced side effects.

Panax ginseng C.A. Meyer, a widely used traditional medicine in East Asia, shows many beneficial effects on immune function, male erectile dysfunction, cancer, excessive oxidants, and aging issues. However, its effect on benign prostatic hyperplasia (BPH) and its potential in the treatment of side effects related to finasteride (Fi), an FDA-approved drug for BPH, are less known. This study aimed to verify the therapeutic effects of a water extract of P. ginseng (PGWE) on BPH in testosterone propionate (TP)-induced BPH rats and TP-treated RWPE-1 human epithelial cells, and the inhibitory potential on the Fi-induced side effects is also explored. In the TP-induced BPH rat model, PGWE alleviated the pathological markers of BPH such as weight and epithelial thickness of the prostate, and the serum level of dihydrotestosterone. PGWE downregulated androgen-related BPH factors such as 5α-reductase 2 and androgen receptor. PGWE also showed prostatic cell apoptosis accompanied by increased expression of Bax and decreased expression of Bcl-xL and cleaved-caspase 3, respectively, in addition to increasing mitochondrial dynamics in both in vivo and in vitro BPH models. Notably, reduced sperm count, one of the serious side effects of Fi, in the epididymis of BPH rats was recovered with PGWE treatment, suggesting less toxicity to sperm development by PGWE. PGWE also protected against Fi-induced sperm loss when PGWE was administered in combination with Fi without compromising the therapeutic effects of Fi on BPH. Based on these findings, we propose that PGWE could be an alternative therapeutic agent for BPH.

Patterns of initial disease recurrence after resection of biliary tract cancer.

OBJECTIVES: This study aimed to provide further insights into the indications for adjuvant therapeutic strategies via analysis of the sites of initial recurrence after resection of gallbladder cancer (GBC) and intrahepatic (IHC) and extrahepatic cholangiocarcinoma (EHC). METHODS: Patients with biliary tract cancer who underwent potentially curative resection were identified from the database. Sites of initial disease recurrence were categorized as locoregional or distant. RESULTS: Between March 2001 and April 2009, 231 patients underwent curative resection. Initial GBC and IHC recurrence involving a distant site occurred in 70.8 and 86.8% patients, respectively, compared to 56.9% patients with EHC (p = 0.002). The median time to disease recurrence (TTR) was shorter among the GBC and IHC groups compared with that in EHC patients (6.3 and 6.7 vs. 13.1 months, respectively; p = 0.003). Moreover, median times to distant recurrence in GBC and IHC groups were shorter than that in EHC (5.8 and 6.5 vs. 14.1 months, respectively; p = 0.002). CONCLUSIONS: After resection, recurrent GBC and IHC are more likely to involve a distant site and are associated with significantly shorter TTR than recurrent EHC. These findings suggest that an adjuvant therapeutic strategy targeting distant disease is likely to have a significant impact on the overall management of GBC and IHC.

Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular carcinoma.

BACKGROUND AND AIM: Patients with hepatocellular carcinoma (HCC) that is refractory to repeated transarterial chemoembolization (TACE) are considered for systemic therapy, but TACE refractoriness is not well defined. The aim of this study was to determine the characteristics of patients whose HCC is refractory to repetitive TACE. METHODS: We evaluated 264 patients with intermediate-stage HCC who underwent TACE between January 2006 and September 2009. We designated the development of vascular invasion or extrahepatic spread during follow up as "stage progression" (SP), and hypothesized that SP might be the surrogate end-point for TACE refractoriness. RESULTS: The median follow up was 18.2 months, and median number of TACE was 3.0 (range, 1-13). Median time-to-progression was 5.5 months (95% confidence interval, 4.8-6.2), and median overall survival was 25.3 months (95% confidence interval, 21.6-29.0). We classified the patients according to disease course as: no progressive disease (PD(-); n = 33); PD without SP (PD(+)SP(-); n = 113); PD followed by SP (PD→SP; n = 47); and simultaneous PD and SP (PD&SP; n = 64). PD(-) and PD(+)SP(-) groups showed no difference in overall survival, PD→SP group had worse overall survival than PD(-) and PD(+)SP(-) groups, and PD&SP group had the worst overall survival. The significant prognostic factors for SP-free survival were development of PD and need for three sessions of TACE during the first 6 months. CONCLUSIONS: SP-free survival can be regarded as an end-point for TACE refractoriness. Development of progression or need for three sessions of TACE within the first 6 months could be predictive of TACE refractoriness.

Anmyungambi Decoction Ameliorates Obesity through Activation of Non-Shivering Thermogenesis in Brown and White Adipose Tissues.

Obesity is a burden to global health. Non-shivering thermogenesis of brown adipose tissue (BAT) and white adipose tissue (WAT) is a novel strategy for obesity treatment. Anmyungambi (AMGB) decoction is a multi-herb decoction with clinical anti-obesity effects. Here, we show the effects of AMGB decoction using high-fat diet (HFD)-fed C57BL6/J mice. All four versions of AMGB decoction (100 mg/kg/day, oral gavage for 28 days) suppressed body weight gain and obesity-related blood parameters in the HFD-fed obese mice. They also inhibited adipogenesis and induced lipolysis in inguinal WAT (iWAT). Especially, the AMGB-4 with 2:1:3:3 composition was the most effective; thus, further studies were performed with the AMGB-4 decoction. The AMGB-4 decoction displayed a dose-dependent body weight gain suppression. Serum triglyceride, total cholesterol, and blood glucose decreased as well. In epididymal WAT, iWAT, and BAT, the AMGB-4 decoction increased lipolysis markers. Additionally, the AMGB-4 decoction-fed mice showed an increased non-shivering thermogenic program in BAT and iWAT. Excessive reactive oxygen species (ROS) and suppressed antioxidative factors induced by the HFD feeding were also altered to normal levels by the AMGB-4 decoction treatment. Overall, our study supports the clinical use of AMGB decoction for obesity treatment by studying its mechanisms. AMGB decoction alleviates obesity through the activation of the lipolysis-thermogenesis program and the elimination of pathological ROS in thermogenic adipose tissues.

Retroperitoneal fibrosis in 27 Korean patients: single center experience.

Retroperitoneal fibrosis (RPF) is a rare disease with unclear etiology, which is characterized by chronic non-specific inflammation of the retroperitoneum. This study was performed to investigate the clinical characteristics, laboratory findings, radiologic findings, treatment and outcome in Korean patients with RPF. We retrospectively reviewed medical records of 27 RPF patients who were admitted to Yonsei University Medical Center between 1998 and 2009. Twenty-two patients (81%) were male. The mean age at diagnosis was 56 yr. Nine patients had identifiable risk factors of RPF and three patients had combined autoimmune diseases. Acute phase reactants were elevated in most patients. Rheumatoid factor was positive in 3 of 16 patients (19%) and antinuclear antibody in 4 of 17 (24%). Five of 6 patients who were taken positron-emission tomography showed positive uptake. Glucocorticoids were used in 16 patients (59%) and four of them received combination therapy with azathioprine. After immunosuppressive treatment, the levels of acute phase reactants dropped, and the size of mass also decreased in most patients. In conclusion, the clinical characteristics of RPF in Korean patients are similar with other series except for higher proportion of male. Some patients with RPF have autoimmune features. The effect of immunosuppressive treatment on RPF is good.

Lymphocyte-activating gene-3 expression is associated with tumor-infiltrating lymphocyte levels in HER2-positive breast cancers.

ABSTRACT: Lymphocyte-activating gene-3 (LAG-3, CD223) is the third inhibitory receptor targeted for immunotherapy. Several clinical trials investigating the use of interventions targeting LAG-3 are underway. The exact signaling mechanism downstream of LAG-3 is largely unknown, especially in breast cancer. The prognostic significance of tumor-infiltrating lymphocytes (TILs) in breast cancer has been previously determined.Among 167 human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, 90 and 78 patients were positive and negative for the hormone receptor, respectively. LAG-3 mRNA and protein expression levels in TILs were evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, among 12 and 167 HER2-positive breast cancer samples, respectively.High expression of LAG-3 in TILs was significantly correlated with high levels of TILs (P = .003) and an abundance of tertiary lymphoid structures around invasive components (P = .014). In addition, high expression of LAG3 was significantly associated with positivity for programmed death-ligand 1 (PD-L1) in tumor cells, a high immunostaining score of PD-L1 in TILs, and a high total immunostaining score for PD-L1 in tumor cells and TILs (all, P < .001). High expression levels of LAG-3 mRNA were associated with high levels of TILs (P = .091).LAG-3 protein expression was not a prognostic factor in HER2-positive breast cancers, and LAG-3 expression in TILs was significantly associated with the levels of TILs in HER2-positive breast cancer, although it was not a prognostic factor.

DRG2 supports the growth of primary tumors and metastases of melanoma by enhancing VEGF-A expression.

Malignant metastatic melanoma (MM) is the most lethal of all skin cancers, but detailed mechanisms for regulation of melanoma metastasis are not fully understood. Here, we demonstrated that developmentally regulated GTP-binding protein 2 (DRG2) is required for the growth of primary tumors and for metastasis. DRG2 expression was significantly increased in MM compared with primary melanoma (PM) and dysplastic nevi. A correlation between DRG2 expression and poor disease-specific survival in melanoma patients was also identified. Furthermore, inhibition of DRG2 suppressed the binding of Hypoxia-inducible factor 1α to the VEGF-A promoter region, expression of vascular endothelial growth factor (VEGF)-A, and formation of endothelial cell tubes. In experimental mice, DRG2 depletion inhibited the growth of PM and lung metastases and increased survival. These results identify DRG2 as a critical regulator of VEGF-A expression and of growth of PMs and lung metastases.

Does low-dose aspirin increase blood loss after spinal fusion surgery?

BACKGROUND CONTEXT: Low-dose aspirin for the prevention of cardiovascular disease is recommended to be discontinued at least 7 days before spinal surgery. PURPOSE: To determine the effect of stopping low-dose aspirin at least 7 days before surgery on the level of the perioperative blood loss or complications related to hemorrhage. STUDY DESIGN: Retrospective case study. PATIENT SAMPLE: Patients who underwent spinal fusion surgery for degenerative lumbar disease. OUTCOME MEASURE: Clinical outcome was measured by the Oswestry Disability Index. METHODS: The aspirin group included 38 patients who had taken 100 mg aspirin for an average of 40.3 months. They stopped aspirin for at least 7 days before surgery (mean, 9.0 days). The control group included 38 patients who had not taken aspirin. Both groups were matched in terms of age, gender, number of fused segments, and surgical procedures. The diagnosis in all patients was degenerative spinal disease. RESULTS: The mean age in the aspirin and control groups was 68.5 and 69.1 years, respectively. The mean number of levels fused was 2.0 segments in both groups. During surgery, the estimated blood loss was 855.3 cc in the aspirin group and 840.8 cc in the control group with no significant difference (p=.84). However, there was a significant difference in blood drainage after surgery. The hemovac blood drainage after surgery was 864.4 cc in the aspirin group but only 458.4 cc in the control group (p<.001). Therefore, the transfusion requirement after surgery was significantly greater in the aspirin group than in the control group (p=.03). The rate of complications related to hemorrhage was higher in the aspirin group than in the control group. CONCLUSIONS: The intraoperative blood loss during spinal fusion surgery was similar in both groups. However, the blood drainage after surgery was significantly higher in the aspirin group despite stopping aspirin 7 days before surgery. Hence, surgeons should pay careful attention to postoperative blood loss and complications related to hemorrhage in patients who have been taking low-dose aspirin.