Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer.

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERß expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.

Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients.

BACKGROUND: The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME and generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical, angiogenic, and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC). METHODS: Utilizing combined immunohistochemistry and digital image analysis, we assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC. Subsequently, the potential association between M2 TAMs and angiogenic VEGF-A and/or lymphangiogenic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored via an in vitro co-culture system. RESULTS: CD68 and CD163 expression were found to directly correlate with VEGF-A and/or VEGF-C expression (all p < 0.001). Furthermore, elevated M2 ratio (CD163+/CD68+) was significantly associated with poor overall survival (p = 0.023). Dual expression of M2 ratiohigh and VEGF-Chigh (M2 ratiohighVEGF-Chigh) was correlated with worse overall survival (p = 0.033). Multivariate analysis revealed that M2 ratiohigh [HR (95% CI) = 1.53 (1.01-2.33), p = 0.046] and combined M2 ratiohighVEGF-Chigh expression [HR (95% CI) = 2.01 (1.28-3.16), p = 0.003] were independent predictors of poor overall survival. Notably, we confirmed that M2 macrophages significantly enhanced the protein and mRNA expression of both VEGF-A and VEGF-C, while M1 macrophages induced only mRNA expression of VEGF-A in A549 cells. CONCLUSIONS: This study suggests that TAMs are significantly associated with angiogenesis and lymphangiogenesis, contributing to the progression of NSCLC. Furthermore, elevated M2 ratio, similar to combined high M2 ratio and high VEGF-C expression, is a strong indicator of poor prognosis in patients with NSCLC, providing insight for future TAM-based immunotherapy strategies.

CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer.

OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.

Different TERT Expression between Colorectal Adenoma and Serrated Polyp.

Background and Objectives: Telomere regulation have an association with colorectal cancer. Previous studies demonstrated its implication in colorectal carcinogenesis. This study aimed to identify the role of telomerase reverse transcriptase (TERT) in colorectal carcinogenesis and determine TERT expression and their associated genes in precancerous lesions. Materials and Methods: TERT expression in 93 colorectal precursor lesions was analyzed. This included 61 tubular adenomas (TAs) and 32 serrated polyps (SPs). Furthermore, KRAS and BRAF gene mutations and microsatellite instability were analyzed. Statistical tests were performed to analyze the relationship between variables. Results: TERT expression in TAs, when compared with those observed in paired adjacent nontumor tissues, was 0.92 ± 0.78. TERT expression levels were significantly lower in SPs (0.38 ± 0.14, p < 0.001). KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001). TERT expression tended to be associated with KRAS mutations (46.7% vs. 22.0%, p = 0.098) and low-grade tumors (35.0% vs. 16.0%, p = 0.096), but this difference was insignificant. Conclusions: TERT expression has a pivotal role in progression to TAs in colorectal tissue. Considering the association between TERT expression and KRAS mutation, therapeutic drugs targeting this pathway can be developed for cancer prevention.

Role of matrix metalloproteinases 2 and 9 in the development of frozen shoulder: human data and experimental analysis in a rat contracture model.

BACKGROUND: Although frozen shoulder (FS) is a common shoulder disorder, its pathogenesis is not yet determined. The function of matrix metalloproteinases (MMPs) is related to extracellular matrix remodeling. The purposes of this study were to investigate the pattern of sequential expression of MMPs in a rat model of shoulder contracture and to compare the expression of MMPs in the joint capsule between patients with FS and a control group. METHODS: We obtained joint capsules from rats immobilized by molding plaster (a shoulder contracture model) at baseline, 3 days, 1 week, and 3 weeks (4 rats per time point; 16 rats in total). The expression of the inflammatory cytokine interleukin 6 (IL-6), MMP-2, and MMP-9 was examined by immunohistochemistry. We also obtained joint capsules from 21 patients with FS and 13 control patients with instability to quantify the expression levels of MMP-2 and MMP-9 by immunohistochemistry. RESULTS: In the rat model, IL-6 and MMP-9 tended to be overexpressed in the joint capsule at 3 days and 1 week and MMP-2 at 3 days, 1 week, and 3 weeks. MMP-2 and MMP-9 were significantly overexpressed in the joint capsules of the patients with FS compared with those of control patients. CONCLUSION: The results from both human and animal studies suggest the involvement of MMP-2 and MMP-9 in the development of FS. Animal study showed that the sequential expression of IL-6 and MMPs may be associated with fibrosis of the joint capsule.

PIK3CA Amplification Is Common in Left Side-Tubular Adenomas but Uncommon Sessile Serrated Adenomas Exclusively with KRAS Mutation.

Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation.

Does Rotator Cuff Repair Improve Psychologic Status and Quality of Life in Patients With Rotator Cuff Tear?

BACKGROUND: Recently, psychological status, patient-centered outcomes, and health-related quality of life (HRQoL) in patients with scheduled or who underwent orthopaedic surgeries have been emphasized. The relationship between preoperative psychological status and postoperative clinical outcome in patients with rotator cuff repair has not yet been investigated. QUESTIONS/PURPOSES: The primary objective of this study was to investigate changes in psychological status (depression, anxiety, insomnia) and HRQoL after rotator cuff repair. The secondary objective was to assess whether preoperative depression, anxiety, and insomnia predict clinical outcome after rotator cuff repair. METHODS: Forty-seven patients who underwent rotator cuff repair prospectively completed the visual analog scale (VAS) pain score, the UCLA Scale, the American Shoulder and Elbow Surgeons' Scale (ASES), the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), and the World Health Organization Quality-of-life Scale Abbreviated Version (WHOQOL-BREF) before surgery and at 3, 6, and 12 months after surgery. Repeated-measures analysis of variance was used to evaluate the serial changes in psychological parameters and outcome measurements. The chi-square test was also used to compare preoperative and postoperative prevalence of depression, anxiety, and insomnia. Finally, multiple regression analysis was applied to determine the relationship between preoperative psychological status and postoperative clinical outcome. RESULTS: With surgery, depression, anxiety, and insomnia decreased, whereas quality of life increased. The mean HADS-D and HADS-A scores and the mean PSQI score decreased from 3.7 ± 3.3, 4.3 ± 4.3, and 6.6 ± 3.6, respectively, before surgery to 2.1 ± 2.3, 1.4 ± 2.4, and 4.2 ± 3.3, respectively, at 12 months after surgery (HADS-D mean difference 1.6 [95% confidence interval {CI}, 0.6-2.6], p = 0.003; HADS-A mean difference 2.9 [1.5-4.4], p < 0.001; PSQI mean difference 2.4 [1.3-3.4], p < 0.001). The mean WHOQOL-BREF score increased from 60.4 ± 11.0 before surgery to 67.4 ± 11.8 at 12 months after surgery (mean difference -7.0 [95% CI, -10.7 to -3.4], p < 0.001). At 12 months after surgery, there were decreases in the prevalence of depression (six of 47 [22.8%] versus three of 47 [6.4%], p = 0.002), anxiety (11 of 47 [23.4%] versus two of 47 [4.3%], p = 0.016), and insomnia (33 of 47 [70.2%] versus 20 of 47 [42.6%], p = 0.022). Preoperative HADS-depression, HADS-anxiety, and PSQI scores did not correlate with the VAS pain score, UCLA, or ASES scores at 12 months after surgery. CONCLUSIONS: Psychological status and HRQoL improved with decreasing pain and increasing functional ability from 3 months after surgery. Preoperative depression, anxiety, and insomnia did not predict poor outcome after rotator cuff repair. Our findings suggest that successful rotator cuff repair may improve psychological status and HRQoL. LEVEL OF EVIDENCE: Level II, prospective study.

Clinical outcomes of rotator cuff repair with arthroscopic capsular release and manipulation for rotator cuff tear with stiffness: a matched-pair comparative study between patients with and without stiffness.

PURPOSE: To compare clinical outcomes after surgical treatment between rotator cuff tears with and without shoulder stiffness and evaluate the serial changes in pain intensity, functional scores, and range of motion (ROM). METHODS: The study comprised 26 patients with preoperative stiffness (stiff group) and 26 patients without stiffness (non-stiff group). The stiff group underwent arthroscopic or mini-open rotator cuff repair with arthroscopic capsular release and manipulation. The non-stiff group with rotator cuff repair only was matched for age and sex with the stiff group. The visual analog scale (VAS) pain score; University of California, Los Angeles (UCLA) score; American Shoulder and Elbow Surgeons (ASES) score; and ROM were evaluated preoperatively; 3, 6, and 12 months after surgery; and at final follow-up. RESULTS: Both groups had significant improvements in the VAS pain score, UCLA score, ASES score, and ROM at final follow-up. There were no significant differences between the 2 groups regarding VAS pain score, UCLA score, and ASES score at any period after surgery. In the stiff group, mean forward flexion was significantly lower than that in the non-stiff group at 3 months after surgery (143.1° v 154.2°, P = .003). Mean external rotation and internal rotation were significantly lower than those in the non-stiff group at 3 months after surgery (37.9° v 44.2°, P = .043, and 15.8 v 13.9, P < .001, respectively) and 6 months after surgery (49.1° v 57.3°, P = .002, and 13.2 v 12.0, P = .033, respectively). CONCLUSIONS: Overall satisfactory clinical outcomes could be achieved in both the stiff and non-stiff groups, although the stiff group had slower postoperative recovery of ROM until 6 months after surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study, prognosis study.

Differences in intravascular ultrasound and histological findings in culprit coronary plaques between ST-segment elevation myocardial infarction and stable angina.

A comprehensive evaluation of culprit coronary lesions may help to understand vulnerable plaques responsible for ST-segment elevation myocardial infarction (STEMI). We compared intravascular ultrasound (IVUS) and histological findings in culprit coronary plaques from 94 patients with STEMI (n = 54) or stable angina (n = 40). Tissue specimens were obtained by directional coronary atherectomy and IVUS was performed before percutaneous coronary intervention. IVUS and histological data were analyzed. Clinical characteristics were largely similar between the two groups. Plaque rupture and thrombi were more frequently found in the STEMI group than in the stable angina group. There were no significant differences between plaque types or proximal and distal reference measurements in the two groups. However, the site of minimal lumen area had a greater vessel area, remodeling index, and plaque burden with lesser lumen area in the STEMI group than in the stable angina group. Plaque areas immunopositive for CD68 and CD31 were significantly larger in the STEMI group, while the area immunopositive for α-smooth muscle actin was larger in the stable angina group. In conclusion, culprit lesions in STEMI patients showed a greater plaque burden, remodeling index, and more frequent thrombi with increased inflammation and neovascularization compared to the stable angina group, supporting the current concept of vulnerable plaques being responsible for STEMI.

Reliability of the classification and treatment of dislocations of the acromioclavicular joint.

BACKGROUND: We evaluated interobserver and intraobserver reliability of the classification and treatment of acromioclavicular (AC) joint dislocations and assessed the impact of adding 3-dimensional computed tomography (3D CT) on the reliability of classification and treatment choice. METHODS: Ten surgeons independently reviewed plain radiographs and 3D CT in 28 cases with AC joint dislocation. Images from each case were randomly presented to the observers, with plain radiographs alone being presented first, followed by plain radiographs plus 3D CT 2 weeks later. Four weeks later, they repeated the same survey to evaluate intraobserver reliability. Reliability was assessed on the basis of Fleiss κ values. RESULTS: On the basis of plain radiographs alone, interobserver and intraobserver reliability of the Rockwood classification were fair (κ = .214) and moderate (κ = .474), respectively. Interobserver and intraobserver reliability of treatment were both fair (κ = .213 and .399, respectively). On the basis of a combination of plain radiographs and 3D CT, interobserver and intraobserver reliability of the Rockwood classification were slight (κ = .177) and moderate (κ = .565), respectively. Interobserver and intraobserver reliability of treatment were fair (κ = .253) and moderate (κ = .554), respectively. There were no significant differences in reliability between the two groups in terms of any κ values. CONCLUSION: This study suggests an overall lack of reliability of the Rockwood classification of AC joint dislocations and of decisions regarding their treatment. There is especially poor agreement between experienced shoulder surgeons. The addition of 3D CT did not improve reliability of classification and treatment of AC joint dislocations.

Proteome-wide Characterization and Pathophysiology Correlation in Non-ischemic Cardiomyopathies.

BACKGROUND AND OBJECTIVES: Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies. METHODS: Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings. RESULTS: The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes. CONCLUSIONS: Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.

PPIB/Cyclophilin B expression associates with tumor progression and unfavorable survival in patients with pulmonary adenocarcinoma.

Cyclophilin B (CypB), encoded by peptidylprolyl isomerase B (PPIB), is involved in cellular transcriptional regulation, immune responses, chemotaxis, and proliferation. Recent studies have shown that PPIB/CypB is associated with tumor progression and chemoresistance in various cancers. However, the clinicopathologic significance and mechanism of action of PPIB/CypB in non-small cell lung cancer (NSCLC) remain unclear. In this study, we used RNA in situ hybridization to examine PPIB expression in 431 NSCLC tissue microarrays consisting of 295 adenocarcinomas (ADCs) and 136 squamous cell carcinomas (SCCs). Additionally, Ki-67 expression was evaluated using immunohistochemistry. The role of PPIB/CypB was assessed in five human NSCLC cell lines. There was a significant correlation between PPIB/CypB expression and Ki-67 expression in ADC (Spearman correlation r=0.374, P<0.001) and a weak correlation in SCC (r=0.229, P=0.007). In ADCs, high PPIB expression (PPIBhigh) was associated with lymph node metastasis (P=0.023), advanced disease stage (P=0.014), disease recurrence (P=0.013), and patient mortality (P=0.015). Meanwhile, high Ki-67 expression (Ki-67high) was correlated with male sex, smoking history, high pT stage, lymph node metastasis, advanced stage, disease recurrence, and patient mortality in ADC (all P<0.001). However, there was no association between either marker or clinicopathological factors, except for old age and PPIBhigh (P=0.038) in SCC. Survival analyses revealed that the combined expression of PPIBhigh/Ki-67high was an independent prognosis factor for poor disease-free survival (HR 1.424, 95% CI 1.177-1.723, P<0.001) and overall survival (HR 1.266, 95% CI 1.036-1.548, P=0.021) in ADC, but not in SCC. Furthermore, PPIB/CypB promoted the proliferation, colony formation, and migration of NSCLC cells. We also observed the oncogenic properties of PPIB/CypB expression in human bronchial epithelial cells. In conclusion, PPIB/CypB contributes to tumor growth in NSCLC, and elevated PPIB/Ki-67 levels are linked to unfavorable survival, especially in ADC.

Predictors for underestimated pathology in forceps biopsy compared with resection specimen of colorectal neoplasia; focus on surface appearance.

BACKGROUND: There have been substantial differences in pathologic results between forceps biopsies (FB) and resection specimen (RS) of the colorectal neoplasm. The aim of this study was to investigate predictive factors of the underestimated pathology in FB compared with RS. METHODS: Data from 248 consecutive patients with colorectal intraepithelial neoplasm ≥10 mm, which was removed by endoscopic mucosal resection or endoscopic submucosal dissection, were reviewed retrospectively. We excluded patients with no FB on the neoplasm before the resection. Demographic data and tumor characteristics including size, locations, surface appearances, and the number of FB fragments were evaluated as potential factors associated with the discrepancies by logistic regression analysis. RESULTS: Overall, 179 lesions from 171 patients were included in the study (size, 28.37 ± 12.00 mm; range 10-80 mm). The overall number of discrepancy cases was 103 (57.5%), where 90 (50.3%) were underestimated in FB and 13 (7.2%) downgraded in their RS. In the multivariate analysis, round [odds ratio (OR) 4.46, 95% confidence interval (CI) 1.76-11.30, p = 0.002], depressed (OR 3.23, 95% CI 1.11-9.39, p = 0.031), and mixed type of surface appearance (OR 5.47, 95% CI 2.38-12.60, p < 0.001), and tumor size ≥30 mm (OR 2.14, 95% CI 1.12-4.10, p = 0.021) were significant predictive factors for underestimated pathology in FB. CONCLUSIONS: Underestimation in FB is remarkable in colorectal tumors ≥10 mm in size. This discrepancy is associated with the tumor characteristics, such as surface appearance and size. Endoscopic characteristics of tumor should be carefully examined for an adequate management strategy of colorectal epithelial neoplasm.

Green tea extract co-administered with a polymer effectively prevents alcoholic liver damage by prolonged inhibition of alcohol absorption in mice.

AIMS: Alcohol toxicity can induce multiple organ dysfunction, including the liver. Gallated catechins (GCs), the components of green tea extract (GTE), have been known to inhibit intestinal lipid absorption. This study was designed to investigate the inhibitory effect of GC on the absorption of the lipid-soluble ethanol in normal mice. In addition, the effectiveness of prolonging the GC-mediated effect was evaluated as a means of preventing alcoholic liver damage. METHODS: GTE was administered orally immediately or 90 min before ethanol administration and the blood ethanol and acetaldehyde levels were measured. Binge ethanol administration (by gavage every 6 h for 24 h) was used to induce acute liver injury, and GTE was administered 90 min prior to every ethanol administration. RESULTS: When GTE, but not GC-decreased GTE, was administered immediately before ethanol intake, the blood ethanol and acetaldehyde levels were significantly lower than those in the control. On the other hand, GTE has no effect when GTE was administered 90 min before ethanol intake. When GTE was co-administered with polyethylene glycol (PEG) or poly-γ-glutamate (PGA) 90 min before ethanol intake, the lowering effect of GTE on the blood ethanol and acetaldehyde levels was maintained in contrast to the GTE-alone-treated group. After binge ethanol administration, liver weight decreased, and serum alanine aminotransferase and aspartate aminotransferase levels were elevated. Additionally, histopathological changes, such as macrovesicular steatosis and necrosis, were induced in the liver, together with reactive oxygen species generation. When GTE + PEG or GTE + PGA, but not GTE alone, was administered 90 min before ethanol intake, acute liver injury was ameliorated. CONCLUSION: These findings support the development of GTE + PEG or GTE + PGA as an inhibitor of intestinal alcohol absorption for the preventative treatment of acute alcohol toxicity.

Multi-center study regarding the risk factors for bleeding in gastrointestinal stromal tumor.

BACKGROUNDS/AIMS: In spite of several case reports about gastrointestinal stromal tumor (GIST) complicated with hemorrhage, study regarding the risk factors of bleeding in this tumor is scanty. Therefore, we analyzed the clinical characteristics of bled GISTs and tried to find risk factors of bleeding by comparing with non-bled cases. METHODOLOGY: Medical records of 49 bled GIST cases from 5 university hospitals in Korea between year 2001 to 2010 were compared with 96 non-bled cases. Whole pathological slides were reviewed by an experienced pathologist. RESULTS: Female predominance (58.6%) was noted and the mean age of the included patients was 58.4±13.1 years. In univariate analysis, location of jejunum, prolonged prothrombin time, presence of surface dimpling in CT, cellular pleomorphism and positivity of S100 was significantly dominant in the bled cases. Multivariate analysis showed significant differences in the location of jejunum (p=0.004, OR=3.533), prolonged prothrombin time (p=0003, OR=19.643), presence of surface dimpling (p=0.026, OR=6.250) in CT, and positivity of S100 (p=0.001, OR=12.941). CONCLUSIONS: Location of jejunum, prolonged prothrombin time, presence of surface dimpling in CT, and positivity of S100 are independent risk factors associated with bleeding in GI GIST patients.

The impact of depression and anxiety on self-assessed pain, disability, and quality of life in patients scheduled for rotator cuff repair.

BACKGROUND: Psychological status may be an important predictor of outcome and patient satisfaction after treatment for rotator cuff disease. Few prior studies have considered these factors. The objective of the study was to investigate the prevalence of psychological distress and its effect on self-assessed pain, disability, and health-related quality of life in patients scheduled for rotator cuff repair. MATERIALS AND METHODS: We assessed 107 consecutive patients preoperatively using the Hospital Anxiety and Depression Scale (HADS); visual analog scale pain score; American Shoulder and Elbow Surgeons (ASES) scale; Korean Shoulder Scale (KSS); and World Health Organization Quality of Life Scale, Abbreviated Version (WHOQOL-BREF). Preoperative demographic, clinical, and radiologic parameters were also evaluated. RESULTS: Of the patients, 28 (26.2%) had depression and 25 (23.4%) had anxiety. The HADS depression score was positively correlated with the visual analog scale pain score (P = .048) and negatively correlated with the ASES, KSS, and WHOQOL-BREF scores (P = .005, P = .004, and P < .0001, respectively). The HADS anxiety score was negatively correlated with the ASES, KSS, and WHOQOL-BREF scores (P = .034, P = .037, and P < .0001, respectively). On multivariate analysis with a linear regression model, the HADS depression score was an independent predictor of ASES, KSS, and WHOQOL-BREF scores (P = .02, P = .005, and P = .001, respectively). CONCLUSION: Depression and anxiety had a negative impact on self-assessed outcome measurements in patients scheduled for rotator cuff repair. Depression was a strong predictor of functional disability and health-related quality of life. Our results suggest that preoperative psychological status may influence postoperative outcome after rotator cuff repair and thus is an essential part of preoperative assessment.

Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder.

BACKGROUND: Frozen shoulder is a debilitating condition characterized by gradual loss of glenohumeral motion with chronic inflammation and capsular fibrosis. Yet its pathogenesis remains largely unknown. We hypothesized that the subacromial bursa may be responsible for the pathogenesis of frozen shoulder by producing inflammatory cytokines. MATERIALS AND METHODS: We obtained joint capsules and subacromial bursae from 14 patients with idiopathic frozen shoulder and from 7 control subjects to determine the expression levels of interleukin (IL) 1α, IL-1ß, IL-6, tumor necrosis factor α (TNF-α), cyclooxygenase (COX) 1, and COX-2 by real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: IL-1α, IL-1ß, TNF-α, COX-1, and COX-2 were expressed at significantly high levels in the joint capsules of the frozen shoulder group compared with those of the control group. Intriguingly, IL-1α, TNF-α, and COX-2 were also expressed at significantly high levels in the subacromial bursae of the frozen shoulder group compared with those of the control group. Immunohistochemical analysis showed increased expression of COX-2 in both the joint capsules and subacromial bursae of the frozen shoulder group. CONCLUSIONS: These findings imply that elevated levels of inflammatory cytokines in the subacromial bursa may be associated with the pathogenesis of inflammation evolving into fibrosis.

Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.

Innate immunity markers in culprit plaques of acute myocardial infarction or stable angina.

We analyzed the innate immunity markers, C-reactive protein (CRP), serum amyloid P component (SAP) and pentraxin-3 (PTX-3), and metalloproteinase-9 (MMP-9) in coronary atherectomy tissues obtained from patients with acute ST elevation myocardial infarction (STEMI) (n=27) or stable angina (n=15). The relative areas immunopositive for CRP and SAP were similar in the two groups. In contrast, the proportion of areas immunopositive for PTX-3 and MMP-9 was higher in the STEMI group, compared to the stable angina group. PTX-3 or MMP-9-stained areas largely overlapped with those positive for CD68. We concluded that PTX-3 plays a role in the pathogenesis of STEMI.

Expression of ADAMTS-2, -3, -13, and -14 in culprit coronary lesions in patients with acute myocardial infarction or stable angina.

ADAMTS (a disintegrin and metalloproteinase with thrombospondin type 1 motifs) proteases are emerging as key participants in the pathogenesis of vascular diseases. We studied the expression of ADAMTS-2, -3, -4 and -14 in the culprit plaques from patients presenting with acute myocardial infarction (AMI) versus stable angina. Tissue samples were gathered from 52 patients with AMI (n = 35) or stable angina (n = 17) who underwent directional coronary atherectomy. The specimens were stained with hematoxylin-eosin and analyzed immunohistochemically using antibodies specific to ADAMTS-2, -3, -13 and -14, and markers for endothelial cells, macrophages, and smooth muscle cells. Baseline characteristics of the groups were mostly similar. The proportion of smooth muscle α-actin-immunopositive area was smaller in the AMI group than in the stable angina group, but the areas immunopositive for CD31 or CD68 were higher in the AMI group. The relative areas immunopositive for ADAMTS-2, -3, and -13 in AMI were significantly larger than those in stable angina. However, the proportion of areas immunopositive for ADAMTS-14 did not differ between the two groups. Areas that stained for ADAMTS-2, -3, -13, and -14 largely overlapped with those positive for CD31 or CD68. The areas immunopositive for ADAMTS proteases were significantly correlated with CD31- or CD68-immunostained areas. In conclusions, ADAMTS-2, -3, and -13 expression, but not that of ADAMTS-14, are increased in plaques causing AMI compared those associated with stable angina. These results support a role for these enzymes in the pathogenesis of AMI.