Cytokine-related genes play critical roles in extrafollicular growth of follicular lymphoma cells

Follicular lymphoma (FL) is a germinal center-derived B-cell lymphoma that is known to proliferate in the intrafollicular region. However, lymphoma cells can be identified in the extrafollicular regions, which are related to disease dissemination. We purified the intrafollicular and extrafollicular regions of FL cells by laser microdissection and conducted microarray analysis in order to characterize the gene expression profiles of FL cells from both regions. BCL2 and genes of germinal B-cell markers clearly separated intrafollicular and extrafollicular regions of reactive follicular hyperplasia, suggesting the adequacy of the current analysis. In FL cases, cytokine-related genes were significantly enriched in extrafollicular regions compared with those in the intrafollicular regions. In intrafollicular regions of FL, cell-cycle–related genes were enriched. We found that the FL cells in the extrafollicular region more strongly expressed IL3RA and CXCL12 than those of intrafollicular regions. The cytokines might be also derived from stroma cells in the extrafollicular regions, which may initiate activation and migration of the tumor cells to this region. Our results suggest that FL cell interaction with surrounding stroma cells plays an important role in the pathophysiology of FL and that such interactions should be a good target for therapy.     

Clinicopathological analysis of immunohistochemical expression of CD47 and SIRPα in adult T-cell leukemia/lymphoma

The interaction of CD47 and signal-regulatory protein alpha (SIRPα) induces “don't eat me signal”, leading suppression of phagocytosis. This signal can affect the clinical course of malignant disease. Although CD47 and SIRPα expression are associated with clinicopathological features in several neoplasms, the investigation for adult T-cell leukemia/lymphoma (ATLL) has not been well-documented. This study aimed to declare the association between CD47 and SIRPα expression and clinicopathological features in ATLL. We performed immunostaining on 73 biopsy samples and found that CD47 is primarily expressed in tumor cells, while SIRPα is expressed in non-neoplastic stromal cells. CD47 positive cases showed significantly higher FoxP3 (P = .0232) and lower CCR4 (P = .0214). SIRPα positive cases presented significantly better overall survival than SIRPα negative cases (P = .0132). SIRPα positive cases showed significantly HLA class I (P = .0062), HLA class II (P = .0133), microenvironment PD-L1 (miPD-L1) (P = .0032), and FoxP3 (P = .0229) positivity. In univariate analysis, SIRPα expression was significantly related to prognosis (Hazard ratio [HR] 0.470; 95% confidence interval [CI] 0.253-0.870; P = .0167], although multivariate analysis did not show SIPRα as an independent prognostic factor. The expression of SIRPα on stromal cells reflects activated immune surveillance mechanism in tumor microenvironment and induce good prognosis in ATLL. More detailed studies for gene expression or genomic abnormalities will disclose clinical and biological significance of the CD47 and SIRPα in ATLL.     

Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a valuable diagnostic marker for rupture of thin-cap fibroatheroma: Verification by optical coherence tomography

Background

Relationships between plaque morphology on optical coherence tomography (OCT) and biomarker levels in the patients with acute coronary syndrome (ACS) have not been fully investigated.

Methods

ACS patients (n = 128) were prospectively enrolled and their plasma levels of soluble lectin-like oxidized LDL receptor-1 (sLOX-1), high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity troponin T (hs-TnT) were measured. Another set of 20 patients with stable angina pectoris (SAP) without plaque rupture or erosion served as controls. Among 128 ACS patients, 75 patients underwent OCT procedure to evaluate culprit plaque morphology, and were categorized into two groups; ACS with plaque rupture (ruptured ACS; R-ACS, n = 54) and ACS without plaque rupture (non-ruptured ACS; N-ACS, n = 21).

Results

Levels of sLOX-1 (p < 0.001), hs-CRP (p = 0.048) and hs-TnT (p < 0.001) were significantly higher in R-ACS than SAP. Levels of sLOX-1 were also significantly higher in R-ACS than in N-ACS (p < 0.001); whereas levels of hs-CRP (p = 0.675), as well as those of hs-TnT (p = 0.055), were comparable between R-ACS and N-ACS. Comparison of receiver operating characteristic (ROC) curves among sLOX-1, hs-CRP and hs-TnT to differentiate R-ACS from N-ACS revealed that the area under the curve (AUC) values of sLOX-1, hs-CRP and hs-TnT were 0.782, 0.531 and 0.643, respectively. ROC curves, generated for these biomarkers, to differentiate ACS with thin-cap fibroatheroma (TCFA) from those without demonstrated that the AUC values of sLOX-1, hs-CRP and hs-TnT were 0.718, 0.506 and 0.524, respectively.

Conclusion

sLOX-1, but not hs-CRP or hs-TnT, can differentiate ACS with plaque rupture from those without, and ACS with TCFA from those without.     

Effects of Statin Therapy on Cardiac Sympathetic Nerve Activity and Left Ventricular Remodeling in Patients With Chronic Heart Failure: A Propensity Score-Matched Analysis

Statin therapy reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and prevents left ventricular (LV) remodeling in chronic heart failure (CHF) patients. We sought to evaluate the effects of statin therapy on CSNA, as evaluated by ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy, and LV remodeling in CHF patients.This study was sub-analysis of our previous report of the result that the serial ¹²³I-MIBG studies were the most useful prognostic indicator in CHF patients. Patients with CHF (n = 208; left ventricular ejection fraction <45%) but no cardiac events for at least 5 months before the study, were identified according to their history of decompensated acute heart failure requiring hospitalization. The patients underwent ¹²³I-MIBG scintigraphy and echocardiography immediately before hospital discharge and after 6 months. The delayed % denervation, delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined by ¹²³I-MIBG scintigraphy. The LV end-diastolic volume (EDV) and end-systolic volume (ESV) were also determined by echocardiography. We selected 164 patients and used propensity score matching to compare patients who received oral statin (n = 82), and those who did not (n = 82).The changes in ¹²³I-MIBG scintigraphic parameters improved, and in echocardiographic LVEDV and LVESV reduced in the statin group compared with those in the non-statin group. Moreover, there were significant correlations between changes in the ¹²³I-MIBG scintigraphic findings and those in the LVEDV (% denervation, r = 0.534, P < 0.001; H/M ratio, r = −0.516, P < 0.001; and WR, r = 0.558, P < 0.001); or the LVESV (% denervation, r = 0.479, P < 0.001; H/M ratio, r = −0.450, P < 0.001; and WR, r = 0.520, P < 0.001) in the statin group. In contrast, there was no relationship between these parameters in the non-statin group.Statin therapy not only improved CSNA, but also reduced LV volume, in other wards, prevented LV remodeling in CHF patients.     

Hepatic artery aneurysm in a patient with hepatitis C liver cirrhosis: report of a case

Visceral artery aneurysms are rare, with an incidence rate of only 0.01–0.2 % in routine autopsies, and hepatic artery aneurysms account for approximately 20 % of these aneurysms. Despite recent advances in therapeutic techniques and diagnostic tools, the management of visceral artery aneurysms remains clinically challenging. We report a case of hepatic artery aneurysm with liver cirrhosis due to hepatitis C in an 81-year-old woman. A computed tomography scan demonstrated a hepatic artery aneurysm 4.4 cm in diameter. She underwent successful aneurysmectomy with vascular anastomosis. A computed tomography scan on postoperative day 7 demonstrated patent hepatic artery. The patient was followed-up for 1 year after surgery and died owing to progressive liver failure. However, she did not show any hepatic artery problem such as hepatic arterial thrombosis or occlusion. We discuss the risk factors of atherosclerosis in patients with liver cirrhosis, and present an overview of the treatment of hepatic artery aneurysms.     

Association Between Pulse Wave Velocity and a Marker of Renal Tubular Damage (N‐Acetyl‐β‐D‐Glucosaminidase) in Patients Without Diabetes

The authors assessed the association between the ratio of urinary activity of N‐acetyl‐β‐D‐glucosaminidase (NAG) to creatinine and the brachial‐ankle pulse wave velocity (baPWV) in patients without overt diabetes mellitus (DM). This was a cross‐sectional study of 233 patients who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and no history of kidney disease. Patients were divided into two groups: high NAG group (>5.8 U/g creatinine) and low NAG group (≤5.8 U/g creatinine). Mean baPWVs of the high NAG group were significantly higher than those of the low NAG group in both the eGFR ≥30 and <60 tertiles and the eGFR ≥60 and <90 tertiles. The baPWV was positively correlated with NAG in all patients (r=0.341, P<.001). Stepwise multivariate regression analysis showed that the baPWV was significantly related with NAG, age, and systolic blood pressure. Elevated NAG is related to elevated arterial stiffness in patients without DM.     

Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14

Toll-like receptors (TLRs) are innate recognition molecules for microbial products, but their direct interactions with corresponding ligands remain unclarified. LPS, a membrane constituent of gram-negative bacteria, is the best-studied TLR ligand and is recognized by TLR4 and MD-2, a molecule associated with the extracellular domain of TLR4. Although TLR4-MD-2 recognizes LPS, little is known about the physical interaction between LPS and TLR4-MD-2. Here, we demonstrate cell surface LPS-TLR4-MD-2 complexes. CD14 greatly enhances the formation of LPS-TLR4-MD-2 complexes, but is not coprecipitated with LPS-TLR4-MD-2 complexes, suggesting a role for CD14 in LPS loading onto TLR4-MD-2 but not in the interaction itself between LPS and TLR4-MD-2. A tentative dissociation constant (Kd) for LPS-TLR4-MD-2 complexes was approximately 3 nM, which is approximately 10-20 times lower than the reported Kd for LPS-MD-2 or LPS-CD14. The presence of detergent disrupts LPS interaction with CD14 but not with TLR4-MD-2. E5531, a lipid A antagonist developed for therapeutic intervention of endotoxin shock, blocks LPS interaction with TLR4-MD-2 at a concentration 100 times lower than that required for blocking LPS interaction with CD14. These results reveal direct LPS interaction with cell surface TLR4-MD-2 that is distinct from that with MD-2 or CD14.     

Utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device （Mammotome@） for the diagnosis of breast microcalcifications

Objective： The aim of this study was to evaluate the utility of an upright-type 11-gauge stereotactic vacuum-assisted biopsy device （Mammotome@） for the diagnosis of breast microcalcifications Methods： Between May 2001 and October 2005, 154 biopsies in 152 patients with microcalcifications were performed using the upright-type 11-gauge stereotactic vacuum-assisted biopsy device. Patients in whom this biopsy was diagnosed as carcinoma or a borderline lesion, had a subsequent surgical excision of the lesion. Histopathological and radiological features of the two specimens were then compared with each other. Results： Microcalcification was identified on specimen mammograms and microscopic slides in 97.4% of cases. Of 154 Mammotome biopsies 98 （63.6%） were benign, 51 （33.1%） were malignant, 3 （1.9%） showed atypical hyperplasia, and 2 （1.3%） were indeterminate, respectively. Of the 48 cases that received surgical excision, 6 of 36 ductal carcinomas in situ （16.7%） upstaged to invasive ductal carcinoma and 1 of 2 atypical ductal hyperplasias was upstaged to ductal carcinoma in situ. The positive predictive value of the 11-gauge Mammotome for the diagnosis of invasion in breast cancer was 100%. Linear calcification and pleomorphic calcification linear/segmental distribution was reliable indications of malignancy. The mean follow-up time of the benign lesions was 22 months, and without evidence of lesion growth. Complications included vasovagal reactions （6.3%）, bleeding （0.6%） and hematoma （2.6%）. Conclusion： The upright stereotactic 11-gauge Mammotome procedure is an effective and reliable method for the diagnosis of breast microcalcifications. It has minimal side effects. For lesions diagnosed as ADH or DCIS with the 11-gauge Mammotome, subsequent surgical excision should be performed.     

Cervical myelopathy due to OPLL: clinical evaluation by MRI and intraoperative spinal sonography

BACKGROUND: Concerning the relationship between morphology and clinical outcome, there have been many reports using computed tomography/myelography but not so many using axial magnetic resonance imaging (MRI) of the spinal cord. This is the first report to correlate axial cord image, intensity changes in MRI, and cord expansion pattern using intraoperative ultrasonography. OBJECTIVE: The objectives were to correlate MRI studies, axial cord images/expansion, and changes in MRI intensity to see if there is a direct prognostic significance to these changes and to determine whether preoperative axial MRI images of the spinal cord predict recovery from compressive myelopathy. METHODS: Posterior cervical decompressions with laminoplasty were performed in 44 patients with cervical myelopathy due to ossification of the posterior longitudinal ligament. On T2-weighted MR images, the cross-sectional shape of the cord at the level of maximal compression was categorized as boomerang, teardrop, or triangle. Additionally, with use of intraoperative ultrasonography, the expansion pattern of the cord that occurred intraoperatively was contrasted with that seen on postoperative MR images. RESULTS: Clinical recovery rates were the worst for those with triangular, intermediate for those with boomerang, and the best for those with teardrop shape. Preoperative low T1 and high T2 signals were found in most cases with triangular cord configurations. Triangular cord configurations showed the least expansion among the three categorized spinal cords. CONCLUSION: Patients with triangular deformity of the cord have atrophy as confirmed on MR studies where there is a low T1 and high T2 signal in the cord. Poor postoperative clinical recovery correlates with the lack of postoperative cord expansion on either MR or ultrasound evaluations. Those with either teardrop or boomerang deformities demonstrate a relatively good recovery rate.