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1.  Clinicopathologic Impacts of Poorly Differentiated Cluster-Based Grading System in Colorectal Carcinoma 
Differentiation-based histologic grading of colorectal carcinoma (CRC) is widely used, but its clinical impact is limited by insufficient prognostic value, interobserver disagreement, and the difficulty of its application to CRC with specific histologic types such as mucinous and medullary carcinoma. A recently proposed novel grading system based on quantifying poorly differentiated clusters (PDCs) claims to have the advantages of reproducibility and improved prognostic value, and might apply to heterogeneous CRC. We aimed to validate the clinicopathologic significance of the PDCs-based grading system and to determine the relationship between this grading system and microsatellite instability (MSI). Two hundred and one patients who had undergone radical surgery were reviewed. Based on the number of PDCs, 85, 58, and 58 tumors were classified as grade (G) 1 (42.3%), G2 (28.9%), and G3 (28.9%), respectively. PDCs-based grade was significantly associated with T, N, and M stages; lymphovascular invasion; conventional histologic grade; and frequent tumor budding (all P <0.001). In multivariate analysis, PDCs-based grade was found to be an independent prognostic factor for disease-free survival (P = 0.022; hazard ratio, 3.709 [G2], 7.461 [G3]). G3 CRC significantly correlated with high MSI (MSI-H) compared to G1 and G2 (P = 0.002; odds ratio, 5.750). In conclusion, this novel grading would provide valuable prognostic information to a greater number of patients and would require continued verification. PDCs-based grading is feasible for CRCs with heterogeneous morphology, and we propose that the association between G3 and MSI-H be further evaluated in different histological subtypes of CRC.
Graphical Abstract
doi:10.3346/jkms.2015.30.1.16
PMCID: PMC4278023  PMID: 25552879
Colorectal Neoplasms; Carcinoma; Prognosis; Neoplasm Grading; Microsatellite Instability
2.  Chronic Intermittent Hypoxia Induces Atherosclerosis via Activation of Adipose Angiopoietin-like 4 
Rationale: Obstructive sleep apnea is a risk factor for dyslipidemia and atherosclerosis, which have been attributed to chronic intermittent hypoxia (CIH). Intermittent hypoxia inhibits a key enzyme of lipoprotein clearance, lipoprotein lipase, and up-regulates a lipoprotein lipase inhibitor, angiopoietin-like 4 (Angptl4), in adipose tissue. The effects and mechanisms of Angptl4 up-regulation in sleep apnea are unknown.
Objectives: To examine whether CIH induces dyslipidemia and atherosclerosis by increasing adipose Angptl4 via hypoxia-inducible factor-1 (HIF-1).
Methods: ApoE−/− mice were exposed to intermittent hypoxia or air for 4 weeks while being treated with Angptl4-neutralizing antibody or vehicle.
Measurements and Main Results: In vehicle-treated mice, hypoxia increased adipose Angptl4 levels, inhibited adipose lipoprotein lipase, increased fasting levels of plasma triglycerides and very low density lipoprotein cholesterol, and increased the size of atherosclerotic plaques. The effects of CIH were abolished by the antibody. Hypoxia-induced increases in plasma fasting triglycerides and adipose Angptl4 were not observed in mice with germline heterozygosity for a HIF-1α knockout allele. Transgenic overexpression of HIF-1α in adipose tissue led to dyslipidemia and increased levels of adipose Angptl4. In cultured adipocytes, constitutive expression of HIF-1α increased Angptl4 levels, which was abolished by siRNA. Finally, in obese patients undergoing bariatric surgery, the severity of nocturnal hypoxemia predicted Angptl4 levels in subcutaneous adipose tissue.
Conclusions: HIF-1–mediated increase in adipose Angptl4 and the ensuing lipoprotein lipase inactivation may contribute to atherosclerosis in patients with sleep apnea.
doi:10.1164/rccm.201209-1688OC
PMCID: PMC3778753  PMID: 23328524
sleep apnea; lipoprotein clearance; lipoprotein lipase; adipose tissue; hypoxia-inducible factor-1
3.  A Case of Synchronous Presentation of Primary Non-Small Cell Lung Carcinoma and Pheochromocytoma 
We report a rare synchronous presentation of primary lung cancer and adrenal pheochromocytoma. A 59-year-old woman was diagnosed with right upper lobe non-small cell lung carcinoma measuring 2.8 cm and a right adrenal gland mass measuring 3.5 cm, which displayed increased metabolic activity on 18F-fluorodeoxyglucose positron emission tomography-computed tomography. The adrenal lesion was revealed to be asymptomatic. The patient underwent right adrenalectomy and histological examination revealed a pheochromocytoma. Ten days later, right upper lobectomy was performed for lung cancer. This case indicates that incidental adrenal lesions found in cases of resectable primary lung cancer should be investigated.
doi:10.4046/trd.2013.74.4.181
PMCID: PMC3651929  PMID: 23678360
Carcinoma; Lung; Pheochromocytoma
4.  Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea 
European Heart Journal  2011;33(6):783-790.
Aims
Delayed lipoprotein clearance is associated with atherosclerosis. This study examined whether chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnoea (OSA), can lead to hyperlipidaemia by inhibiting clearance of triglyceride rich lipoproteins (TRLP).
Methods and results
Male C57BL/6J mice on high-cholesterol diet were exposed to 4 weeks of CIH or chronic intermittent air (control). FIO2 was decreased to 6.5% once per minute during the 12 h light phase in the CIH group. After the exposure, we measured fasting lipid profile. TRLP clearance was assessed by oral gavage of retinyl palmitate followed by serum retinyl esters (REs) measurements at 0, 1, 2, 4, 10, and 24 h. Activity of lipoprotein lipase (LpL), a key enzyme of lipoprotein clearance, and levels of angiopoietin-like protein 4 (Angptl4), a potent inhibitor of the LpL activity, were determined in the epididymal fat pads, skeletal muscles, and heart. Chronic intermittent hypoxia induced significant increases in levels of total cholesterol and triglycerides, which occurred in TRLP and LDL fractions (P< 0.05 for each comparison). Compared with control mice, animals exposed to CIH showed increases in REs throughout first 10 h after oral gavage of retinyl palmitate (P< 0.05), indicating that CIH inhibited TRLP clearance. CIH induced a >5-fold decrease in LpL activity (P< 0.01) and an 80% increase in Angptl4 mRNA and protein levels in the epididymal fat, but not in the skeletal muscle or heart.
Conclusions
CIH decreases TRLP clearance and inhibits LpL activity in adipose tissue, which may contribute to atherogenesis observed in OSA.
doi:10.1093/eurheartj/ehr097
PMCID: PMC3303712  PMID: 21478490
Intermittent hypoxia; Sleep apnoea; Dyslipidemia; Lipoprotein clearance; Atherosclerosis
5.  Metabolic Consequences of High-Fat Diet Are Attenuated by Suppression of HIF-1α 
PLoS ONE  2012;7(10):e46562.
Obesity is associated with tissue hypoxia and the up-regulation of hypoxia inducible factor 1 alpha (HIF-1α). Prior studies in transgenic mice have shown that HIF-1α plays a role in the metabolic dysfunction associated with obesity. Therefore, we hypothesized that, after the development of diet-induced obesity (DIO), metabolic function could be improved by administration of HIF-1α antisense oligonucleotides (ASO). DIO mice were treated with HIF-1α ASO or with control ASO for 8 weeks and compared with an untreated group. We found that HIF-1α ASO markedly suppressed Hif-1α gene expression in adipose tissue and the liver. HIF-1α ASO administration induced weight loss. Final body weight was 41.6±1.4 g in the HIF-1α ASO group vs 46.7±0.9 g in the control ASO group and 47.9±0.8 g in untreated mice (p<0.001). HIF-1α ASO increased energy expenditure (13.3±0.6 vs 12±0.1 and 11.9±0.4 kcal/kg/hr, respectively, p<0.001) and decreased the respiratory exchange ratio (0.71±0.01 vs 0.75±0.01 and 0.76±0.01, respectively, p<0.001), which suggested switching metabolism to fat oxidation. In contrast, HIF-1a ASO had no effect on food intake or activity. HIF-1α ASO treatment decreased fasting blood glucose (195.5±8.4 mg/dl vs 239±7.8 mg/dl in the control ASO group and 222±8.2 mg/dl in untreated mice, p<0.01), plasma insulin, hepatic glucose output, and liver fat content. These findings demonstrate that the metabolic consequences of DIO are attenuated by HIF-1α ASO treatment.
doi:10.1371/journal.pone.0046562
PMCID: PMC3462192  PMID: 23049707
6.  Hyaline Vascular Castleman Disease Involving Renal Parenchyma and a Lymph Node: A Case Report 
Korean Journal of Pathology  2012;46(1):79-82.
Castleman disease is a rare lymphoproliferative lesion that is predominantly found in the mediastinum. Retroperitoneal and pararenal localizations are very rare. We describe a 36-year-old man with a hyaline vascular type of Castleman disease involving renal parenchyma and a paraaortic lymph node. Most reported renal Castleman disease was plasma cell type with systemic symptoms. Herein, we report the first Korean case of the hyaline vascular type of Castleman disease involving the renal parenchyma and the paraaortic lymph node simultaneously.
doi:10.4132/KoreanJPathol.2012.46.1.79
PMCID: PMC3479711  PMID: 23109983
Kidney; Hyaline vascular type, Multicentric; Giant lymph node hyperplasia
7.  Time Dependent Bladder Apoptosis Induced by Acute Bladder Outlet Obstruction and Subsequent Emptying is Associated with Decreased MnSOD Expression and Bcl-2/Bax Ratio 
Journal of Korean Medical Science  2010;25(11):1652-1656.
Ischemia/reperfusion (I/R) injury-induced oxidative stress plays an important role in the functional impairment of the bladder following acute bladder outlet obstruction (BOO) via induction of apoptosis. The purpose of this study was to investigate the time course of the bladder apoptosis, and apoptosis related molecular changes in the early stage of acute BOO. Twelve-week-old male Sprague Dawley rats were divided into control, acute BOO only (I), and acute BOO plus subsequent emptying (I/R) for 30, 60, 120 min, 3 days and 2 weeks. We examined the extent of bladder apoptosis, expression of Mn-superoxide dismutase (Mn-SOD), Bcl-2, Bax, caspase 3 and poly (ADP-ribose) (PAR) in the bladder. Bladder apoptosis was significantly increased in the I/R group at 30, 60, and 120 min following bladder emptying. BOO plus subsequent emptying for 30, 60, 120 min showed significant decrease in MnSOD and Bcl-2 expression, and significant increase in caspase 3, Bax expression, and amounts of PAR. These results indicate that bladder apoptosis, induced by acute BOO and subsequent emptying, is associated with decreased MnSOD expression, increased PARP activity and imbalance in apoptosis pathways.
doi:10.3346/jkms.2010.25.11.1652
PMCID: PMC2967004  PMID: 21060756
Urinary Bladder Neck Obstruction; Apoptosis; Oxidative Stress; Poly (ADP-ribose) Polymerases
8.  F-18 FDG PET-positive Fibrous Dysplasia in a Patient with Intestinal Non-Hodgkin's Lymphoma 
Fibrous dysplasia (FD) is a common benign bone disorder of an unclear etiology. It is known that FD can appear without an increased FDG uptake on F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). However, there are also several reports that FD showed increased FDG uptake and this mimicked malignant bone involvement on FDG-PET. Herein we describe a case of biopsy-proven FDG-PET positive FD in a patient with intestinal non-Hodgkin's lymphoma (NHL). A 45-year-old woman was diagnosed with intestinal NHL, which was removed by right hemicolectomy. After the operation, the FDG-PET/CT scan showed hypermetabolic activity in the right transverse process of the T10 vertebra. The patient then received a total of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy every 3 weeks. After completion of the planned chemotherapy, the 2nd FDG-PET/CT showed increased FDG uptake (SUVmax=6.0 g/mL) of the previous bone lesion. The MR images revealed a T1-hypointense lesion with sharp borders in the same region, and this showed homogenous contrast enhancement on the fat-suppressed T1-weighted images. After the radiologic studies were carefully reviewed, the bone lesion was assumed to be benign such as FD. We performed bone biopsy and the histological examination confirmed the diagnosis of FD. In conclusion, bone lesions with FDG uptake need to be carefully interpreted when evaluating patients with known malignancy.
doi:10.4143/crt.2009.41.3.171
PMCID: PMC2757660  PMID: 19809567
Fibrous dysplasia; Non-Hodgkin lymphoma; FDG-PET

Results 1-8 (8)