Lymphoproliferative disorder involving body fluid: diagnostic approaches and roles of ancillary studies

Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.

A prospective randomized clinical study evaluating the efficacy and compliance of oral sulfate solution and 2-L ascorbic acid plus polyethylene glycol

Oral sulfate solution (OSS) is an emerging cleansing agent for bowel preparation. However, data comparing OSS to other conventional bowel preparations in Asian patients are limited. Therefore, the objective of this study was to compare the efficacy and tolerability of OSS to ascorbic acid plus polyethylene glycol (AA + PEG) in Asian patients. Methods: This was a prospective, randomized, parallel, investigator-blind study performed in two university hospitals in Korea. Bowel preparation efficacy was evaluated using both the Ottawa Bowel Preparation Scale (OBPS) and Boston Bowel Preparation Scale (BBPS). Results: Among 173 patients, 86 received OSS while 87 received AA + PEG for bowel preparation. Total OBPS score was 2.80 ± 2.48 in the OSS group and 4.49 ± 3.08 in the AA + PEG group, indicating significantly (p < 0.001) better efficacy with OSS. Total BBPS was higher in the OSS group (7.43 ± 1.49 vs. 6.51 ± 1.76, p < 0.001), indicating superior bowel preparation quality with OSS. Preparation-related adverse events were generally acceptable. Patients receiving OSS had more nausea (1.92 ± 0.94 vs. 1.54 ± 0.76, p = 0.004) and abdominal cramping (1.45 ± 0.78 vs. 1.17 ± 0.51, p = 0.006) than those receiving AA + PEG. However, overall satisfaction and taste were similar between the two groups. Conclusions: OSS had a non-inferior bowel cleansing efficacy than AA + PEG regardless of colon segment.

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma

BACKGROUND: SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC. METHODS: We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs. RESULTS: A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancer-specific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022). CONCLUSIONS: We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps

BACKGROUND: Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation. METHODS: The CpG island methylator phenotype (CIMP) status of 132 non-dysplastic SSA/Ps was determined using eight CIMP-specific promoter markers. SSA/Ps with CIMP-high and/or MLH1 promoter methylation were regarded as a high-risk subgroup. RESULTS: Based on the CIMP analysis results, methylation frequency of each CIMP marker suggested a sequential pattern of CpG island methylation during progression of SSA/P, indicating MLH1 as a late-methylated marker. Among the 132 non-dysplastic SSA/Ps, 34 (26%) were determined to be high-risk lesions (33 CIMP-high and 8 MLH1-methylated cases; seven cases overlapped). All 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%, p = .001) and were significantly associated with older age (≥ 50 years, 100%; p = .003) and a larger histologically measured lesion size (> 5 mm, 100%; p = .004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts. CONCLUSIONS: Both CIMP-high and MLH1 methylation are late-step molecular events during progression of SSA/Ps and rarely occur in SSA/Ps of young patients. Comprehensive consideration of age (≥ 50), location (proximal colon), and histologic size (> 5 mm) may be important for the prediction of high-risk lesions among non-dysplastic SSA/Ps.

The Novel Neuroprotective Compound KMS99220 Has an Early Anti-neuroinflammatory Effect via AMPK and HO-1, Independent of Nrf2

We have previously reported a novel synthetic compound KMS99220 that prevented degeneration of the nigral dopaminergic neurons and the associated motor deficits, suggesting a neuroprotective therapeutic utility for Parkinson's disease. Microglia are closely associated with neuroinflammation, which plays a key role in the pathogenesis of neurodegenerative diseases. In this study, we investigated the effects of KMS99220 on the signaling involving AMP-activated protein kinase (AMPK) and heme oxygenase-1 (HO-1), the enzymes thought to regulate inflammation. KMS99220 was shown to elevate the enzyme activity of purified AMPK, and phosphorylation of cellular AMPK in BV2 microglia. It increased the level of HO-1, and this was attenuated by AMPK inhibitors. KMS99220 lowered phosphorylation of IκB, nuclear translocation of NFκB, induction of inducible nitric oxide synthase, and generation of nitric oxide in BV2 cells that had been challenged with lipopolysaccharide. This anti-inflammatory response involved HO-1, because both its pharmacological inhibition and knockdown of its expression abolished the response. The AMPK inhibitors also reversed the anti-inflammatory effects of KMS99220. The induction of HO-1 by KMS99220 occurred within 1 h, and this appeared not to involve the transcription factor Nrf2, because Nrf2 knockdown did not affect the compound's HO-1 inducing- and anti-inflammatory effects in this time window. These findings indicated that KMS99220 leads to AMPK-induced HO-1 expression in microglia, which in turn plays an important role in early anti-inflammatory signaling. Together with its neuroprotective property, KMS99220 may serve as a feasible therapeutic agent against neuroinflammation and neurodegeneration.

Clinical Outcomes of Endoscopic Hemostasis for Bleeding in Patients with Unresectable Advanced Gastric Cancer

PURPOSE: Bleeding is one of the most serious complications of advanced gastric cancer (AGC) and is associated with a poor prognosis. This study aimed to evaluate the clinical outcomes of endoscopic hemostasis for bleeding in patients with unresectable AGC. MATERIALS AND METHODS: This study included 106 patients with bleeding associated with gastric cancer who had undergone endoscopic hemostasis between January 2010 and December 2013. Clinical characteristics, treatment outcomes, including rates of successful endoscopic hemostasis and rebleeding, risk factors for rebleeding, and overall survival (OS) were investigated. RESULTS: Successful initial hemostasis was achieved in 83% of patients. Rebleeding occurred in 28.3% of patients within 30 days. The median OS after initial hemostasis was lower in patients with rebleeding than in those without rebleeding (2.7 and 3.9 months, respectively, P=0.02). There were no significant differences in disease status and rebleeding rates among patients with partial response or stable disease (n=4), progressive disease (n=64), and first diagnosis of disease (n=38). Univariate and multivariate analyses (P=0.038 and 0.034, respectively) revealed that transfusion of ≥5 units of RBCs was a significant risk factor for rebleeding. CONCLUSIONS: Despite favorable success rates of endoscopic hemostasis for bleeding associated with gastric cancer, the 30-day rebleeding rate was 28.3% and the median OS was significantly lower in patients with rebleeding than in those without rebleeding. Massive transfusion (≥5 units of RBCs) was the only significant risk factor for rebleeding. Patients with bleeding associated with AGC who have undergone massive transfusion should be observed closely following endoscopic hemostasis. Further research on approaches to reduce rebleeding rate and prevent death is needed.

Inverted Hyperplastic Polyp in Stomach: A Case Report and Literature Review / 대한소화기학회지

An inverted hyperplastic polyp (IHP) found in stomach is rare and characterized by downward growth of hyperplastic mucosal component into the submucosa. Because of such characteristic, IHP can be misdiagnosed as subepithelial tumor or malignant tumor. In fact, adenocarcinoma was reported to have coexisted with gastric IHP in several previous reports. Because only 18 cases on gastric IHP have been reported in English and Korean literature until now, pathogenesis and clinical features of gastric IHP and correlation with adenocarcinoma have not been clearly established. Herein, we report a case of gastric IHP which was initially misdiagnosed as gastrointestinal stromal tumor and resected using endoscopic submucosal dissection. Literature review of previously published case reports on gastric IHP is also presented.

Severe Endobronchial Inflammation Induced by Aspiration of a Ferrous Sulfate Tablet / 결핵및호흡기질환

Iron supplements such as ferrous sulfate tablets are usually used to treat iron-deficiency anemia in some elderly patients with primary neurologic disorders or decreased gag reflexes due to stroke, senile dementia, or parkinsonism. While the aspiration of ferrous sulfate is rarely reported, it is a potentially life-threatening condition that can lead to airway necrosis and bronchial stenosis. A detailed history and high suspicion of aspiration are required to avoid delays in diagnosis and treatment. The diagnosis can be confirmed by bronchoscopic examination and a tissue biopsy. Early removal of the aspirated tablet prevents acute complications, such as bronchial necrosis, hemoptysis, and lobar consolidation. Tablet removal is also necessary to prevent late bronchial stenosis. We presented the first case in Korea of a ferrous sulfate tablet aspiration that induced severe endobronchial inflammation.

Good Response of a Salivary Duct Carcinoma to Androgen Deprivation Therapy / 대한내과학회지

Salivary duct carcinoma (SDC) is a rare, aggressive tumor. Androgen deprivation therapy (ADT) has been shown to have beneficial effects on SDC-expressing androgen receptors (ARs). A 69-year-old male with a right neck mass presented to our clinic. Computed tomography (CT) of the neck revealed a mass (6 cm diameter) on the right parotid gland, and enlarged lymph nodes. Examination of a needle biopsy sample identified SDC-expressing ARs. We performed total parotidectomy with bilateral neck dissection and concurrent postoperative chemoradiotherapy (total 66 Gy) with cisplatin (35 mg/m2), followed by another two cycles of chemotherapy (cisplatin 60 mg/m2, 5 FU 750 mg/m2). Post-treatment neck CT indicated that no residual tumor tissue remained; however, chest CT indicated recurrence in the right axilla. We initiated ADT with bicalutamide and leuprolide. Five months later, the axillar tumor tissue had almost disappeared. Our case demonstrates that ADT is effective for SDC of ARs. Therefore, clinicians should consider ADT in recurrent or metastatic SDC of ARs.

Acute Necrotizing Pancreatitis during L-asparaginase Treatment in a Patient with Acute Lymphoblastic Leukemia / 대한췌담도학회지

L-asparaginase is an important component of antileukemic therapy in patients with acute lymphoblastic leukemia. The degree of L-asparaginase toxicity is variable. Several cases of L-asparaginase related pancreatitis have been reported in the literature. However, necrotizing pancreatitis in adult has not been reported yet. Herein, we present a case of necrotizing pancreatitis caused by L-asparaginase that was complicated by pancreatic duct leakage and pseudocyst formation, but successfully treated with percutaneous drainage and octreotide treatment.

A Case of Acinar Cell Carcinoma of Pancreas, Manifested by Subcutaneous Nodule as Initial Clinical Symptom / 대한소화기학회지

Pancreas acinar cell carcinoma (ACC) accounts for only 1-2% of pancreatic exocrine malignant tumor. The symptoms of patients with ACC are usually non-specific, for example the anorexia and weight loss. Patients may develop Schmid's triad including subcutaneous fat necrosis, polyarthritis, and eosinophilia. We reported a case of ACC which was manifested by subcutaneous nodule as initial clinical symptom. To our knowledge, this is the first reported case of ACC presenting as subcutaneous fat necrosis in Korea.

A Case of Undifferentiated (Embryonal) Liver Sarcoma Mimicking Klatskin Tumor in an Adult / 대한소화기학회지

Undifferentiated sarcoma is an uncommon primary malignant tumor of the liver typically occurring in older children. It is also referred to as malignant mesenchymoma, fibromyxosarcoma, or mesenchymal sarcoma. We experienced a case of undifferentiated sarcoma in 72-year-old male. Contrast enhanced liver CT scan revealed a 3.4 cm heterogeneously enhancing, ill-defined, and low attenuated mass in the left liver and subtle intrahepatic duct dilatation. And, in tubogram, there were segmental stenosis and occlusion from the hilum to the proximal common bile duct. We did ultrasonography guided liver biopsy. The pathologic finding revealed infiltrative growth of atypical cells with rhabdoid features. Some atypical cells showed clear cytoplasm, but no organoid pattern was identified. The stroma around atypical cells was filled with eosinophilic hyaline material. These tumor cells were positive for vimentin only, and the tumor was consistent with undifferentiated sarcoma of the liver.

A Case of Dieulafoy's Lesion with Pseudoaneurysm in the Sigmoid Colon / 대한소화기내시경학회지

Dieulafoy's lesions are characterized by a single large tortuous arteriole in the submucosa, and this arteriole does not undergo normal branching. These lesions are an uncommon cause of massive, sometimes fatal gastrointestinal bleeding; this had been reported to be the cause of 0.3~1.5% of the cases of major gastrointestinal bleeding. The lesions mainly occur in the proximal stomach, but they may occur in all parts of the gastrointestinal tract, including the small bowel, colon and rectum. Endoscopy is a common method for the diagnosis and treatment of Dieulafoy's lesions. However, in the case of a high risk lesion, angiography, laparoscopy or laparotomy can be performed instead. We experienced a rare case of bleeding from a Dieulafoy's lesion with pseudoaneurysm in the sigmoid colon. Angiography with embolization was performed, but the patient expired due to rebleeding. We report on this case along with a review of the relevant literature.

The relationship between the ApoB/ApoA-I ratio and non-alcoholic fatty liver disease in prediabetic patients / 대한내과학회지

BACKGROUND/AIMS: The apolipoprotein B/A-I ratio (ApoB/A-I) is a powerful clinical indicator of atherosclerosis. Although numerous reports have shown the effect of non-alcoholic fatty liver disease (NAFLD) on cardiovascular disease, few reports have examined the relationship between NAFLD and the ApoB/A-I ratio. The aim of the study was to determine the association between NAFLD and the ApoB/A-I ratio in prediabetic patients. METHODS: This cross-sectional study was performed with data obtained from 701 patients (mean age, 47.9+/-9.6 years) diagnosed with prediabetes. Serum lipid profiles including lipoprotein, apolipoprotein, and calculated ApoB/A-I ratio as well as metabolic syndrome parameters such as fasting glucose and insulin were measured in each subject. RESULTS: Among the 701 patients, 340 (48%) had NAFLD. The number of male patients was 490 (NAFLD+, 276; and NAFLD-, 214). The odds ratios for the prevalence of NAFLD increased according to the quartiles of the ApoB/A-I ratio (1.886, 2.245, and 2.587) (p<0.001). CONCLUSIONS: The prevalence of NAFLD correlated with high ApoB/A-I ratio, suggesting that NAFLD increases the risk for atherosclerosis progression in male prediabetic patients.

A Case of Successful Management of Paraquat Poisoning with Severe Pulmonary Fibrosis

Paraquat, a potent herbicide, has caused many fatalities through indiscriminate use and suicides. With ingestion of more than one mouthful of 20% paraquat, death is usually caused by pulmonary fibrosis. We experienced a case of paraquat poisoning with severe pulmonary injury. The patient had swallowed about two mouthfuls of 24% commercial paraquat. Hemoperfusion was done within a few hours after ingestion, and then combination therapy with several antioxidants, steroids, and diuretics was given. Initially, ground glass opacities, consolidation, and irregular lines appeared in the patient's high resolution computed tomography (HRCT). Several months later, lung lesions had improved. The improvement has continued until recently.

Extracellular HIV-1 Tat up-regulates expression of matrix metalloproteinase-9 via a MAPK-NF-kappaB dependent pathway in human astrocytes

The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-alpha, but not IL-1beta and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-kappaB-dependent mechanisms as well as Tat-induced TNF-alpha production in astrocytes.

A Case of Gastric Adenocarcinoma Mimicking a Gastrointestinal Stromal Tumor / 대한소화기내시경학회지

Gastric adenocarcinoma is the second most common cause of cancer death worldwide, but there are some geographical differences in its incidence. Gastointestinal stromal tumor (GIST) is an uncommon disease with a wide spectrum of aggressive behavior. These two tumors have a distinct pathogenesis. GIST is frequently identified as an incidental lesion found by routine endoscopy or in resection specimens that are removed for other reasons. We report a case of a gastric adenocarcinoma mimicking GIST in a 79-year-old woman. GIST was suggested by endoscopic ultrasonography and computed tomography scanning, but gastric adenocarcinoma was confirmed by gastroduodenoscopic biopsy. We performed a subtotal gastrectomy with Billroth I, lymph node dissection and transverse colon segmentectomy, and a 15.0x7.5x5.5 cm-sized gastric tumor was confirmed pathologically. Immunohistochemistry was positive for carcinoembryonic antigen and focal weakly positive for cytokeratin7 and cytokeratin20.

Differential regulation of inducible nitric oxide synthase and cyclooxygenase-2 expression by superoxide dismutase in lipopolysaccharide stimulated RAW 264.7 cells

Inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) have been known to be involved in various pathophysiological processes such as inflammation. This study was performed to determine the regulatory function of superoxide dismutase (SOD) on the LPS-induced expression of iNOS, and COX-2 in RAW 264.7 cells. When a cell-permeable SOD, Tat-SOD, was added to the culture medium of RAW 264.7 cells, it rapidly entered the cells in a dose-dependent manner. Treatment of RAW 264.7 cells with Tat-SOD led to decrease in LPS-induced ROS generation. Pretreatment with Tat-SOD significantly inhibited LPS-induced expression of iNOS and NO production but had no effect on the expression of COX-2 and PGE2 production in RAW 264.7 cells. Tat-SOD inhibited LPS-induced NF-kappaB DNA binding activity, IkappaBalpha degradation and activation of MAP kinases. These data suggest that SOD differentially regulate expression of iNOS and COX-2 in LPS-stimulated RAW 264.7 cells.

Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-kappaB activation in astrocytes

One of characteristic features of AIDS-related encephalitis and dementia is the infiltration of monocytes into the CNS. HIV-1 Tat was demonstrated to facilitate monocyte entry into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of adhesion molecules, generation of reactive oxygen species (ROS) and NF-kappaB activation in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein and mRNA levels of ICAM-1 and VCAM-1, as measured by Western blot analysis and RT-PCR, indicating that Tat increases these protein levels at an mRNA level. In addition, Tat induced the activation of NF-kappaB in astrocytes. Treatment of CRT-MG with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of ICAM-1 and VCAM-1. Furthermore, HIV-1 Tat protein increased ROS generation. Inhibition of Tat-induced ROS generation by N-acetyl cysteine, vitamin C and diphenyl iodonium suppressed Tat-induced NF-kappaB activation, ICAM-1 and VCAM-1 expression, and monocyte adhesion in CRT-MG. These data indicate that HIV-1 Tat can modulate monocyte adhesiveness by increasing expression of adhesion molecules such as ICAM-1 and VCAM-1 via ROS- and NF-kappaB-dependent mechanisms in astrocytes.

Trend of Socioeconomic Inequality in Participation in Cervical Cancer Screening among Korean Women / 예방의학회지

OBJECTIVES: While cervical cancer is one of the leading cancers among women worldwide, there are a number of effective early detection tests available. However, the participation rates in cervical cancer screening among Korean women remain low. After the nationwide efforts in 1988 and thereafter to encourage participation in cervical cancer screening, few studies have investigated the effects of socioeconomic inequality on participation in cervical cancer screening. The purpose of this study was to investigate 1) the level of socioeconomic disparities in receiving cervical cancer screening by age group and 2) if there was an improvement in reducing these disparities between 1995 and 2001. METHODS: Using data from the Korean National Health Status, Health Behavior and Belief Survey in 1995, and the Korean National Health and Nutrition Examination Surveys from 1998 and 2001 (sample sizes of 2,297, 3,738, and 3,283), age-standardized participation rates were calculated according to education level, equivalized household income, and job status. Odds ratios and the relative inequality index (RII) were also calculated after controlling for age. RESULTS: Women with lower education levels were less likely to attend the screening test, and the disparities by education level were most pronounced among women aged 60 years and older. The RIIs among women 60 years and older were 3.64, 4.46, and 8.64 in 1995, 1998, and 2001, respectively. Higher rates of participation were reported among those in the highest income category, which was more notable among the middle aged women (40s and 50s). An inconsistent trend in the rate of participation in cervical cancer screening by occupational level was found. CONCLUSIONS: Indicators of socioeconomic position seem to have varying impacts on the inequalities in the rates of participation in cervical cancer screening according to age group. These results demonstrate the need for more aggressive and age-based interventions and policy programs to eliminate the remaining inequalities.