Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. OBJECTIVES: To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. METHODS: This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n = 358). All relevant information documented prior to 31 March 2020 was included. RESULTS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P < 0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P = 0·001] and overall survival (HR 0·58, P = 0·007) compared with those who did not. CONCLUSIONS: CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.

PHRF1 promotes genome integrity by modulating non-homologous end-joining.

Methylated histone readers are critical for chromatin dynamics, transcription, and DNA repair. Human PHRF1 contains a plant homeodomain (PHD) that recognizes methylated histones and a RING domain, which ubiquitinates substrates. A recent study reveals that PHRF1 is a tumor suppressor that promotes TGF-ß cytostatic signaling through TGIF ubiquitination. Also, PHRF1 is a putative phosphorylation substrate of ataxia telangiectasia-mutated/ataxia telangiectasia and Rad3-related kinases; however, the role of PHRF1 in DNA damage response is unclear. Here we report a novel function of PHRF1 in modulating non-homologous end-joining (NHEJ). PHRF1 quickly localizes to DNA damage lesions upon genotoxic insults. Ablation of PHRF1 decreases the efficiency of plasmid-based end-joining, whereas PHRF1 overexpression leads to an elevated NHEJ in H1299 reporter cells. Immunoprecipitation and peptide pull-down assays verify that PHRF1 constitutively binds to di- and trimethylated histone H3 lysine 36 (H3K36) (H3K36me2 and H3K36me3) via its PHD domain. Substitution of S915DT917E to ADAE in PHRF1 decreases its affinity for NBS1. Both PHD domain and SDTE motif are required for its NHEJ-promoting activity. Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation. These results suggest that PHRF1 may combine with H3K36 methylation and NBS1 to promote NHEJ and stabilize genomic integrity upon DNA damage insults.

A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis.

BACKGROUND: The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-κB (NF-κB) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer. METHODS: Nuclear expressions of HIF-1α and NF-κB/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IκBα (IκBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IκBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription-polymerase chain reaction. In addition, NF-κB effects on the HIF-1α degradation and synthesis were examined. RESULTS: Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P<0.001). The IκBαM overexpression suppressed tumour growth, microvessel density, and HIF-1α activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1α expression was reduced by NF-κB inhibition under hypoxic conditions at the translational level. CONCLUSION: The hypoxia-dependent activation of the NF-κB/HIF-1α/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis.

Eruptive pseudo-angiomatosis lesions are associated with intravascular neutrophils and do not harbour Epstein-Barr virus.

BACKGROUND: Eruptive pseudo-angiomatosis (EPA) is a rare, relatively newly described cutaneous disorder characterized by the sudden onset of several bright red, angioma-like papules surrounded by blanched halo. Its aetiology is unknown; however, viral infection or mosquito bites have been speculated as possible causes. OBJECTIVE: This study aims to determine the clinical and histopathological features of EPA, and whether it is associated with Epstein-Barr virus (EBV) infection. METHODS: We conducted a retrospective chart review of 25 EPA cases from 2006 to 2008. In order to determine latent EBV infection, EBV-encoded small RNA (EBER) in situ hybridization was performed in 18 subjects. To determine EPA's distinguishing histological characteristics, we compared the cases with 22 control cases of perivascular lymphocytic infiltration for haematoxylin and eosin, CD3, CD4, CD8, CD31 and c-kit staining patterns. RESULTS: The patient sample's female-to-male ratio was 2.1 : 1, and the patients' age ranged from 5 to 79 years (average 46 years). The lesions appeared during the months of July to September in all but 3 patients. Skin biopsies demonstrated capillary ectasia with perivascular mononuclear cellular infiltrates in the upper dermis. Most patients were otherwise healthy, and routine laboratory results were all normal except in one patient who had diabetes. The skin lesions faded without any treatment in 1-2 weeks. Results of EBER in situ hybridization were all negative. The only histological distinguishing feature of EPA was the presence of intravascular neutrophils, which was found to be present in 19 of the 20 EPA cases (95%), in contrast to only 3 of the 22 control subjects (14%) (P < 0.0001). CONCLUSION: The sudden onset of lesions during the summer months among our patients supports the 'paraviral eruption' concept of this probably underdiagnosed condition. The significant presence of intravascular neutrophils may be a diagnostic clue of EPA in South Korea.

Accuracy of corneal flap thickness achieved by two different age MK-2000 microkeratomes.

AIMS: To investigate the accuracy of corneal flap thickness (FT) using two different age MK-2000 microkeratomes. METHODS: The prospective cohort study enroled 260 patients with refractive error. Flaps were created using two microkeratomes A and B (new and aged, respectively) with 130-mum heads in two patient groups and two times the same blade in both treated eyes of each patient. The variations in FTs were compared between two groups and between both operated eyes of each patient. The correlations were analysed between FT and CCT or keratometric power. RESULTS: In the A and B groups, the average FTs were 123.3+/-18.7 and 147.5+/-19.1 mum respectively. Difference in measurements between the actual FTs of first eye operations in the A group and intended 130 mum of FTs was not significant (P=0.462), but those of second operated eyes in the A group and both treated eyes in the B group were significant (P<0.001). Second cut achieved a thinner flap and increased the variability in FT, and an aged microkeratome achieved a thicker flap than a new microkeratome and than that claimed by the manufacturer. Positive correlations were observed between preoperative CCT and FT (P<0.05). CONCLUSIONS: The first eye operation by a new MK-2000 microkeratome achieves the accuracy of the intended FT. FTs varied between first and second cuts of each patient and between two different age MK-2000 microkeratomes. LASIK surgeons should compare FT when using an aged MK-2000 microkeratome, and frequent and periodic comparison of FT achieved by all microkeratomes may be also recommended.

Interleukin-20 promotes angiogenesis in a direct and indirect manner.

IL-20 belongs to the IL-10 family and is involved in the pathogenesis of keratinocyte hyperproliferation in vivo. Endothelial cells express IL-20 receptors. To explore the function of IL-20 on endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) with human IL-20 and analyzed its effect on endothelial cells. IL-20 induced proliferation of endothelial cells and the activity was specifically blocked by anti-human-IL-20 monoclonal antibody and soluble (s)IL-20 receptor (R)1 and sIL-20R2. An alternatively spliced variant of IL-20 was isolated and also was shown to induce proliferation of HUVECs and HMECs. Treatment of HUVECs with both IL-10 and IL-20 demonstrated that IL-10 antagonized the activity of IL-20 because it diminished IL-20-induced proliferation of HUVECs. IL-20 significantly induced HUVECs migration and vascular tube formation on Matrigel in vitro. In vivo, IL-20 also enhanced tumor angiogenesis. Incubation of IL-20 with HUVECs induced transcripts of bFGF, VEGF, MMP-2, MMP-9, and IL-8. Furthermore, incubation of HUVECs with IL-20 induced phosphorylation of ERK1/2, p38, and JNK. Thus, IL-20 is a pleiotropic cytokine and promotes angiogenesis.

Effect of fresh gas flow on isoflurane concentrations during low-flow anaesthesia.

The effect of fresh gas flow (FGF) on isoflurane concentrations at given vaporizer settings during low-flow anaesthesia was investigated. Ninety patients (American Society of Anaesthesiologists physical status I or II) were randomly allocated to three groups (FGF 1 l/min, FGF 2 l/min and FGF 4 l/min). Anaesthesia was maintained for 10 min with vaporizer setting isoflurane 2 vol% and FGF 4 l/min for full-tissue anaesthetic uptake in a semi-closed circle system. Low-flow anaesthesia was maintained for 20 min with end-tidal isoflurane 1.5 vol% and FGF 2 l/min. FGF was then changed to FGF 1 l/min, FGF 2 l/min or FGF 4 l/min. Measurements during the 20-min period showed that inspired and end-tidal isoflurane concentrations decreased in the FGF 1-l/min group but increased in the FGF 4-l/min group compared with baseline values. No haemodynamic changes were observed. Monitoring of anaesthetic concentrations and appropriate control of vaporizer settings are necessary during low-flow anaesthesia.

Effect of administration of ketorolac and local anaesthetic infiltration for pain relief after laparoscopic-assisted vaginal hysterectomy.

The efficacy of local anaesthetic infiltration and/or non-steroidal anti-inflammatory drugs for post-operative analgesia following laparoscopic-assisted vaginal hysterectomy (LAVH) was investigated in 83 patients, randomized into four groups in this double-blind, placebo-controlled study: group BK, local infiltration with bupivacaine and pre-incisional intramuscular (IM) ketorolac; group NN, saline local infiltration IM; group BN, local infiltration with bupivacaine and saline IM; group NK, local infiltration with saline and ketorolac IM. Post-operative pain scores were assessed at 1 h, 3 h, 6 h, 12 h and 24 h using a visual analogue scale (VAS). The major pain site, first analgesic request time and incidence of analgesic requests were also recorded. At 1 h, 3 h and 6 h after surgery, group BK patients had significantly lower VAS pain scores than group NN patients. The first analgesic request time was significantly longer in group BK than in groups NN, BN and NK. Pre-incisional treatment with ketorolac IM and local infiltration with bupivacaine reduced post-operative pain after LAVH.

Magnetoencephalographic yield of interictal spikes in temporal lobe epilepsy. Comparison with scalp EEG recordings.

To compare magnetoencephalography (MEG) with scalp electroencephalography (EEG) in the detection of interictal spikes in temporal lobe epilepsy (TLE), we simultaneously recorded MEG and scalp EEG with a whole-scalp neuromagnetometer in 46 TLE patients. We visually searched interictal spikes on MEG and EEG channels and classified them into three types according to their presentation on MEG alone (M-spikes), EEG alone (E-spikes), or concomitantly on both modalities (M/E-spikes). The M-spikes and M/E-spikes were localized with MEG equivalent current dipole modeling. We analyzed the relative contribution of MEG and EEG in the overall yield of spike detection and also compared M-spikes with M/E-spikes in terms of dipole locations and strengths. During the 30- to 40-min MEG recordings, interictal spikes were obtained in 36 (78.3%) of the 46 patients. Among the 36 patients, most spikes were M/E-spikes (68.3%), some were M-spikes (22.1%), and some were E-spikes (9.7%). In comparison with EEG, MEG gave better spike yield in patients with lateral TLE. Sources of M/E- and M-spikes were situated in the same anatomical regions, whereas the average dipole strength was larger for M/E- than M-spikes. In conclusion, some interictal spikes appeared selectively on either MEG or EEG channels in TLE patients although more spikes were simultaneously identified on both modalities. Thus, simultaneous MEG and EEG recordings help to enhance spike detection. Identification of M-spikes would offer important localization of irritative foci, especially in patients with lateral TLE.

Byakangelicol, isolated from Angelica dahurica, inhibits both the activity and induction of cyclooxygenase-2 in human pulmonary epithelial cells.

We examined the inhibitory mechanism of byakangelicol, isolated from Angelica dahurica, on interleukin-1beta (IL-1beta)-induced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in human pulmonary epithelial cell line (A549). Byakangelicol (10-50 microM) concentration-dependently attenuated IL-1beta-induced COX-2 expression and PGE2 release. The selective COX-2 inhibitor, NS-398 (0.01-1 microM), and byakangelicol (10-50 microM) both concentration-dependently inhibited the activity of the COX-2 enzyme. Byakangelicol, at a concentration up to 200 microM, did not affect the activity and expression of COX-1 enzyme. IL-1beta-induced p44/42 mitogen-activated protein kinase (MAPK) activation was inhibited by the MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor, PD 98059 (30 microM), while byakangelicol (50 microM) had no effect. Treatment of cells with byakangelicol (50 microM) or pyrrolidine dithiocarbamate (PDTC; 50 microM) partially inhibited IL-1beta-induced degradation of IkappaB-alpha in the cytosol, translocation of p65 NF-kappaB from the cytosol to the nucleus and the NF-kappaB-specific DNA-protein complex formation. Taken together, we have demonstrated that byakangelicol inhibits IL-1beta-induced PGE2 release in A549 cells; this inhibition may be mediated by suppression of COX-2 expression and the activity of COX-2 enzyme. The inhibitory mechanism of byakangelicol on IL-1beta-induced COX-2 expression may be, at least in part, through suppression of NF-kappaB activity. Therefore, byakangelicol may have therapeutic potential as an anti-inflammatory drug on airway inflammation.

Frequent gain of copy number on the long arm of chromosome 3 in human cervical adenocarcinoma.

We analyzed genomic aberrations in 20 cervical adenocarcinomas by comparative genomic hybridization (CGH). Most tissue samples (85%) showed DNA copy number changes; gains were more common than losses. The most consistent region of chromosomal gain was mapped to chromosome arm 3q, found in 70% of the cases, with a minimal common region of 3q28-ter. Other recurrent amplifications of genetic material were detected on 17q (45%), 1p (30%), 1q (25%), and 11q (20%). High-level copy number increases were found in chromosomal regions 3q27-ter and 9pter-13. DNA losses were seldom observed, occurring primarily in underrepresented regions of chromosome arms 4q, 13q, and 18q. The presence of high-risk human papilloma virus genomes in the cervical adenocarcinoma samples was detected in 90% of the cases. However, there was no correlation between human papilloma virus type and the pattern of genomic changes. This study is the first report of CGH analysis in human cervical adenocarcinoma. Among the major genomic alterations, our results demonstrate the importance of DNA copy increases of chromosome arm 3q in the development of cervical adenocarcinoma and identify other amplified chromosomal regions that are also associated with cervical carcinogenesis.

Metabotropic glutamate receptor 5-induced phosphorylation of extracellular signal-regulated kinase in astrocytes depends on transactivation of the epidermal growth factor receptor.

G-protein-coupled receptors (GPCRs) induce the phosphorylation of mitogen-activated protein (MAP) kinase by actions on any of a number of signal transduction systems. Previous studies have revealed that activation of the G(q)-coupled metabotropic glutamate receptor 5 (mGluR5) induces phosphorylation of the MAP kinase extracellular signal-regulated kinase 2 (ERK2) in cultured rat cortical astrocytes. We performed a series of studies to determine the mechanisms underlying mGluR5-induced phosphorylation of MAP kinase in these cells. Interestingly, our studies suggest that mGluR5-mediated ERK2 phosphorylation is dependent on the activation of G(alphaq) but is not mediated by the activation of phospholipase Cbeta1, activation of protein kinase C, or increases in intracellular calcium. Studies with peptide inhibitors suggest that this response is not dependent on G(betagamma) subunits. However, the activation of ERK2 was dependent on activation of the epidermal growth factor (EGF) receptor and activation of a Src family tyrosine kinase. Furthermore, activation of mGluR5 induced an association of this receptor and the EGF receptor, suggesting the formation of a signaling complex involved in the activation of ERK2. These data suggest that mGluR5 increases ERK2 phosphorylation in astrocytes by a novel mechanism involving the activation of G(alphaq) and both receptor and nonreceptor tyrosine kinases but that is independent of the activation of phospholipase Cbeta1.

Differential coronary calcification on electron-beam CT between syndrome X and coronary artery disease in patients with chronic stable angina pectoris.

STUDY OBJECTIVES: The differential diagnosis of syndrome X and coronary artery disease (CAD) in patients with evidence of myocardial ischemia may be difficult. The possible difference in coronary calcium detected by electron-beam CT (EBCT) between syndrome X and CAD is rarely evaluated, especially in aged patients with chronic, stable angina. DESIGN AND SETTINGS: Prospective, controlled study at a tertiary referral medical center. PATIENTS AND MEASUREMENTS: Forty patients with syndrome X (85% male) and 53 patients with CAD (89% male) were enrolled. Ten control subjects (90% male) with negative exercise treadmill test results and normal coronary angiographic findings served as control subjects. EBCT determined the coronary calcium scores (CCSs), and standard cardiovascular risk factors of all study subjects were analyzed. RESULTS: The 93 study patients had CCSs that ranged from 0 to 1,857. Coronary calcification was seen in 2 of the 10 control subjects (20%), 21 of the 40 syndrome X patients (52.5%), and 51 of the 53 CAD patients (96.2%) [p < 0.01]. The CCS (median [range]) was significantly lower in syndrome X patients than in CAD patients: 1 (0 to 117) vs 202 (0 to 1,857) [p < 0.001]. Receiver operating characteristic curve analyses also demonstrated that coronary calcification differentiated syndrome X from CAD (area under curve, 0.891; 95% confidence interval, 0.806 to 0.947). Of the CAD patients whose CCSs were < 117 and overlapped with CCSs of syndrome X, multivariate analyses determined CCS > 5 (odds ratio, 13.1; 95% confidence interval, 2.86 to 59.7), hypertension (odds ratio, 6.4; 95% confidence interval, 1.5 to 27.4), and hypercholesterolemia (odds ratio, 6.7; 95% confidence interval, 1.5 to 30.5) to be independent discriminators to differentiate CAD from syndrome X. Patients with CAD had more frequent hypertension than patients with syndrome X. CONCLUSIONS: The coronary calcium detected noninvasively by EBCT was different, though with some overlapping, between patients with syndrome X and CAD. In addition to standard cardiovascular risk factors, CCS determined by EBCT (especially > 117 or = 0) could differentiate between syndrome X and CAD in patients with chronic, stable angina with evidence of myocardial ischemia. Larger trials would be useful to validate CCS on EBCT as a predictor of clinical outcome in these patients.

Coronary artery calcium determined by electron beam computed tomography for predicting angiographic coronary artery disease in moderate- to high-risk Chinese patients.

The aim of this study was to evaluate the prevalence of coronary calcification among moderate- to high-risk Chinese patients and to evaluate the ability of the coronary calcium score determined by electron beam computed tomography (EBCT) to predict angiographic coronary artery disease in this population. We enrolled 163 consecutive patients and analyzed their cardiovascular risk factors, coronary calcium scores and coronary angiogram results. One hundred and twenty-five patients (76.7%) had a positive EBCT scan result (coronary calcium score >0). The prevalence of calcification and the calcium scores showed a graded relation to the number of cardiovascular risk factors and age (p < 0.001 for trend). Coronary calcium scores showed statistically significant differences between patients with angiographic evidence of coronary artery disease and patients with normal coronary angiography (p < 0.05), but could not differentiate between patients with significant and insignificant coronary artery disease. Receiver operating characteristic curve analysis showed that a coronary calcium score >5 predicted angiographic coronary artery disease with 93% sensitivity and 86% specificity (area under the curve 0.95 +/- 0.019). Multivariate analysis showed a coronary calcium score >5 to be the strongest independent predictor of angiographic coronary artery disease (odds ratio 120.7, 95% confidence interval 21.7-671.4; p < 0.001). Coronary calcium score determined by EBCT appears to have a similar predictive value in Chinese patients as it does in other ethnic populations that have been reported to date.

RNA editing of the human serotonin 5-HT2C receptor alters receptor-mediated activation of G13 protein.

The recent completion of the human genome predicted the presence of only 30,000 genes, stressing the importance of mechanisms that increase molecular diversity at the post-transcriptional level. One such post-transcriptional event is RNA editing, which generates multiple protein isoforms from a single gene, often with profound functional consequences. The human serotonin 5-HT(2C) receptor undergoes RNA editing that creates multiple receptor isoforms. One consequence of RNA editing of cell surface receptors may be to alter the pattern of activation of heterotrimeric G-proteins and thereby shift preferred intracellular signaling pathways. We examined the ability of the nonedited 5-HT(2C) receptor isoform (INI) and two extensively edited isoforms, VSV and VGV, to interact with various G-protein alpha subunits. Two functional assays were utilized: the cell-based functional assay, Receptor Selection/Amplification Technology(TM), in which the pharmacological consequences of co-expression of 5HT(2C) receptor isoforms with G-protein alpha subunits in fibroblasts were studied, and 5HT(2C) receptor-mediated rearrangements of the actin cytoskeleton in stable cell lines. These studies revealed that the nonedited 5-HT(2C) receptor functionally couples to G(q) and G(13). In contrast, coupling to G(13) was not detected for the extensively edited 5-HT(2C) receptors. Thus, RNA editing represents a novel mechanism for regulating the pattern of activation of heterotrimeric G-proteins, molecular switches that control an enormous variety of biological processes.

Evidence for inhibition of low density lipoprotein oxidation and cholesterol accumulation by apolipoprotein H (beta2-glycoprotein I).

Low density lipoprotein (LDL) oxidation and lipid accumulation are thought to enhance the progression of atherosclerosis. Apolipoprotein H (apoH) has been implicated in the development of human atherosclerosis. However, the roles of apoH in the oxidative modification of LDL and cellular accumulation of lipid constituents remained uncharacterized. In this study, the level of plasma apoH was found to be significantly associated with the oxidative susceptibility of LDL in human subjects. Plasma levels of apoH were positively correlated with the lag time but negatively correlated with LDL oxidation rate in conjugated diene formation. By using a J774 A.1 macrophage culture system, we found that apoH could not only inhibit the formation of conjugated diene and thiobarbituric acid-reactive substances, but also reduce the electrophoretic mobility of oxidized LDL. Furthermore, apoH decreased cellular accumulation of cholesterol via a reduction in cholesterol influx and an increase in cholesterol efflux. This is the first demonstration that apoH appears to have "antioxidant"-like effects on LDL oxidation. The results also suggest that apoH can inhibit the translocation of cholesterol from extracellular pools to macrophages, suggesting that apoH may play an important role in the prevention of atherosclerosis.

Association of p53 and BCL-2 expression with Epstein-Barr virus infection in the cancers of head and neck.

BACKGROUND: Reports that have both evaluated the site-specific Epstein-Barr virus (EBV) infection and compared it with the expression of the EBV-related proto-oncogenes and tumor suppressor genes in the various cancers of head and neck are scarce. METHODS: Thirty-eight nasopharyngeal carcinoma (NPC) cases, 32 oropharyngeal or hypopharyngeal carcinoma (OPC/HPC) cases, and 93 laryngeal carcinoma (LC) cases were evaluated with in situ hybridization on EBV-encoded small RNA (EBER) and immunohistochemical assessments of the p53, bcl-2, and epidermal growth factor receptor (EGFR) by use of formalin-fixed paraffin-embedded tissue array slides. RESULTS: The expression of viral EBERs was observed in more than two thirds (71.1%) of the NPC cases. In contrast, only 1 case of OPC and none of the HPC or LC cases exhibited EBV positivity. In the nonkeratinizing NPC, the EBV positivity was significantly associated with both frequent p53 overexpression (p =.033) and bcl-2 expression (p =.001). In the EBV-positive nonkeratinizing NPC, a correlation between p53 overexpression and the tumor infiltration lymphocyte (TIL) density was noted (p =.012). CONCLUSIONS: A site-specific expression of viral EBER was demonstrated in the head and neck cancers, which suggests an important role for both p53 and bcl-2 in the carcinogenesis of an EBV-infected NPC. The correlation between p53 overexpression and the TIL density in the EBV-infected NPC suggests that the product of a lymphoepithelial interaction, such as A20, can induce a dysfunctional p53 protein.

Clinicopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea.

We evaluated the rate of Epstein-Barr virus (EBV) infection in gastric carcinomas of Korean patients and investigated the associations between EBV infection and clinicopathological characteristics, the survival rates of patients, and p53 overexpression. EBV-encoded small RNA (EBER)-in situ hybridization and immunohistochemistry for p53 protein were done in 306 consecutive gastric carcinoma cases, of which 17 (5.6%) showed EBV infection. Of these 17 EBV-positive cases, one case strongly expressed p53 protein, while 98 (34%) of 285 EBV-negative cases overexpressed p53 (p < 0.05). The EBV-positive gastric carcinomas tended to have lymphoid stroma. They were mostly of the poorly differentiated type, negative for p53 immunoexpression, more prevalent in male patients, and diffuse according to Lauren's classification (p < 0.05). There was no significant difference in the survival rate for the EBV status. In conclusion, the EBV infection rate among gastric carcinomas in Korea is similar to that ascertained in other countries. An inverse correlation between EBV and p53 overexpression was disclosed. Further study is needed to find out whether or not two genetic changes could be functionally overlapping during gastric carcinogenesis.