Efficacy of tocilizumab therapy in Korean patients with adult-onset Still's disease: a multicentre retrospective study of 22 cases.

OBJECTIVES: To evaluate the efficacy of tocilizumab (TCZ), a monoclonal antibody against the interleukin (IL)-6 receptor, for refractory adult-onset Still's disease (AOSD) in the Korean population. METHODS: This retrospective study included 22 Korean patients with refractory AOSD who were given TCZ at one of seven university hospital-based clinics for rheumatic disease. Patients were subdivided into groups according to disease course: monocyclic, systemic polycyclic, and chronic articular. Modified Pouchot scores, including laboratory and clinical findings, were analysed at 6 months and 12 months. RESULTS: TCZ was given at 4-8 mg/kg every 4-5 weeks (8 mg/kg every 4-5 weeks in 18 patients, 6 mg/kg every 4 weeks in 2, and 4 mg/kg every 4 weeks in 2) for 7.5 months (median, IQR: 4.0-12.3). A good response (measured as a decrease of >2 in the modified Pouchot score) was achieved in 50.0% of patients (11 of 22) at 6 months and in 64.3% (9 of 14) at 12 months. The dose of corticosteroid dose was reduced from 11.5 mg/day (median, IQR: 10.0-21.3) immediately before TCZ therapy to 7.5 mg/day (median, IQR: 5.0-10.0, p=0.002) at 6 months and finally to 6.3 mg/day (median, IQR: 5.0-7.5, p=0.002) at 12 months. Only one patient discontinued TCZ treatment due to facial swelling accompanied by high blood pressure. In all others, adverse events subsided with delayed TCZ therapy, and TCZ therapy was continued successfully without problems. CONCLUSIONS: TCZ was effective for treating Korean AOSD patients who were refractory to conventional therapy or other anti-cytokine biologics, showing a corticosteroid-sparing effect and an acceptable tolerance profile.

Complete Tumor Resection for a Hepatocellular Carcinoma Secreting Parathyroid Hormone-related Peptide.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in Korea. Diverse paraneoplastic syndromes can occur in patients with HCC, but parathyroid hormone-related peptide (PTH-rP)-induced hypercalcemia is uncommon. Hypercalcemia due to PTH or particularly PTH-rP-secreting HCC is associated with poor outcomes. We report a 71-year-old man who presented with symptoms of vague abdominal discomfort, somnolence, lethargy, nausea, vomiting, and weight loss. Imaging studies revealed a large HCC without metastasis. The laboratory findings showed elevated serum calcium level, low intact parathyroid hormone (iPTH) level and elevated PTH-rP level. These results led to a diagnosis of a PTH-rP-secreting HCC and paraneoplastic hypercalcemia. After emergency management of the hypercalcemia, the patient underwent an extended right hemihepatectomy with cholecystectomy. One year after the surgery, he is alive with normal calcium, PTH-rP, and iPTH levels. This case demonstrates that the rare phenomenon of life-threatening hypercalcemia caused by HCC should not be overlooked. These symptoms offer a good opportunity to diagnose HCC early. Radical tumor resection makes it possible to cure patients with PTH-rP-secreting HCC.

Clinicopathological characteristics of colon cancer diagnosed at primary health care institutions.

BACKGROUND/AIMS: The purpose of this study was to evaluate the clinicopathologic characteristics of colon cancers detected at the SOK Sokpeynhan Internal Medical Network, a nationwide system of primary health care institutions. METHODS: We analyzed 579 colon cancer patients diagnosed using colonoscopy at the SOK network from January 2011 through December 2012. Cancers from the rectum to the splenic flexure were classified as left colon cancer. Patients over 65 were classified as senior. RESULTS: The mean age (±SD) of subjects was 60.9±10.5 years and 61.1% were men. More than one quarter (28.2%) of patients were asymptomatic. The prevalence of left colon cancer was higher (77.9%) than that for right colon cancer. The most frequent macroscopic and histologic types were depressed (58.9%) and moderately differentiated adenocarcinoma (52.2%), respectively. Asymptomatic subjects displayed protruding or well differentiated adenocarcinoma, while symptomatic patients were more likely to display depressed or moderately differentiated adenocarcinoma (P<0.05). The mean age of the right colon cancer group was higher than that for the left colon cancer group (P<0.05). Among symptomatic patients, the most frequent symptoms were bloody stool for patients with left colon cancer and abdominal discomfort for patients with right colon cancer (P<0.05). The prevalence of depressed cancer was higher in older subjects as compared to younger subjects (P<0.05). The prevalence of right colon cancer tended to increase with age, although this difference did not achieve statistical significance (P>0.05). CONCLUSIONS: Study results indicated an increase of colon cancer amongst younger demographics in recent years. The effectiveness of colonoscopy screening was also evident, as asymptomatic patients demonstrated frequent findings of well differentiated adenocarcinomas. Study results also suggested a need for closer examination of older patients, as right colon cancer tended to increase with age.

The clinicopathologic characteristics of granulomatosis with polyangiitis (Wegener's): a retrospective study of 45 patients in Korea.

OBJECTIVES: The aim of this study was to determine the clinicopathologic characteristics of granulomatosis with polyangiitis (Wegener's) (GPA) in Korean patients. METHODS: The medical records of 45 patients with GPA treated in a single tertiary referral hospital were retrospectively analyzed with respect to clinical manifestations, including histology, ANCA positivity, disease stage, and disease activity. Patients were categorized into granulomatous, vasculitic, or mixed form based on an immunopathologic scoring system of granulomatous-vasculitic activity. RESULTS: Thirty-one patients (68.9 %) showed ANCA positivity (C-ANCA/P-ANCA, 42.2 %/20.0 %, proteinase-3 (PR3) ANCA/myeloperoxidase (MPO) ANCA, 44.1 %/16.1 %), and these patients (female 48.4 %) were found to be associated with a higher frequency of renal involvement (51.6 vs. 7.1 %, p = 0.004), elevated serum creatinine (29.0 vs. 0 %, p = 0.018), and higher mortality (29 vs. 7.1 %, p = 0.041) than ANCA-negative patients. Thirty-three patients (73.3 %, female 60.6 %) had the granulomatous form, whereas 8.9 and 17.8 % had the vasculitic and mixed forms, respectively. Patients with the granulomatous form were diagnosed earlier in their lives (mean age 51.2 vs. 62.3, p = 0.002) and had a lower frequency of renal involvement (21.2 vs. 100 %, p = 0.005) compared with those with the vasculitic form. Initial remission (69.7 vs. 25.0 %) and relapse (60.8 vs. 0 %) rates were higher for the granulomatous than for the vasculitic form. CONCLUSIONS: Taken together, in Korean patients with GPA, the granulomatous form was predominant and associated with a younger age at diagnosis and a lower frequency of renal involvement than the vasculitic form. ANCA positivity was found in 68.9 % and associated with renal involvement and higher mortality.

[Clinicopathologic characteristics of superficial gastric cancer diagnosed at primary health care institutions in 2011].

BACKGROUND/AIMS: Stomach cancer is prevalent in Korea. The purpose of this study was to evaluate the characteristics of superficial gastric cancers detected at SOK Sokpeynhan Internal Medical Network, the nationwide primary health care institutions. METHODS: We prospectively analysed the clinicopathologic and endoscopic characteristics of 218 superficial gastric cancer patients diagnosed using gastric endoscopy at SOK network from January 2011 through December 2011. RESULTS: The mean age was 58.5 years old and male to female ratio was 1.7 : 1. Asymptomatic patients were most common (45.0%). The macroscopic classification revealed that simple types (63.8%) were more common than complex types (36.2%). The most common type was IIc (28.4%) and other types were as follows; IIb (16.1%), IIb+IIc (13.3%), IIa (10.6%), III (9.2%), IIa+IIc (7.3%), IIc+IIa (6.0%), IIc+IIb (5.0%). The most commonly involved sites were the body (53.1%) and greater curvature (32.6%) of the stomach. The size of lesion was less than 1 cm (69.3%) and less than 5 mm (33.5%) in diameter. The most common pathologic type was tubular adenocarcinoma (75.7%). Helicobacter pylori infection rate was 50.2%. Fifty five percent of the cases were diagnosed via endoscopy of National Health Insurance Corporation screenings. CONCLUSIONS: Superficial gastric cancers in 2011 at primary health care SOK network were different from those of previous reports. Type IIc was most common but type IIb was more prevalent and the body and greater curvature of the stomach were the most commonly involved sites. Therefore, careful observation of the proximal gastric mucosa and mucosal color change is needed.

Cost of illness and quality of life of patients with rheumatoid arthritis in South Korea.

OBJECTIVE: To estimate the cost of illness (COI) and health-related quality of life (HRQOL) of rheumatoid arthritis (RA) according to four different levels of functional severity. METHODS: A face-to-face interview survey was administered to patients with RA recruited at the Rheumatology Clinic of Seoul National University Hospital. Direct costs (medical costs [treatment, drug, private physiotherapy, traditional Chinese medicine, other alternative medicine], nonmedical costs [travel, dietary supplements, auxiliary device, home assistance]), indirect costs (productivity loss due to job loss and sick leave), and deterioration in the HRQOL of patients with RA were measured. Factors associated with the COI and the HRQOL were analyzed by using multiple regression and multivariate logistic regression. RESULTS: A total of 196 patients were enrolled for this study. As RA functional severity worsened, the total costs increased accordingly (class I: 4,230,204 Korean won, class II: 7,250,674 Korean won, class III: 8,046,434 Korean won, class IV: 8,206,215 Korean won). Direct costs also increased with the severity of the functional status, with a sharp decrease in class IV. The average HRQOL score was 0.49, showing an evident impact of RA severity (class I: 0.67, class II: 0.50, class III: 0.29, class IV: 0.23). Functional class and comorbidity were significant determinants of the COI and the HRQOL. CONCLUSION: Functional severity was a major factor associated with higher COI and lower HRQOL scores. Therefore, preventing the aggravation of functional severity is crucial for decreasing the COI and improving the HRQOL of patients with RA.

[Clinical, radiological and pathological exploration of focal nodular hyperplasia of liver reported in Korea].

BACKGROUND/AIMS: Focal nodular hyperplasia (FNH) is mandatory to be differentiated from other hepatic tumorous conditions such as hepatocellular carcinoma and adenoma. The purpose of this study was to explore the clinical, radiological and pathological features of FNH cases reported in Korea. METHODS: We have searched the journals from the web site "http://koreamed.org" using keywords "focal nodular hyperplasia" and "liver" - total of 38 cases of FNH, 37 cases from 17 published articles and one case from our experience confirmed histologically, were reviewed and analyzed. RESULTS: Thirty eight cases were diagnosed between gestational age of 36 weeks and 67 years. Seventeen female patients (45%) had no history of taking oral contraceptives. Twenty cases (52.6%) experienced clinical symptoms such as abdominal pain and palpable mass. Computed tomography revealed contrast-enhancement in 34 nodules (85%) and typical central stellate scar in 9 (22.5%) of 40 nodules. Magnetic resonance imaging showed T1 weighted low signal in 18 (60%) and T2 weighted high signal in 22 (73.3%) of 30 nodules. Six (60%) of 10 cases showed hypervascular staining on hepatic angiography. Among 38 cases, 32 (84.2%) cases had single nodule and their mean size was 3.9 cm (0.5-16 cm). Pathologically, fibrous septa, proliferation of bile ductules and arterial wall thickening were seen in most cases. CONCLUSIONS: Of all the FNH cases reported in Korea, there were some differences in clinical aspects of sex ratio, accompanying clinical symptoms, and relationship with oral contraceptives, compared with previous reports. Further prospective studies are needed by means of nation-wide clinical survey and analysis.

[Down-regulation of survivin in growth inhibition of hepatoma cells induced by a selective cyclooxygenase-2 inhibitor].

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) inhibitors reportedly inhibit the growth of hepatocellular carcinoma (HCC) via caspase-dependent or caspase-independent apoptosis, which is due to COX-2 being associated with hepatocarcinogenesis. Survivin is highly expressed in most human cancers, but the mechanism regulating survivin expression remains unclear. We investigated the regulatory expression of survivin in selective-COX-2-inhibitor-induced growth inhibition of hepatoma cells. METHODS: After treatment with NS-398 (a selective COX-2 inhibitor) at various concentrations (10, 50, 100, 150, and 200 micrometer), the growth inhibition of Hep3B hepatoma cells was assessed by an MTT cell-viability assay, DNA fragmentation gel analysis, and flow cytometry. The expression of survivin transcript was analyzed by reverse-transcription polymerase chain reactions. RESULTS: NS-398 inhibited the growth of hepatoma cells by an amount dependent on the concentration and the time since treatment. Apoptotic DNA ladder and flow-cytometry shifting to the sub-G1 phase were revealed in NS-398-induced growth inhibition of hepatoma cells. NS-398 suppressed the expression of the survivin gene in a concentration- and time-dependent manner. CONCLUSIONS: Survivin was down-regulated in the growth inhibition of hepatoma cells induced by a selective COX-2 inhibitor, NS-398, in a concentration- and time-dependent manner. These results suggest the therapeutic inhibition of COX-2 via suppression of survivin in HCC.

Human cytomegalovirus IE1 protein enhances herpes simplex virus type 1-induced syncytial formation in U373MG cells.

Co-infection of herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (HCMV) is not uncommon in immunocompromised hosts. Importantly, organ transplant recipients concurrently infected with HSV-1 and HCMV have a worse clinical outcome than recipients infected with a single virus. However, factors regulating the pathologic response in HSV-1, HCMV co-infected tissues are unclear. We investigated the potential biologic role of HCMV gene product immediate early 1 (IE1) protein in HSV-1-induced syncytial formation in U373MG cells. We utilized a co-infection model by infecting HSV-1 to U373MG cells constitutively expressing HCMV IE1 protein, UMG1-2. Syncytial formation was assessed by enumerating nuclei number per syncytium and number of syncytia. HSV-1-induced syncytial formation was enhanced after 24 hr in UMG1-2 cells compared with U373MG controls. The amplified phenotype in UMG1-2 cells was effectively suppressed by roscovitine in addition to inhibitors of viral replication. This is the first study to provide histological evidence of the contribution of HCMV IE1 protein to enhanced cytopathogenic responses in active HSV-1 infection.

Short term effects of topical cyclosporine and viscoelastic on the ocular surfaces in patients with dry eye.

PURPOSE: To compare the short term effects of topical 0.05% cyclosporine (CsA) and a mixture of 0.08% chondroitin sulfate and 0.06% sodium hyaluronate (CS-HA) on dry eye ocular surfaces. METHODS: 36 patients with moderate to severe dry eye (5 mm/5 min or less with Schirmer's test or tear break up time (BUT) less than 6 seconds), were treated with topical application of CS-HA on one eye and CsA on the other 4 times a day for 6-8 weeks. BUT, Schirmer's test without anesthesia, and conjunctival impression cytology (CIC; goblet cell density, nucleus to cytoplasmic ratio, and epithelial cell morphology) were evaluated and compared between eyes before and after treatment (repeated measurement of ANOVA). RESULTS: After treatment, BUT and tear wettings were significantly prolonged in each group. Topical CsA treated eyes had greater increase in BUT (p=0.026); there was no significant difference in tear wetting (p=0.132). While the 3 parameters of CIC improved in both groups, goblet cell density was significantly higher in eyes treated with CsA (p=0.033). CONCLUSIONS: While both CS-HA and 0.05% CsA eyedrops improve ocular surfaces, topical CsA may have a better effect on enhancing tear film stability and goblet cell density.

Reversible posterior leukoencephalopathy syndrome in systemic lupus erythematosus with thrombocytopenia treated with cyclosporine.

Thrombocytopenia is one of the common manifestations of systemic lupus erythematosus (SLE). Its treatment consists of corticosteroids and/or other immunosuppressive drug such as azathioprine, vincristine, cyclosporine, and mycophenolate mofetil. Common adverse reactions of immunosuppressive treatment are infections, hematologic and liver function abnormalities, but neurologic complications may also be seen. Reversible posterior leukoencephalopathy syndrome (RPLS) is a syndrome manifested by headache, nausea, vomiting, seizures, cortical blindness, and visual disturbances. Neuroimaging shows bilateral subcortical and cortical edema with prominent posterior distribution. Moreover, treatment with immunosuppressive drugs such as cyclosporine, cisplatin, tacrolimus, and interferon-alpha can induce a condition resembling RPLS. We report a case of a young woman with SLE and thrombocytopenia, who developed severe perspiration, headache, and seizure after receiving cyclosporine. A brain magnetic resonance image showed multiple high signal intensities on T2-weighted images predominantly located at the parietooccipital lobe. The patient recovered completely clinically and radiologically after discontinuing cyclosporine.

Clinical significance of anti-filaggrin antibody recognizing uncitrullinated filaggrin in rheumatoid arthritis.

Filaggrin is expressed in the cornified layer of epidermis and known to be one of the antigenic targets in rheumatoid arthritis. Although the citrulline residue in filaggrin is thought to be an antigenic determinant recognized by autoantibodies, the diagnostic sensitivity of synthetic citrullinated peptide is variable. To investigate the implication of anti-filaggrin antibodies recognizing uncitrullinated filaggrin in rheumatoid arthritis, we assayed antibody titers using unmodified recombinant filaggrin in the sera from 73 patients with rheumatoid arthritis, 150 patients with other connective tissue diseases and 70 normal controls. We also performed the correlation analysis between antibody titers and the clinical variables in patients with rheumatoid arthritis. Titers of IgG anti-filaggrin antibodies were significantly higher in rheumatoid arthritis patients compared to normal controls (P=0.02), but not in patients with osteoarthritis, ankylosing spondylitis or systemic lupus erythematosus. IgG anti-filaggrin antibodies were more frequently found in patients with rheumatoid arthritis compared to normal controls (12.3% vs 1.4% respectively, P=0.04). An anti-filaggrin antibody titer was correlated with visual analogue scale of pain, tender joint count, Ritchie articular index or C-reactive protein, but not with anti-nuclear antibody or rheumatoid factor. These results suggest that anti-filaggrin antibody recognizes the uncitrullinated filaggrin as an antigen and its titer correlates with clinical parameters, explaining the variable sensitivity of anti-filaggrin antibody test.

Decreased serum level of antibody against human cytomegalovirus in patients with Behçet's disease.

Behçet's disease (BD) is a connective tissue disorder characterized by recurrent orogenital ulcer, uveitis, and skin lesions. Recurrent aphthous ulcer is associated with human cytomegalovirus (HCMV). To investigate the possible role of HCMV in BD, we measured the titers of IgG, IgM, and IgA anti-HCMV antibodies in 73 Korean patients with BD, 50 with scleroderma, 70 with systemic lupus erythematosus, and 50 from healthy controls by indirect immunofluorescent staining. The titer of IgG anti-HCMV antibody was significantly lower in patients with BD than in controls (geometric mean 3115.4 vs 9687.6, P = 0.0001 by Wilcoxon's rank sum test), as was the titer of IgA anti-HCMV antibody (geometric mean 1.9 vs 15.7, P = 0.0001, Wilcoxon's rank sum test). In conclusion, we found significantly lower antibody responses to HCMV in patients with BD.

Juvenile onset ankylosing spondylitis (JAS) has less severe spinal disease course than adult onset ankylosing spondylitis (AAS): clinical comparison between JAS and AAS in Korea.

OBJECTIVE: To assess the frequency of juvenile onset ankylosing spondylitis (JAS) in Korean patients with AS and to differentiate the clinical characteristics of JAS from adult onset ankylosing spondylitis (AAS). METHODS: We studied 98 consecutive patients with AS who visited the rheumatology clinic of a tertiary referral center and compared clinical and radiographic features of JAS (n = 41) with those of AAS (n = 57). RESULTS: Median age at onset in JAS was 14 years (range 7-16) and in AAS 22 years (range 17-38) (p < 0.01). Patients with JAS at presentation showed fewer spinal symptoms and more frequent peripheral joint symptoms than those with AAS (41.5% vs 80.7% and 73.2% vs 36.8%, respectively; p < 0.01). Current cervical spine disease was more frequent in AAS (66.7% vs 43.9%; p = 0.02) and current knee disease in JAS (26.8% vs 8.8%; p = 0.02). Patients with JAS showed a shorter tragus-wall distance (mean +/- SD 10.6 +/- 1.7 vs 13.1 +/- 6.9 cm; p < 0.01), more mobility on the modified Schober test (5.7 +/- 2.0 vs 4.0 +/- 2.6 cm; p < 0.01) and chest expansion (4.4 +/- 1.7 vs 3.2 +/- 1.8 cm; p < 0.01), and a better forced vital capacity (75.1 +/- 14.1% vs 82.1 +/- 16.1% of predicted value; p = 0.03) than those with AAS. Totally ankylosed sacroiliitis and spinal syndesmophyte on radiographs were less frequent in JAS patients than in AAS (19.5% vs 47.4% and 17.1% vs 54.4%, respectively; p < 0.01). CONCLUSION: The frequency of JAS (41.3%) among Koreans was higher than that reported for Caucasians. General joint involvement pattern at disease onset in JAS was similar to previous reports. Our data suggest that clinically and radiographically JAS has a less severe spinal disease course than AAS.

Detection of JC virus type 1 in peripheral lymphocytes, brain and cerebrospinal fluid from two Korean AIDS patients with progressive multifocal leukoencephalopathy.

The human polyomavirus JC virus (JCV) is the etiologic agent of the fatal demyelinating central nervous system disease progressive multifocal leukoencephalopathy (PML), which occurs in 4-7% of AIDS patients. Two Korean AIDS patients with PML were assayed for JCV, and the virus was genotyped by polymerase chain reaction, DNA sequencing and phylogenetic analysis. Using immunohistochemical analysis, we also examined the distribution of JCV antigen in the brains of the patients. The JCV genome was detected in peripheral lymphocytes, brain and cerebrospinal fluid from these Korean PML patients. Although type 2 is the most common genotype in Asia, the genotype of the JCV in these two AIDS patients was characterized as type 1, which is of European origin. We found that JCV antigen was selectively detected in oligodendrocytes and astrocytes of the brains from these patients. Compared to the prototype type 1 (Mad-1), two different nucleotides (G-->C) in the KOR-1 strain identified here were found at positions 2488 and 2490 of the major capsid protein VP1 gene. In summary, this is the first report of PML in Korean AIDS patients; it is also the first isolation of JCV type 1 in PML in East Asians.

Enhanced second-harmonic generation by use of the photonic effect in a ferroelectric smectic C* liquid crystal.

Special phase matching of second-harmonic generation (SHG) by use of the photonic effect was experimentally confirmed for an obliquely propagating fundamental beam in the helical smectic C>(*) liquid-crystal phase, as suggested by Belyakov [JETP Lett. 70, 811 (1999)]. The enhancement of SHG occurs when the second-harmonic wave is close to a photonic bandgap (half-pitch band) and consequently the fundamental wave is close to another photonic bandgap (full-pitch band). The enhanced signal was observed from both the transmitted and the reflected directions and was compared with our recently developed simulation.