The effect of oral prostaglandin analogue on painful diabetic neuropathy: a double-blind, randomized, controlled trial.

This study was performed to assess the efficacy of beraprost sodium (BPS) in painful diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. In this randomized clinical trial, 99 T2DM patients (41% male, age 60 ± 6 years) with DPN but without evidence of peripheral artery disease were randomized to receive either BPS (40 µg, tid) or placebo for 8 weeks. The primary end point was the improvement of the total symptom score (TSS), temperature rebound (TR) and nadir to peak (NP) above baseline. After 8 weeks treatment, the change of TSS in the BPS group showed a significant improvement compared to the placebo group (2.80 ± 2.48 vs. 1.60 ± 1.94 points, p = 0.009). Furthermore, the number of patients who showed signs of improvement in TSS and the proportion of patients with 50% relief of symptom was also significantly greater in the BPS group than in the placebo group (83.7 vs. 62%, p = 0.015, 36.2 vs. 14%, p = 0.009, respectively). In conclusion, treatment with BPS significantly improved TSS over an 8-week period.

Protective mechanism of agmatine pretreatment on RGC-5 cells injured by oxidative stress.

Agmatine has neuroprotective effects on retinal ganglion cells (RGCs) as well as cortical and spinal neurons. It protects RGCs from oxidative stress even when it is not present at the time of injury. As agmatine has high affinity for various cellular receptors, we assessed protective mechanisms of agmatine using transformed RGCs (RGC-5 cell line). Differentiated RGC-5 cells were pretreated with 100 muM agmatine and consecutively exposed to 1.0 mM hydrogen peroxide (H2O2). Cell viability was determined by measuring lactate dehydrogenase (LDH), and the effects of selective alpha 2-adrenergic receptor antagonist yohimbine (0-500 nM) and N-methyl-D-aspartic acid (NMDA) receptor agonist NMDA (0-100 microM) were evaluated. Agmatine's protective effect was compared to a selective NMDA receptor antagonist MK-801. After a 16-h exposure to H2O2, the LDH assay showed cell loss greater than 50%, which was reduced to about 30% when agmatine was pretreated before injury. Yohimbine almost completely inhibited agmatine's protective effect, but NMDA did not. In addition, MK-801 (0-100 microM) did not significantly attenuate the H2O2-induced cytotoxicity. Our results suggest that neuroprotective effects of agmatine on RGCs under oxidative stress may be mainly attributed to the alpha 2-adrenergic receptor signaling pathway.

Protective mechanism of agmatine pretreatment on RGC-5 cells injured by oxidative stress

Agmatine has neuroprotective effects on retinal ganglion cells (RGCs) as well as cortical and spinal neurons. It protects RGCs from oxidative stress even when it is not present at the time of injury. As agmatine has high affinity for various cellular receptors, we assessed protective mechanisms of agmatine using transformed RGCs (RGC-5 cell line). Differentiated RGC-5 cells were pretreated with 100 ìM agmatine and consecutively exposed to 1.0 mM hydrogen peroxide (H2O2). Cell viability was determined by measuring lactate dehydrogenase (LDH), and the effects of selective alpha 2-adrenergic receptor antagonist yohimbine (0-500 nM) and N-methyl-D-aspartic acid (NMDA) receptor agonist NMDA (0-100 µM) were evaluated. Agmatine’s protective effect was compared to a selective NMDA receptor antagonist MK-801. After a 16-h exposure to H2O2, the LDH assay showed cell loss greater than 50 percent, which was reduced to about 30 percent when agmatine was pretreated before injury. Yohimbine almost completely inhibited agmatine’s protective effect, but NMDA did not. In addition, MK-801 (0-100 µM) did not significantly attenuate the H2O2-induced cytotoxicity. Our results suggest that neuroprotective effects of agmatine on RGCs under oxidative stress may be mainly attributed to the alpha 2-adrenergic receptor signaling pathway.

Russell body gastritis associated with Helicobacter pylori infection: a case report.

An unusual and rare gastric mucosal lesion histologically consisting of a localised accumulation of Russell bodies and Russell body-containing plasma cells, the so-called Mott cells, has been recognised only recently and termed as "Russell body gastritis". This lesion, despite its densely monomorphous appearance is easily confirmed to be non-neoplastic by its polyclonal immunoreactive pattern to immunoglobulin light chains. However, the aetiology of Russell body gastritis is controversial and hence the optimal treatment for this disease has not been established. Two cases of Russell body gastritis associated with Helicobacter pylori infection are reported, and the possible role of H pylori infection in the pathogenesis is discussed.

Neoadjuvant chemotherapy with infusional 5-fluorouracil, adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer: an early response predicts good prognosis.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy with infusional 5-fluorouracil (5-FU), adriamycin and cyclophosphamide (iFAC) in locally advanced breast cancer (LABC). PATIENTS AND METHODS: Eighty-two LABC patients were treated with neoadjuvant iFAC chemotherapy including infusional 5-FU (1000 mg/m2, continuous intravenous infusion, days 1-3), adriamycin (40 mg/m2, intravenous bolus, day 1) and cyclophosphamide (600 mg/m2, intravenous bolus, day 1) every 3 weeks until maximum tumor response. Patients subsequently received surgery, adjuvant chemotherapy, radiotherapy and hormonal therapy as appropriate. RESULTS: Downstaging occurred in 71 of the 82 patients (86.6%). Seventy-two patients (67 patients with downstaging and five patients without downstaging) were resectable (resectability rate, 87.8%). The clinical response rate was 84.2%, with a complete response (CR) rate of 17.1% and a pathological CR rate of 7.8%. During 891 cycles of chemotherapy, the most common grade 3/4 hematological toxicity was leukopenia (36.0%). There were no treatment-related deaths. The median follow-up period was 51 months, with a median overall survival (OS) of 66 months, and a 5 year OS rate of 50.9% for all patients. The 5 year OS and disease-free survival (DFS) rates of the 64 patients who underwent surgery were 55.8% and 44.7%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy with iFAC had a comparable response rate and DFS to the conventional bolus FAC regimen, with an acceptable toxicity in LABC using the AJCC 2002 staging system. An early response to neoadjuvant iFAC was a favorable prognostic factor.

Malignant mixed müllerian tumor of fallopian tube with multiple distinct heterologous components.

We experienced a case of primary malignant mixed müllerian tumors (MMMTs) of the fallopian tube of FIGO stage I. In addition to endometrioid adenocarcinomas, multiple apparent heterologous elements encompassing myxoid chondrosarcoma, osteosarcoma, myxoid liposarcoma, and well-differentiated angiosarcoma were recognized separately in each nodule. Those findings that divergent sarcomatoid differentiations are apparently present masquerading malignant mesenchymoma have not been described in MMMTs of the female genital tract.

Granulocytic sarcoma of the uterine cervix.

Granulocytic sarcoma (GS) is a rare manifestation of leukemia and has been reported in 3-5% of acute myelogenous leukemia (AML) patients. GS in the uterine cervix is very rare and is also called chloroma because of its greenish appearance. We present the case of a patient whose disease relapsed as chloroma of the uterine cervix after bone marrow transplantation (BMT). She remained in continuous complete remission for 2 years after allogeneic BMT. However, she visited the hospital because of painless vaginal bleeding. She was diagnosed as having chloroma by cervical smear and colposcopically directed biopsy of the cervix. Systemic chemotherapy was administered on the presumption that myelogenous leukemia had recurred as chloroma, and a good clinical response was achieved. We describe the first case of AML that relapsed as chloroma of the uterine cervix after complete remission of the AML, which had complete response to only systemic chemotherapy.

NK and NK-like T-cell lymphoma in extranasal sites: a comparative clinicopathological study according to site and EBV status.

AIMS: To analyse the clinicopathological findings of extranasal CD56+ cytotoxic T- or NK-cell lymphomas in different organs and to compare Epstein-Barr virus (EBV)+ and EBV- lymphoma of non-blastoid cytomorphology. METHODS AND RESULTS: Fifty-one cases of cCD3+ T-cell intracellular antigen (TIA-1)+ CD56+ lymphomas of extranodal/extranasal origin were included in the study. The primary sites of the CD56+ tumours were soft tissue (n = 10), the gastrointestinal (GI) tract (n = 13), the skin (n = 15), upper aerodigestive tract excluding nasal and nasopharyngeal regions (n = 11), the testis (n = 1), and parotid gland (n = 1). TCR gene rearrangement was detected in seven of 47 cases examined (16%). EBV was positive in 39 of 51 cases (76%). The positive rate of EBV was higher in tumours of soft tissue (80%), GI tract (92%), and skin (80%), and lowest in the upper aerodigestive tract excluding the nasal and nasopharyngeal region (50%). Tumours of the soft tissue and the upper aerodigestive tract tended to present with localized disease (P = 0.002). The 2-year survival rate was lowest for tumours of the GI tract (P = 0.0256). EBV- TCR- lymphoma showed less necrosis (P = 0.0133) and a better 2-year survival rate (P = 0.0066) than EBV+ TCR- lymphoma. Patients with EBV+ TCR+ lymphomas tended to present with localized disease, more often than EBV+ TCR- lymphoma (P = 0.0186). Significant prognostic factors in all CD56+ lymphomas were the site (P = 0.0256), EBV status (P = 0.0026), necrosis with or without perforation (P = 0.0338) and the presence of pleomorphic large tumour cells (P = 0.0428). Cox's regression analysis adjusting for other pathological parameters showed EBV status to be the only independent prognostic factor (P = 0.018). CONCLUSIONS: Extranodal CD56+ EBV- lymphoma at extranasal sites is a clinically less aggressive malignancy and displays less necrosis than CD56+ EBV+ lymphoma. Because CD56+ EBV+ TCR+ lymphomas show similar pathological and clinical findings to CD56+ EBV+ TCR- lymphomas, nasal-type NK/T-cell lymphomas at extranasal sites should be diagnosed as such on the basis of EBV+, cytotoxic T or NK phenotype irrespective of the genotype determined by molecular study.

Solitary plasmacytoma of the mandible in a renal transplant recipient.

A solitary plasmacytoma occurring in the mandible of a 15-year-old Korean male 6 years after renal transplantation is reported. The tumour presented as a hyperplastic gingival overgrowth in the right madibular molar area. Histology and immunohistochemistry revealed plasmacytoma and monoclonality of the kappa chain and IgG. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) showed positive signals in the tumour cells. The tumour regressed after reducing the immunosuppressive agents with concurrent radiotherapy. The patient remains in a stable condition with normal renal functions after 7 years without recurrence. This case confirms that Epstein-Barr virus associated B-lymphoproliferative disorders are still a major complication of immunosuppression.

Expressions of p53 and p21 in primary gastric lymphomas.

The p21 overexpression is thought to be a consequence of the p53 induced activation of the p21 gene. The immunohistochemical evaluation of p53 and p21 can be a valuable means of assessing the functional status of the p53 gene product. We examined the overexpression of p21 and p53 proteins in primary gastric lymphomas and the correlation with prognosis. A total of 32 cases of gastric lymphomas was classified into low-grade lymphomas of mucosa-associated lymphoid tissue type (n=16) and high-grade B-cell lymphomas (n=16). In low-grade lymphomas, only one case showed p53 positivity and all cases were p21-negative. In high-grade lymphomas, seven cases were p53+/p21- (44%), one case was p53+/p21+ (6%), and eight cases were p53-/p21- (50%). The p53+/p21- cases had a much lower percentage of patients sustaining a continuous complete remission state (3/7, 43%) compared with other cases (6/7, 86%). From these results, we concluded that p21 expression is rare in primary gastric lymphomas. Therefore, p53-positive lymphomas can be assumed as having p53 mutation. And combined studies of p53 and p21 may be used as a prognostic indicator in primary gastric high-grade lymphomas.

A morphological study of drill holes applied with mitomycin-C in hydroxyapatite orbital implants.

For maximum motility of the prosthesis, the hydroxyapatite orbital implant should be drilled and coupled to the prosthesis via a motility peg. However, problems of peg extrusion have been reported to occur in 25-30% of cases. In this animal study, serial histopathological changes within the drill hole after hydroxyapatite implantation were observed and the effect of mitomycin-C (MMC) was evaluated as a new method of hole maintenance. A hole was drilled into each hydroxyapatite implant 20 weeks after enucleation and different concentrations of MMC solution were applied. The morphological changes of the holes were evaluated with proliferating cell nuclear antigen. In the control group (non-MMC-treated), all the motility pegs were extruded showing occluded holes. In the groups treated with 0.5 and 1.0 mg/ ml MMC, all the motility pegs were maintained in position with the holes at ample depth and width. However, toxicity, such as conjunctival ulcer and implant exposure around the hole, was observed in the 1.0 mg/ml MMC group. A 0.5 mg/ml MMC application for 5 min to the drill hole effectively reduced the risk of peg extrusion in this albino rabbit model.

Primary squamous cell carcinoma of the parotid gland.

PURPOSE: To investigate the clinical behavior and treatment outcome of patients with primary squamous cell carcinoma (SCC) of the parotid gland. PATIENTS AND METHODS: Twelve cases of primary SCC originating in the parotid gland were retrospectively reviewed. The majority of patients had a locally advanced disease. Eight cases underwent a combination of radical surgery and postoperative radiotherapy, whereas the remaining four cases were treated with radiotherapy alone. Patterns of treatment failure, survival rate, and prognostic factors for these patients were investigated. RESULTS: The predominant pattern of failure was local failure, either alone or in combination with other failures. Two patients who were treated with radiation alone had persistent disease after completion of treatment, whereas 4 of 8 patients who received combined modality treatment and 2 of 4 patients who were treated with radiation alone subsequently developed local recurrences in the primary site or surgical bed. The local failure rate and regional failure rate were 58% and 25%, respectively. Most locoregional recurrences developed within 1 year after initial treatment. Only 2 patients had distant metastasis. The prognosis appeared to be relatively poor for those patients, compared with those with SCC in other head and neck sites. The overall 5-year actuarial survival rate and the disease-free survival rate were 31% and 33%, respectively. Although advanced stage, facial nerve palsy, and regional lymph node metastasis all portended an unfavorable prognosis, only patient age and treatment modality were found to be statistically significant poor prognostic factors. CONCLUSIONS: Primary SCC of the parotid gland is an uncommon tumor with a highly malignant potential. Our results indicate that a combination of radical surgery and postoperative radiotherapy is the treatment of choice for achieving better locoregional control rates and improved cure rates in the treatment of these patients.

Expression of CD40 and apoptosis related molecules in autoimmune thyroid diseases.

Apoptosis is responsible for the loss of thyrocytes in autoimmune thyroiditis. Recent investigations into the pathogenesis of apoptosis have revealed that the important roles of suicide molecules expression on both thyrocytes and cytotoxic T-lymphocytes. To study the mechanism of thyrocyte loss in various forms of thyroiditis, we evaluated in situ expression patterns of CD40, Fas, and Fas-L on thyrocytes and infiltrating inflammatory cells by immunohistochemical staining of thyroid samples obtained from 49 patients (Graves' disease, n=10: Hashimoto's thyroiditis, n=14; nonspecific lymphocytic thyroiditis, n=11; subacute granulomatous thyroiditis, n=11; normal, n=3). The role of cytotoxic T-lymphocytes was also evaluated by analyzing the expression of granzyme B along with their phenotypic characteristics. CD40 was not expressed on thyrocytes of normal controls while they showed a diffuse expression of Fas and a scattered focal expression of Fas-L. The plump thyrocytes proximal to the inflammatory infiltrates showed more intense expressions of these three molecules in various forms of thyroiditis and a close correlation was found between CD40 and Fas-L expression on thyrocytes. Unlike Fas, which was expressed on infiltrating lymphocytes in all groups, Fas-L was not expressed on infiltrating lymphocytes, except those in subacute granulomatous thyroiditis. Granzyme B expressing activated cytotoxic T-lymphocytes occupied a negligible proportion of CD8+ T-lymphocytes in various forms of thyroiditis, and no difference was found in terms of their proportions according to the type of thyroiditis. These results show the acquisition of CD40, Fas and Fas-L molecules on thyrocytes proximal to inflammatory cell aggregates and the negligible expression of granzyme B and Fas-L on the infiltrating lymphocytes, and suggest that Fas and Fas-L mediated apoptosis of thyrocytes (fratricide) may be more important than T cell-mediated cytotoxicity in various forms of thyroiditis.

Thymoma with pseudosarcomatous stroma.

Thymoma with psuedosarcomatous stroma is a recently described, rare variant of thymomas that are characterized by having a biphasic histologic pattern which consists of both an epithelial and a spindle cell stromal component. So far only 11 cases having similar histologic findings have been reported worldwide. At this time we report a case of this rare variant of thymoma which occurred in a 53-year-old Korean man. This previously healthy patient presented with coughing and an anterior mediastinal mass was then detected radiographically. Mediastinal exploration revealed a 9 x 8 x 8 cm-sized well- encapsulated, ovoid, cystic mass. Histological examination showed a biphasic neoplasm composed of anastomosing nests of epithelial cells and somewhat cellular stromal spindle cells that had advanced degenerative changes. Immunohistochemical staining using the antibodies for cytokeratins, EMA, e-cadherin, and p75NGFR showed a strong expression of these markers in the epithelial component but no expression in the spindle stromal cells. The epithelial tumor cells showed no reactivity to CD5 and L26 and a high proportion of the infiltrated lymphocytes were the cortical type that expressed CD99 and terminal deoxynucleotidyl transferase. Ultrastructural examinations revealed tonofilaments in the spindle cells. Follow up has been done for 5 years after the surgical excision and the patient has been free of disease during that period. Similar to previous reports, this patient had a benign clinical course that was unassociated with myasthenia gravis which appears to be a characteristic of this histologic variant of thymoma. However, our case also showed advanced degenerative features and we could demonstrate ultrastructural evidence of epithelial differentiation in the stromal spindle cells that were not mentioned in the previously reported cases. Based on the results of our studies, we suggest this entity is a distinct type of organotypic thymoma that shows cortical differentiation and abundant cellular stroma.

Coexpression of Bcl-6 and CD10 in diffuse large B-cell lymphomas: significance of Bcl-6 expression patterns in identifying germinal center B-cell lymphoma.

Most follicular lymphomas (FLs) transform to diffuse lymphoma eventually, comprising a significant proportion of diffuse large B-cell lymphoma (DLBCL). Judging by bcl-2 rearrangement (bcl-2R), one third of DLBCLs are believed to be of FL derivation in the Western population. However, bcl-2R is not specific and is not detectable in every case of FL. In East Asia, FL is uncommon but DLBCL is not. The proportion of tumors of FL origin in DLBCL is not known in this region. The coexpression of Bcl-6 and CD10 proteins, a reliable marker to identify germinal center (GC) B-cell lymphoma including FL, was analyzed in primary nodal DLBCLs (n = 104) diagnosed at major hospitals in Seoul during a recent 2-year period, along with well-defined cases (n = 17) of nodal FL as controls. Bcl-2 protein expression (n = 77) was also studied along with bcl-2R (n = 64), by polymerase chain reaction. Formalin-fixed archival specimens were used in all these assays. The Bcl-6/CD10 coexpression was observed in 35 DLBCLs (34%) and 14 FLs (82%), and most of them showed a pattern of Bcl-6 expression similar to that of the GC. Bcl-2 expression or bcl-2R did not correlate with Bcl-6/CD10 coexpression. Histologically, compartmentalizing sclerosis was associated with a high rate of the coexpression (8 of 10). In conclusion, to detect GC B-cell lymphoma in routine biopsy specimens, a pattern of Bcl-6 staining similar to the GC must be identified. Bcl-6+/CD10+ GC B-cell lymphomas thus defined comprised one third of primary nodal DLBCLs in Korea. The incidence rate is similar to that in the West. The reasons for the discrepancy between the incidence of GC B-cell lymphoma and the paucity of the follicular pattern in East Asian subjects warrant further studies.

Extraovarian granulosa cell tumor.

A 54-year-old woman was admitted to our hospital complaining of postcoital bleeding. Sonography of the abdomen showed a 8.2 x 8.9 cm-sized solid heterogeneous mass occupying the cul-de-sac, which appeared to be in no way connected with the ovary. On exploratory laparotomy, the tumor mass protruded from the posterolateral retroperitoneum of the pelvic cavity and severely replaced the uterus and adnexa with the outer surface being grossly intact. It grossly measured 10 cm in maximal diameter. The histologic features closely resembled those of ovarian granulosa cell tumor. The primary extraovarian granulosa cell tumor is extremely rare such that in the English literature only 7 cases have been reported to date. Of those granulosa cell tumors are especially rare and only two cases have been reported to arise from retroperitoneum. We herein present a case of retroperitoneal granulosa cell tumor with special regard to differential diagnosis from other solid tumors with similar histology.

The significance of granzyme B expression in patients with angiocentric lymphoma of the head and neck.

BACKGROUND: The objectives of this study were to establish a correlation between granzyme B expression and the clinicopathologic characteristics of patients with angiocentric lymphomas of the head and neck and to determine whether the expression of granzyme B had any influence on the treatment outcomes of such patients. METHODS: Fifty-seven patients with angiocentric lymphoma of the head and neck who were treated between 1987 and 1996 were divided into two groups according to whether their tumors were immunoreactive for granzyme B: the granzyme B negative group (n = 22 patients) and the granzyme B positive group (n = 35 patients). The clinicopathologic features, immunohistochemical findings, patterns of disease failure, and survival data for the granzyme B positive group were compared with those for the granzyme B negative group. RESULTS: Greater than 60% of patients with angiocentric lymphoma of the head and neck were shown to have granzyme B positive tumors. All tumors that expressed granzyme B also consistently coexpressed CD56, indicating that they probably are the neoplastic equivalent of either natural killer (NK) cells or activated cytotoxic T cells. Although there were no significant differences in histopathologic features or expression of CD45RO and polyclonal CD3-epsilon between the groups, the Epstein-Barr virus genomes were detected more frequently in the granzyme B positive group compared with the granzyme B negative group. Despite a similar rate of complete remission after initial treatment, the locoregional recurrence rate of patients in the granzyme B positive group was much higher compared with patients in the granzyme B negative group. In addition, compared with patients in the granzyme B negative group, patients in the granzyme B positive group also had an increased risk of systemic disease recurrence and a decreased overall survival rate. CONCLUSIONS: The data indicate that the cytotoxic granule-associated protein, granzyme B, may be used as an additional marker for identifying NK/T-cell lymphoma and as a prognostic indicator for risk assessment in patients with angiocentric lymphoma of the head and neck.