Antitumor effect of simultaneous transfer of interleukin-12 and interleukin-18 genes and its mechanism in a mouse bladder cancer model

BACKGROUND: The objectives of this study were to evaluate the antitumor effects of the simultaneous introduction of interleukin 12 (IL-12) and IL-18 genes into a mouse bladder cancer cell line (MBT2). We intended to compare these with those of either gene alone and to investigate the mechanism of the effects induced by the transfer of IL-12 and/or IL-18 genes in this model system. METHODS: We transfected the IL-12 and/or IL-18 genes into MBT2 cells by the liposome-mediated gene transfer method. We confirmed the secretion of IL-12 and/or IL-18 by enzyme-linked immunosorbent assay. Parental (MBT2/P), IL-12-transfected (MBT2/IL-12), IL-18-transfected (MBT2/IL-18) or both IL-12- and IL-18-transfected (MBT2/Both) cells were subcutaneously or intravenously injected into syngeneic C3H mice. To analyze the mechanism of tumor rejection, these clones were subcutaneously injected into naive nude mice and those depleted with natural killer (NK) cells by antibody. RESULTS: MBT2/IL-12, MBT2/IL-18 and MBT2/Both were completely rejected when they were injected subcutaneously or intravenously into syngeneic mice. However, MBT2/IL-12, but not MBT2/IL-18, could grow in nude mice. Moreover, the antitumor effect of MBT2/IL-18 was partially abrogated when injected into nude mice of which NK cells were depleted by antibody treatment. MBT2/Both was completely rejected in both nude mice with and without NK cells. CONCLUSION: The results of the present study indicate that T cells and NK cells seem to play important roles in the antitumor effects by the secretion of IL-12 and IL-18, respectively, and MBT2/Both possesses both mechanisms.     

Predictors of prostate cancer on repeat transrectal ultrasound-guided systematic prostate biopsy

BACKGROUND: We analyzed the outcome of repeated transrectal ultrasound (TRUS)-guided systematic prostate biopsy in Japanese men whose clinical findings were suspected of prostate cancer after previous negative biopsies. METHODS: Between January 1993 and March 2002, 1045 patients underwent TRUS-guided prostate biopsy. Among them, 104 patients underwent repeat biopsy due to indications of persistent elevated serum prostate-specific antigen (PSA), abnormal digital rectal examination (DRE) or TRUS, increased PSA velocity, and/or previous suspicious biopsy findings. Several clinicopathological factors were evaluated for their ability to predict the detection of prostate cancer on repeat biopsy. RESULTS: Prostate cancer was detected in 22 of 104 patients (21.2%) who underwent repeat biopsies. PSA concentration and PSA density at both the initial and repeat biopsies, and PSA velocity in men with positive repeat biopsy were significantly greater than those in men with negative repeat biopsy. The incidence of abnormal findings in DRE and TRUS at initial biopsy in men with positive repeat biopsy was also significantly higher than that in men with negative repeat biopsy. However, neither the presence of prostatic intraepithelial neoplasia nor number of biopsy cores at initial biopsy had a significant association with the results of the repeat biopsy. Furthermore, multivariate analysis revealed that PSA and PSA density at both the initial and repeat biopsies, PSA velocity, and DRE and TRUS findings at initial biopsy were independent predictors of malignant disease on repeat biopsy. CONCLUSION: Despite an initial negative biopsy, repeat TRUS-guided biopsy should be carried out to exclude prostate cancer in cases of suspicious clinical findings, such as elevated PSA or PSA-related parameters, or abnormal findings of DRE or TRUS.     

Sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility

In this report, we present the overall sexual function and clinical features of patients with Klinefelter's syndrome with the chief complaint of male infertility. The study consisted of 40 patients with a control group of 55 infertile non-azoospermic males with a normal 46,XY karyotype who visited the Reproduction Center of Toho University Hospital during the 5.5-year period between January 1991 and June 1996 with the chief complaint of male infertility. Among the 40 patients with Klinefelter's syndrome, 38 cases were pure 47,XXY, one case was 47,XXY with a pericentric inversion of chromosome 9 and one case was a mosaic of 46,XY/47,XXY(2:28). Thirty-nine of these 40 patients were azoospermic and one (47,XXY) had severe oligoasthenozoospermia. The sexual function of the patients was evaluated according to their responses to a preliminary questionnaire devised by our department. There was no significant difference in the frequency of sexual function disturbances between the patients with Klinefelter's syndrome and the control group (67.5% vs. 60.0%; χ² analysis; p = 0.454). The mean frequency of sexual intercourse per month in the patients with Klinefelter's syndrome was significantly higher than in the control group (4.4 ± 2.8 vs. 3.3 ± 1.6: Welch's t -test, p < 0.05). A possible explanation for this variation may lie in the fact that many of these patients were diagnosed with azoospermia prior to the administration of the questionnaire and may have wished to continue to have relations as a couple.     

Relationship of Helicobacter pylori-associated Gastritis and Polymorphonuclear Leukocyte Elastase

Abstract: Background: Much remains to be clarified about the mechanisms of Helicobacter pylori (H. pylori)-associated gastritis. We considered the possibility of neutrophil involvement and investigated the role of polymorphonuclear leukocyte elastase (PMN-E) in the etiology of H. pylori-associated gastritis. Methods: In 60 patients with gastritis, infection by H. pylori was diagnosed by a combination of the ELISA method and conventional culture method. The hexosamine contents of the mucosal tissues and plasma polymorphonucler leukocyte elastase complexes (PMN-EC) were determined. Results: PMN-EC was found to be elevated in H. pylori-positive gastritis patients, and the degree of elevation was proportionately related to the grade of gastritis inflammation. The hexosamine concentration of the gastric antral mucosa was significantly lower in H. pylori-positive patients than in the H. pylori-negative patients. The ratio of PMN-EC/gastric mucosal hexosamine concentration was significantly higher in the H. pylori-positive group than in the negative group. Conclusion: These data suggest that one of the mechanisms of the H. pylori-associated gastritis may be the infiltration of neutrophils into the gastric mucosa followed by the release of PMN-E which is responsible for the degradation of gastric mucosal proteins and resultant tissue damages.     

Intestinal mast cell response and mucosal defence against Strongyloides venezuelensis in interleukin-3-hyporesponsive mice

Recently several inbred strains of mice were found to be hyporesponsive to Interleukin (IL)-3 because of a 5-bp deletion in the intron 7 of the gene that encodes IL-3 receptor α subunit (IL-3Rα). Due to this mutation, mast cells were not generated in vitro from bone marrow cells of these mice under the presence of IL-3. Intestinal mucosal mast cells, of which growth/differentiation is dependent on IL-3, are important effector cells in immune-mediated expulsion of intestinal nematodes, Strongyloides spp. In the present study, therefore, we examined intestinal mast cell response and mucosal defence against Strongyloides venezuelensis in IL-3-hyporesponsive C58/J and A/J mice. After subcutaneous inoculation with 10 000 infective larvae, C58/J and IL-3-responsive C57BL/6 mice showed identical kinetic patterns of daily faecal egg output and intestinal mast cell response. When these mice were infected with 3000 L3 and, five weeks later, they were challenged by intraduodenal implantation of 800 S. venezuelensis adult worms, the timing of logarithmic decline of faecal egg count as well as intestinal mastocytosis was delayed for two days in C58/J mice. Kinetics of intestinal mastocytosis and faecal egg excretion after a primary and challenge infection in A/J mice, another IL-3-hyporesponsive strain, were identical with those seen in C58/J mice. These results suggest that intestinal mast cell response and mucosal defence against S. venezuelensis of the mutant mice were almost completely compensated in vivo . Possible mechanisms of induction of intestinal mast cell response in IL-3Rα-defective mice are discussed .     

Nocturia Potentially Influences Maintenance of Sexual Function in Elderly Men with Benign Prostatic Hyperplasia

Objective: This study examined the relationship between bothersome symptoms of nocturia and erectile function. Methods: Subjects comprised patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). Patients were prospectively followed on treatment with the alpha‐1 blocker naftopidil for 8 weeks. Patient backgrounds and efficacy of naftopidil associated with LUTS and sexual activity were evaluated. Results: The percentage of patients who identified nocturia as the most bothersome symptom was 30.2% (n = 135), representing the highest percentage among International Prostate Symptom Score (IPSS) items. The number of patients with nocturia as the most bothersome symptom plateaued at an IPSS for nocturia of two or three points. In contrast, the number of patients with slow stream as the most bothersome symptom increased with symptom severity according to IPSS for slow stream. Logistic regression analysis on association between nocturia and erectile function confirmed that the odds ratio was 1.41 (P < 0.05). Naftopidil showed excellent efficacy related to male LUTS, but International Index of Erectile Function 5 (IIEF5) total score was almost unchanged. Among patients with nocturia improved by naftopidil, IIEF5 total score was significantly changed in the group with IPSS nocturia score ≤1 as compared to the group with IPSS nocturia score ≥2 per night (P = 0.038). Conclusion: Nocturia the most bothersome symptom correlated with aging. Nocturia could associate erectile dysfunction, and keeping the frequency of nocturia at ≤1 episode might be meaningful for maintaining quality of life in elderly men.     

Idiopathic retroperitoneal fibrosis associated with IgG4-positive-plasmacyte infiltrations and idiopathic chronic pancreatitis

Idiopathic retroperitoneal fibrosis (IRPF) is an inflammatory fibrosclerosing condition, leading to renal failure by obstruction of the ureters. Idiopathic chronic pancreatitis associated with marked inflammatory infiltrates has recently been referred to as autoimmune pancreatitis (AIP), and infiltrating plasmacytes carrying immunoglobulin-gamma type 4 (IgG4) are relevant to its pathogenesis. The case is described herein of IRPF associated with subclinical pancreatitis that was most probably AIP in a 70-year-old man. Biopsy specimens of the retroperitoneal pseudotumor revealed a marked lymphoplasmacytic infiltration with dense fibrosis. Infiltrating plasma cells were immunoreactive for anti-IgG4 antibodies. Subsequent systemic examinations showed an extremely elevated serum IgG4 level and pancreatitis concordant with AIP. Following oral steroid administration, the serum IgG4 level normalized, although the appearance of the pseudotumor did not alter. Some AIP cases have been associated with idiopathic fibrosclerosing disorders including IRPF, but histological evidence of IgG4-related IRPF has rarely been provided.     

Prognostic significance of vascular invasion in patients with bladder cancer who underwent radical cystectomy

BACKGROUND: The objective of this study was to determine whether vascular invasion (i.e. lymphatic and blood vessel invasion) could be a useful prognostic predictor in patients with locally invasive transitional cell carcinoma (TCC) of the bladder who underwent radical cystectomy. METHODS: This series included 114 consecutive patients undergoing radical cystectomy for primary TCC of the bladder between November 1989 and July 2003. Several clinicopathological characteristics of these patients were analyzed, focusing on the association between vascular invasion and disease recurrence after radical cystectomy. RESULTS: Lymphatic and blood vessel invasions were detected in 55 (48.2%) and 33 (29.8%) specimens, respectively. Lymphatic invasion was significantly associated with pathological stage, tumor grade, lymph node metastasis, blood vessel invasion and disease recurrence, whereas blood vessel invasion was significantly related to pathological stage, lymph node metastasis, lymphatic invasion and disease recurrence. Recurrence-free survival in patients with lymphatic invasion was significantly lower than that in those without lymphatic invasion, and a similar significant difference in recurrence-free survival was observed between patients with and without blood vessel invasion. However, multivariate analysis using the Cox proportional hazards model showed that only pathological stage and lymph node metastasis could be used as independent predictors for disease recurrence after radical cystectomy. CONCLUSIONS: Despite a significant association between several prognostic parameters, vascular invasion was not an independent predictor of disease recurrence; therefore, if there are other conventional parameters available, there might not be any additional advantage to considering the presence of vascular invasion when predicting the prognosis of patients undergoing radical cystectomy for TCC of the bladder.     

Laparoscopic and Histopathologic Features of the Liver in Severe Chronic Active Epstein-Barr Virus Infection Syndrome: A Case Report

Abstract: A 40-year-old man was admitted to our hospital with persistent fever, generalized lymphadenopathy and hepatosplenoamegaly. Immunological examination demonstrated high titers of several anti-Epstein-Barr virus (EBV) antibodies, including anti-viral capsid antigens 1gG-antibody 1: 20, 480, anti-early antigens-DR IgG-antibody 1: 5, 120, and reduced activity of EBV-specific cytotoxic T lymphocytes. Laparoscopic features resembled those of chronic active viral hepatitis, including an uneven surface appearance and diffuse hepatic enlargement. Histopathological examination of a liver biopsy specimen showed inflammatory cell infiltration along sinusoidal surfaces (single file appearance) and enlarged portal areas with intralobular punched-out necrosis. The diagnosis was confirmed by detecting the EB viral genome in serum. Despite treatments with natural alpha-interferon, adenosine arabinocide and recombinant human interleukin-2, the patient died of progressive hepatic failure.     

High dose chemotherapy including paclitaxel (T-ICE) combined with peripheral blood stem cell transplantation for male germ cell tumor. Preliminary report

AIM: To evaluate the feasibility and usefulness of high dose chemotherapy including paclitaxel (T-ICE) combined with peripheral blood stem cell transplantation (PBSCT) for male germ cell tumor. METHODS: Five male patients with advanced germ cell tumor underwent 1-6 courses of high dose chemotherapy including paclitaxel (T-ICE; 175 mg/m2 of paclitaxel, 1250 mg/m2 of carboplatin, 1500 mg/m2 of etoposide and 7.5 g/m2 of ifosfamide) with PBSCT after 2-3 courses of induction chemotherapy (PEB or VIP). RESULTS: In all patients, serum marker levels decreased to within the normal range by T-ICE. Two patients underwent resection of residual tumor. In one patient, viable cancer cells were detected in resected lymph node tissue and adjuvant chemotherapy was then performed. Although the follow-up period was short (7-15.5 months), four of the five patients (80%) showed no evidence of recurrent disease. No significant differences in side-effects were noted between T-ICE and conventional high dose ICE, which was previously performed in 39 patients at the Division of Urology, Kobe University Graduate School of Medicine, Japan. CONCLUSIONS: High dose chemotherapy, including T-ICE, combined with PBSCT showed an almost identical degree of side-effects as seen in previous high dose chemotherapy without paclitaxel. Although 80% of the patients showed no evidence of disease so far, the efficacy of T-ICE should be evaluated with more patients and longer follow up.