Promoter hypermethylation of the bone morphogenetic protein-6 gene in malignant lymphoma.

PURPOSE: Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-beta superfamily, are important regulators of cell growth, differentiation, and apoptosis. The biological effects of BMPs on malignant lymphoma, however, remain unknown. Promoter methylation of the BMP-6 gene in lymphomas was investigated. EXPERIMENTAL DESIGN: We investigated BMP-6 promoter methylation and its gene expression in various histologic types of 90 primary lymphomas and 30 lymphoma cell lines. The effect of BMP-6 promoter hypermethylation on clinical outcome was also evaluated. RESULTS: BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21 of 35) of DLBCL cases and 100% (7 of 7) of DLBCL cell lines, and in 83% (5 of 6) of Burkitt's lymphoma cases and 86% (12 of 14) of Burkitt's lymphoma cell lines. In contrast, other histologic types of primary lymphomas studied had little or no detectable methylation (1 of 49; 2%). The presence of BMP-6 promoter hypermethylation in DLBCL statistically correlated with a decrease in disease-free survival (P = 0.014) and overall survival (P = 0.038). Multivariate analysis showed that the methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.022) and overall survival (P = 0. 046). CONCLUSION: BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethylation is likely to be related to the histologic type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.     

Criteria revision and performance comparison of three methods of signal detection applied to the spontaneous reporting database of a pharmaceutical manufacturer.

BACKGROUND AND OBJECTIVE: Several statistical methods exist for detecting signals of potential adverse drug reactions in spontaneous reporting databases. However, these signal-detection methods were developed using regulatory databases, which contain a far larger number of adverse event reports than the databases maintained by individual pharmaceutical manufacturers. Furthermore, the composition and quality of the spontaneous reporting databases differ between regulatory agencies and pharmaceutical companies. Thus, the signal-detection criteria proposed for regulatory use are considered to be inappropriate for pharmaceutical industry use without modification. The objective of this study was to revise the criteria for signal detection to make them suitable for use by pharmaceutical manufacturers. METHODS: A model comprising 40 drugs and 1000 adverse events was constructed based on a spontaneous reporting database provided by a pharmaceutical company and used in a simulation to investigate appropriate criteria for signal detection. In total, 1000 pseudo datasets were generated with this model, and three statistical methods (proportional reporting ratio [PRR], Bayesian Confidence Propagation Neural Network [BCPNN] and multi-item gamma Poisson shrinker [MGPS]) for signal detection were applied to each dataset. The sensitivity and specificity of each method were evaluated using these pseudo datasets. The optimum critical value for signal detection (i.e. the value that achieved the highest sensitivity with 95% specificity) was identified for each method. The optimum values were also examined with the adverse events classified into two categories according to frequency. The three original detection methods and their revised versions were applied to a real pharmaceutical company database to detect 173 known adverse reactions of four drugs. RESULTS: The 1000 pseudo datasets consisted of an average of 81 862 reports and 11,407 drug-event pairs, including 1192 adverse drug reactions. The sensitivities of PRR, BCPNN and MGPS methods were 49%, 45% and 26%, respectively, whereas their specificities were 95%, 99.6% and 99.99%, respectively; these sensitivities were unacceptably low for pharmaceutical manufacturers, whereas the specificities were acceptable. The highest sensitivity for each method, obtained by changing critical values and maintaining specificity at 95%, was 44%, 62% and 62%, respectively. When adverse events were classified into two categories, sensitivities as high as 75% for regular events and 39% for rare events were achieved with the revised BCPNN method. The critical values of the information component minus two standard deviations (IC - 2SD) index of the revised BCPNN method were greater than -0.7 for regular events and greater than -0.6 for rare events. The revised BCPNN method yielded 51% sensitivity and 89% specificity for the real dataset. CONCLUSION: A lower critical value may be needed when signal-detection methodology is applied to the spontaneous reporting databases of pharmaceutical manufacturers. For example, it is recommended that pharmaceutical manufacturers use the BCPNN method with IC - 2SD criteria of greater than -0.7 for regular events and greater than -0.6 for rare events.     

Association of serum NO x level with clustering of metabolic syndrome components in middle-aged and elderly general populations in Japan

Objectives The aim of this study was to determine whether the serum nitrite plus nitrate (NO _x ) level correlates with biomarkers that are known components of the metabolic syndrome (MetS). Methods Serum NO _x levels were measured using a commercial kit in 608 Japanese men and women between the ages of 39 and 85 years. Multivariate adjustments for age, smoking status, alcohol consumption and exercise were made in the analysis of covariance (ANCOVA). The components of the metabolic syndrome were defined based on the following criteria: body mass index (BMI) ≥25.0 kg/m², glycated hemoglobin (HbA1c) ≥5.6%, systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, high-density lipoprotein-cholesterol (HDL-C) ≤1.03 mmol/l for men and ≤1.29 mmol/l for women and triglyceride ≥1.69 mmol/l. Results The logarithmically transformed age-adjusted serum NO _x (lnNO _x ) value was significantly higher in the low HDL-C group (1.76 ± 0.05 μmol/l; p < 0.05) than MetS component groups (1.65 ± 0.01 μmol/l) in men, but no difference was found in women. The means of serum lnNO _x after multivariate adjustment were 1.64, 1.65, 1.64, 1.66, and 1.81 μmol/l for 0, 1, 2, 3, and 4–5 MetS components for all subjects, respectively. The results of ANCOVA confirmed that the serum lnNO _x level was significantly correlated with the clustering of MetS components in both men and women (p < 0.0001 for trend). Conclusion Our results suggest that an increase in the clustering of MetS components was associated with the increase in serum NO levels in our general population.     

Chronic α1 blockade in a patient with Eisenmenger syndromeblockade in a patient with Eisenmenger syndrome

Summary In an 18-year-old male with Eisenmenger syndrome cyanosis and erythrocytosis were increasing. The erythrocytosis diminished following oral bunazosin and phlebotomy was not needed during the treatment. When bunazosin was stopped, the erythrocytosis increased, but when it was resumed, the erythrocytosis and general fatigue diminished.     

Diagnosis of Atlantoaxial Subluxation in Morquio's Syndrome and Spondyloepiphyseal Dysplasia Congenita

Compression of the spinal cord due to atlantoaxial subluxation was diagnosed in a patient with Morquio's syndrome and in another with spondyloepiphyseal dysplasia (SED) congenita by cervical radiography and magnetic resonance imaging (MRI). The patient with Morquio's syndrome, a 15 year old boy, had no neurologic symptoms and his somatosensory evoked potential (SSEP) was normal. However, MRI demonstrated spinal cord compression at C1-C2. In contrast, the patient with SED congenita, an 11 year old girl, had neck pain, hyperreflexia and loss of vibration sense in both legs. These findings were explained by the absence of P3 and later waves in SSEP and by compression of the spinal cord observed on MRI. Both SSEP and MRI should be used for evaluating disorders in which atlantoaxial subluxation might be present.     

Long-term effects of mass screening for neuroblastoma in infancy

Eighty-four neuroblastoma patients were treated at the Department of Pediatrics, Kyoto Prefectural University of Medicine, during the 27 years from 1962 to 1988. They were divided into three groups: 35 cases in phase 1, the 12 years before mass screening from 1962 to 1974; 22 in phase 2, the 8 years after the onset of mass screening by a qualitative vanillylmandelic acid (VMA) test from 1974 to 1982; and 27 in phase 3, the recent 6 years from 1983 to 1988, after the introduction of mass screening by quantitative assay for VMA and homovanillic acid using high performance liquid chromatography. The clinical findings of these patients were compared for each phase. In Kyoto, the number of annual neuroblastoma cases diagnosed under 1 year of age increased from 0.58 in phase 1 to 1.50 in phase 2 and 3.17 in phase 3. The number of cases over 2 years of age decreased from 2.00 in phase 1 to 0.88 in phase 2 and 1.00 in phase 3. Survival rates increased from 17.1% (six of 35) in phase 1 to 54.5% (12 of 22) in phase 2 and 85.2% (23 of 27) in phase 3. The annual number of neuroblastoma deaths decreased from 2.42 in phase 1 to 1.25 in phase 2 and 0.67 in phase 3. Mass screening for neuroblastoma in infancy has increased the long-term survival rates of neuroblastoma cases treated at this hospital.     

Early infectious complications after peripheral blood stem cell autografts in children

Seventeen children underwent marrowablative high-dose chemotherapy with peripheral blood stem cell autografts and were studied retrospectively to determine the type, frequency, and outcomes associated with infectious complications 3 months postgraft. The patients were kept in isolated rooms with a laminar air flow facility, but no decontamination procedures, such as gut sterilization with nonabsorbable antibiotics, nonmicrobial diet, and skin cleansing, were used. They were under their mothers' daily care to maintain good psychological conditions. After the completion of marrow-ablative chemotherapy and the infusion of stem cells, the absolute granulocyte count exceeded 0.5 × 10⁹/liter with a mean of 17.9 days (range 6–65 days), Fifteen patients developed a total of 16 febrile episodes during the first 4 week period, and the confirmed diagnoses were mucositis (12), enterocolitis (nine), septicemia (four), central venous catheter-associated infection (three), pneumonia (one), perianal abscess (one), and possible invasive fungal infection (one). All episodes were successfully treated with parenteral antibiotic therapy, and no patient died of infectious complications. The observations suggest that high-dose chemotherapy can be performed safely with simple and efficient patient management protocol followed by peripheral blood stem cell autografts.     

Adenosquamous Carcinoma of the Gallbladder: A Clinicopathological, Immunohistochemical and Flow-cytometric Study of Twenty Cases

Twenty patients (7.4%) with adenosquamous carcinoma of the gallbladder were selected from 271 surgically resected gallbladder cancers. The 20 patients were composed of 8 men and 12 women with a mean age of 66.9 years. Histologically, all twenty tumors showed an abrupt transition between the adenocarcinoma (AC) and squamous cell carcinoma (SCC) areas, and well differentiated AC was also found in the peripheral area of the tumor. A histochemical and immunohistochemical study using alcian blue, periodic acid-Schiff, cytokeratins, involculin and tissue polypeptide antigen disclosed a different nature of the two components. DNA heterogeneity between the components was detected in 5 of 7 cases by flow cytometry. The positive rate of immunostaining for proliferating cell nuclear antigen in the SCC areas (mean 20.55%) was larger than that of the AC areas (mean 11.40%) ( P =0.0029), which indicated that the SCC areas had a greater proliferative capacity than AC areas. These results suggest that the SCC component of adenosquamous carcinoma of the gallbladder arose by a stepwise molecular progression of the pre-existing AC. Furthermore, the prognosis of adenosquamous carcinomas of the gallbladder (mean survival: 10 months) in the advanced stage (pTNM 2–4) was less favorable than those of papillary and well differentiated AC (mean survival: 99 months and 86 months) ( p <0.0001).     

Comparison of the prophylactic usefulness of epirubicin and doxorubicin in the treatment of superficial bladder cancer by intravesical instillation: a multicenter randomized trial

A multicentric randomized trial was conducted for the purpose of investigating the prophylactic efficacy of intravesical epirubicin instillation following transurethral resection of superficial bladder cancer in comparison with the efficacy of doxorubicin. The patients were centrally randomized into 2 groups and received 19 intravesical instillations of epirubicin or doxorubicin at 30 mg/30 ml physiological saline twice a week for 4 weeks and then once monthly for 11 months. A total of 150 patients with Ta and T1 superficial bladder cancer were entered in the trial, and 114 were evaluable. The nonrecurrence rates determined for each group at 1 and 2 years by the Kaplan-Meier method were 92.8% and 88.6%, respectively, for the epirubicin group and 86.4% and 81.7%, respectively, for the doxorbicin group. The differences between the two groups were not statistically significant. The main side effects encountered in this study were symptoms of bladder irritation such as micturitional pain, pollakisuria, and hematuria. The respective frequencies of those symptoms were 10%, 15.0%, and 5.0% in the epirubicin group and 14,8%, 14.8%, and O in the doxorubicin group. These results suggest that epirubicin is a useful drug, comparable with doxorubicin, for intravesical instillation chemotherapy in the prophylactic treatment of superficial bladder cancer.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan