Biallelic inactivation by somatic mutations of the MEN1 gene in sporadic parathyroid tumors.

We report three sporadic parathyroid tumors with biallelic inactivation of the multiple endocrine neoplasia type 1 (MEN1) gene. Three parathyroid tumors had two somatic mutations (K119del and 864del8, 363insT and 1767delT, and 508del33 and W341X, respectively). The mutations in both alleles detected by long-range polymerase chain reaction and subcloning in three tumors would likely result in a nonfunctional menin protein in parathyroid glands. These results show that the MEN1 gene is inactivated not only by a combination of somatic mutations and loss of heterozygosity, but also by somatic double mutations located on different alleles. The results directly confirmed the participation of MEN1 in the tumorigenesis of sporadic parathyroid tumors.     

Efficacy of carboplatin with an MEP (mitoxantrone, etoposide and prednisone) regimen for relapsed and CHOP-resistant diffuse large B-cell lymphomas.

Mitoxantrone, etoposide and prednisone (MEP)-based regimens using granulocyte colony-stimulating factor (G-CSF) were designed for relapsed and CHOP-resistant diffuse large B-cell lymphomas in a single institution, and the therapeutic effects and adverse reactions were studied. In a total of 49 patients, the MEP regimen had a 41% (9/22) overall response rate compared with 48% (13/27) for the MEP plus carboplatin (C-MEP) regimen (Chi-squared test, P=0.602). Among 38 CHOP-resistant patients, however, the overall response rate to C-MEP [42% (10/24)] was significantly superior compared with MEP [7% (1/14)] (P=0.023), and the overall survival to C-MEP was superior compared with MEP (P=0.088). Taken together, our results, although non-randomized, suggest that a combination of MEP with carboplatin is better than MEP alone in CHOP-resistant diffuse large B-cell lymphomas.     

Suppression of Lung Metastasis by Aspirin but Not Indomethacin in an in vivo Model of Chemically Induced Hepatocellular Carcinoma

To examine the effect of non-steroidal anti-inflammatory drugs on metastasis formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking water) were applied to an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. Multiplicity of HCC in the liver increased during ASP or IM treatment without any significant histological alteration. Although absent in the rats killed at the end of the period of carcinogen exposure, lung metastasis at the end of the experiment was found in 100%, 89% and 100% of rats in the control, ASP and IM groups, respectively. Degree of metastasis was classified into three groups according to the number of metastatic nodules, i.e., slight (1–5 nodules), moderate (6–50) and severe (more than 51), which amounted to 0%, 43% and 57% in the control group. ASP significantly reduced the degree of metastasis, the incidences being 33%, 44%, and 11%, respectively, whereas IM was without significant influence. Both agents suppressed cell proliferation in HCCs, without any alteration of pan-cadherin expression. However, expression in HCC of mRNAs for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both of which are considered to play key roles in attachment of cancer cells to the endothelium, was significantly suppressed by ASP. Thus, the present study demonstrated that ASP, but not IM, has the potential to inhibit lung metastasis of rat HCC in vivo , possibly via reduced attachment of tumor cells to the vascular endothelium. Moreover, these data indicate this in vivo model for induction of rat highly metastatic HCC to be a useful tool for the assessment of the efficacy of therapeutic treatments to block metastasis formation.     

Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents.

This study reports that a selective COX-2 inhibitor JTE-522inhibits both in vitro and in vivo growth of human lung cancer cells as a single agent. Furthermore, the adjunct use of JTE-522 is shown to significantly enhance treatment efficacy of conventional anticancer drugs not only in vitro but also in vivo without causing any noticeable side effects. Indeed, IC(50)s of various anticancer agents in vitro were reduced by up to 70%, whereas the combination therapy of JTE-522 with docetaxel and vinorelbine inhibited tumor growth in vivo by 65 and 55%, respectively. Taken together, these findings suggest that the use of a selective COX-2 inhibitor in the treatment of lung cancer may be promising, especially because of its enhancement of the treatment efficacy of conventional anticancer agents without compromising quality of life.     

Radical retropubic prostatectomy: time trends, morbidity and mortality in Japan

OBJECTIVES: To assess the time trends, morbidity and mortality of contemporary anatomical radical retropubic prostatectomy (RRP) in a multi-institutional study in Japan, where RRP has become more popular in the last decade. PATIENTS AND METHODS: Between January 1991 and August 1998, 638 patients underwent RRP at seven urological centres in Japan. Major complications (within 30 days of surgery) and the 30-day mortality were reviewed retrospectively. Of the patients, 12.9% were < 60 years old, 56.3% were 60-69 years old and 30.9% were >/= 70 years old (median age 67). Results The number of RRPs increased markedly, by more than sevenfold, from 1991-92 to 1996-97, mainly because there were more patients undergoing RRP in their sixth decade. The contribution of T1c disease increased in absolute and relative terms, from 13.9% in 1991-92 to 37.9% in 1997-98. Over time, the mean blood loss and the allogeneic transfusion rate decreased steadily. There was a trend toward more favourable outcomes for pathological variables (an increased percentage of organ-confined disease, decreased margin positivity and a decreased incidence of positive lymph node metastasis). The most common complications were wound-related (7.5%), or anastomotic leakage (4.1%). Major cardiopulmonary complications occurred in only two patients (0.31%, both pulmonary embolisms). One patient died from cerebral haemorrhage within 30 days of surgery, giving a mortality rate of 0.16%. CONCLUSION: s This study indicates a trend towards selecting patients most likely to benefit from RRP. Although the procedure is technically demanding, it can have an acceptably low rate of early complications, little mortality and need for allogeneic transfusion. The assessment of morbidity suggests a lower incidence of catastrophic thrombo-embolic and cardiac complications in Japanese patients than in Western men. The present data may be useful in decision-analysis models evaluating the role of therapy for Asian men with early-stage prostate cancer.     

Cerebral metabolic impairment in patients with obstructive sleep apnoea: an independent association of obstructive sleep apnoea with white matter change

OBJECTIVES: To determine the relation between severity of obstructive sleep apnoea (OSA) and degree of cerebral metabolic impairment. METHODS: Fifty five patients with habitual snoring and excessive daytime sleepiness underwent standard overnight polysomnography and magnetic resonance spectroscopy separately. Proton MR spectra were measured with two dimensional chemical shift imaging (repetition time; 1500 ms, echo time; 135 ms). Severity of cerebral metabolic impairment was assessed by the N-acetylaspartate (NAA)/choline ratios for the cerebral cortex and white matter. Severity of OSA was assessed by the apnoea-hypopnoea index (AHI) and the minimum value of peripheral oxyhaemoglobin saturation. All patients were evaluated for the presence or absence of comobidities including hypertension, cardiac disease, diabetes mellitus, and hyperlipidaemia. Univariate analysis of variance (ANOVA) and mulitple linear regression analysis were used for statistical analyses. RESULTS: Univariate ANOVA disclosed significant effects of AHI, age, and the presence or absence of hypertension on the NAA/choline ratio for cerebral white matter (p=0.011, p=0.028, p=0.0496, respectively). The AHI had a significant negative association with the NAA/choline ratio for cerebral white matter, independent of age and the presence or absence of cardiac disease, in the final multivariate regression model (standardised partial regression coefficient=-0.417, p<0.001). No significant relation was found between severity of OSA and the NAA/choline ratio for the cerebral cortex. Age alone had a significant effect on the NAA/choline ratio for the cerebral cortex on univariate ANOVA (p<0.001) and a significant negative association with the NAA/choline ratio for the cerebral cortex in the regression model (r=-0.552, p<0.001). CONCLUSIONS: A significant relation exists between AHI and the degree of metabolic impairment in cerebral white matter in patients with OSA.     

Comparison of image reconstruction algorithms in myocardial perfusion scintigraphy

The purpose of this study was to compare the clinical utility of two image reconstruction algorithms in myocardial perfusion SPECT (single-photon emission computed tomography): filtered back-projection (FBP) and ordered subset expectation maximization (OSEM). A rest/stress one-day protocol with 99mTc-MIBI or tetrofosmin was performed on 102 consecutive patients who underwent coronary angiography. After SPECT data acquisition, images were reconstructed with FBP and OSEM algorithms. We assessed diagnostic performance (sensitivity, specificity and accuracy) in detecting coronary artery stenosis and evaluated regional tracer uptake with a 4-point scoring system. Although there were no significant differences in diagnostic performance between FBP and OSEM reconstruction, the OSEM method yielded higher uptake in the RCA area than the FBP method by reducing the count-loss artifact due to hepatic uptake of the tracers. In addition, regional uptake in the LCX area was significantly lower in the OSEM image than in the FBP image; this phenomenon was observed mainly in patients with coronary stenosis and/or infarction in the LCX territory. In conclusion, OSEM and FBP offered comparable diagnostic performance in stress myocardial perfusion SPECT. The OSEM method contributed to reduction of the count-loss artifact in inferior and posterior walls and to easy recognition of hypoperfusion in the LCX area.