Association of C-reactive protein with efficacy of avelumab plus axitinib in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed. RESULTS: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib. CONCLUSIONS: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib.

Comparison of efficacy of pitavastatin and colestimide in Japanese patients with diabetes mellitus complicated by hyperlipidemia and metabolic syndrome.

The present study was undertaken to compare the efficacy of pitavastatin and colestimide in patients with diabetes mellitus complicated by hyperlipidemia and metabolic syndrome. 48 diabetic patients with metabolic syndrome were randomly assigned to a pitavastatin group or colestimide group. The clinical parameters, serum lipids, fasting (FPG) and postprandial plasma glucose(PPG), HOMA-IR, hemoglobin A1c(HbA1c), hs-CRP and urinary albumin were measured before/after 24-week administration. Treatment with pitavastatin reduced LDL-C and TG, while that with colestimide significantly reduced waist circumference, BMI, LDL-C, HbA1c, FPG, PPG, HOMA-R , hs-CRP and urinary albumin. Percent improvement in LDL-C was greater in the pitavastatin group than in the colestimide group. Colestimide appeared to be useful in the management of Japanese patients with diabetes mellitus complicated by metabolic syndrome, since it alleviates obesity and insulin resistance in addition to exhibiting lipid profile-improving effects, and can thus improve markers of atherosclerosis.

Enhancement of osteoclastogenic activity in osteolytic prostate cancer cells by physical contact with osteoblasts.

BACKGROUND: The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood. METHODS: Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay. RESULTS: When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA. CONCLUSION: Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.

The incidence and mechanism of sunitinib-induced thyroid atrophy in patients with metastatic renal cell carcinoma.

BACKGROUND: To elucidate the incidence and mechanisms of sunitinib-induced thyroid atrophy, we investigated serial volumetric and functional changes, and evaluated histological changes of the thyroid gland in metastatic renal cell carcinoma patients who received sunitinib. METHODS: Thyroid volume (by computed tomography volumetry) and thyroid function were measured at baseline, during the treatment, and at post-treatment periods. Histological evaluation of the thyroid gland was performed in four autopsied patients. RESULTS: The median reduction rate in thyroid volume at last evaluation during sunitinib treatment was 30% in all 17 patients. The incidence of hypothyroidism during sunitinib treatment was significantly higher in the high reduction rate group (n=8; more than 50% reduction in volume) than in the low reduction rate group (n=9; less than 50% reduction in volume). Half of the patients in the high reduction rate group exhibited a transient thyroid-stimulating hormone suppression, suggesting thyrotoxicosis during sunitinib treatment. Histological evaluation demonstrated atrophy of thyroid follicles and degeneration of follicular epithelial cells without critical diminution of vascular volume in the thyroid gland. CONCLUSION: Thyroid atrophy is frequently observed following sunitinib treatment and may be brought about by sunitinib-induced thyrotoxicosis or the direct effects of sunitinib that lead to degeneration of thyroid follicular cells.

Effects of exposure to a mobile phone on sexual behavior in adult male rabbit: an observational study.

The accumulating effects of exposure to electromagnetic radiation emitted by a conventional mobile phone (MP) on male sexual behaviour have not yet been analyzed. Therefore, we studied these effects in 18 male rabbits that were randomly divided into phone and control groups. Six female teasers were taken successively to the male's cage and the copulatory behavior was recorded. Serum total testosterone, dopamine and cortisol were evaluated. The animals of the phone group were exposed to MPs (800 MHz) in a standby position for 8 h daily for 12 weeks. At the end of the study, the copulatory behavior and hormonal assays were re-evaluated. Mounts without ejaculation were the main mounts in the phone group and its duration and frequency increased significantly compared with the controls, whereas the reverse was observed in its mounts with ejaculation. Ejaculation frequency dropped significantly, biting/grasping against teasers increased notably and mounting latency in accumulated means from the first to the fourth teasers were noted in the phone group. The hormonal assays did not show any significant differences between the study groups. Therefore, the pulsed radiofrequency emitted by a conventional MP, which was kept on a standby position, could affect the sexual behavior in the rabbit.

Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome.

The aim of this study was to determine whether a relatively low dose of pioglitazone or metformin was effective in diabetic patients with metabolic syndrome. Fifty diabetic patients with metabolic syndrome were randomly assigned to a low-dose pioglitazone (15 mg/day) treatment group or a low-dose metformin (500 mg/day) treatment group. Drugs were administered for 12 weeks. Systolic and diastolic blood pressure, heart rate, body mass index, triglyceride (TG), HDL and LDL-cholesterol, fasting plasma glucose (FPG), fasting plasma insulin (IRI), postprandial glucose, and HOMA-IR in the 75gOGTT, HbA1c, high-sensitivity CRP (hs-CRP) determined by cervical artery echography, and pulse wave velocity (PWV) were measured before/after 12-week drug administration. Significant decreases in HbA1c and HOMA-IR were noted in the pioglitazone group, along with significant decreases in TG, AST, ALT, blood pressure, hs-CRP and PWV. Significant decreases in HbA1c, HOMA-IR, BMI and waist circumference were noted in the metformin group. The pioglitazone group significantly improved the values for ALT, systolic blood pressure, hs-CRP and PWV compared to the metformin group. However, the metformin group demonstrated significant improvement in BMI compared with the pioglitazone group. Using a low dose regimen, pioglitazone significantly improved blood pressure and hepatic function and may be more effective than metformin to reduce risk factors in Japanese diabetic patients with metabolic syndrome at preventing atherosclerosis.

Laparoscopy for impalpable testis: classification-based management.

BACKGROUND: The undescended testis represents one of the most common disorders of childhood. The authors evaluated the safety and efficacy of laparoscopy for the abdominal testis and present a classification of the laparoscopic diagnostic findings to facilitate decision making. METHODS: Between 2000 and 2005, 95 patients (22 bilateral and 73 unilateral testes, for a total of 117 impalpable testes) with a mean age of 5 years underwent laparoscopy. The testis was managed according to a special classification of the diagnostic findings. Testicular position, size, and viability according to technetium-99m ((99m)Tc) were assessed during the follow-up evaluation. RESULTS: The laparoscopic findings were classified into six types: type 0 (no testis or vanished testis proximal to the internal ring; 9 patients [7.5%]); type 1 (atrophic intracanalicular testis; 6 patients [5.4%], for whom no further intervention was administered); type 2 (testis at the internal ring with looping vas; 15 patients [14.5%], for whom laparoscopic orchiopexy was performed); type 3 (testis at the internal ring without looping of the vas; 29 patients [24.7%], for whom laparoscopic orchiopexy also was performed; type 4 (high abdominal testes; 49 patients [41.9%], with Staged Fowler-Stephens orchiopexy performed for 47 testes and laparoscopic orchidectomy for 2 testes; and type 5 (persistence of Müllerian duct structures [PMDS] or other abnormalities; 7 testes [6%]). After a mean follow-up period of 3 years, the laparoscopic orchiopexy testes were of good size and viable, but four testes (8.7%) were at the neck of the scrotum. The laparoscopically staged Fowler-Stephens orchiopexy group showed atrophy in two testes (4.3%), and all were in the bottom of the scrotum. CONCLUSIONS: Classification of the laparoscopic findings facilitates decision making. Laparoscopic orchiopexy is a natural extension of diagnostic laparoscopy for the intraabdominal testis at the internal ring or that seen peeping from it. Laparoscopically staged Fowler-Stephens orchiopexy is the procedure of choice for the high intraabdominal testis not amenable to the one-stage procedure.

cDNA microarray analysis assists in diagnosis of malignant intrarenal pheochromocytoma originally masquerading as a renal cell carcinoma.

Intrarenal pheochromocytoma (paraganglioma) is a very rare tumour. Its diagnosis is often difficult to establish because of its rarity and its histological similarity to renal cell carcinoma (RCC). Recently, we examined the molecular signatures of different subtypes of kidney tumours by using cDNA microarray. The signature pattern for one tumour, which was originally diagnosed as granular cell RCC, was clearly distinct from that of any other subtype of kidney tumour, and led us to re-evaluate the case. Haematoxylin and eosin staining revealed histological features suggestive of pheochromocytoma, and immunohistochemical studies showed positive staining for neuroendocrine markers but not for keratin. A germline missense mutation, D119E, in the familial paraganglioma related gene succinate dehydrogenase subunit D (SDHD), was subsequently identified. The treatment modality was revised and radiotherapy was given, to which the patient responded, leading to a reduction in tumour size of 25% within the first month. To our knowledge, this is the first report of an intrarenal pheochromocytoma that was diagnosed with the assistance of cDNA microarray analysis.

Expression of a splice variant of choline acetyltransferase in magnocellular neurons of the tuberomammillary nucleus of rat.

A splice variant of choline acetyltransferase mRNA has recently been identified in the pterygopalatine ganglion of rat. An antibody against this variant protein (designated pChAT) was demonstrated to immunolabel peripheral cholinergic neurons. In the present study, we investigated the expression of pChAT in rat brain. Amongst the brain regions examined, magnocellular neurons in the tuberomammillary nucleus of the posterior hypothalamus were immunohistochemically labelled with anti-pChAT antibody, whilst no immunolabelling was detected in cholinergic neurons in the basal forebrain or striatum. RT-PCR analysis confirmed the expression of pChAT mRNA in the posterior hypothalamus. The distribution of pChAT-positive neurons in the tuberomammillary nucleus was compared with that of neurons positive for adenosine deaminase, which is contained in all neurons of this nucleus. After colchicine treatment to inhibit axonal transport of enzyme, virtually all pChAT-positive cells contained adenosine deaminase. Conversely, about 85% of adenosine deaminase-positive cells contained pChAT in the ventral area, whilst 19% of adenosine deaminase-positive cells were pChAT-positive in the dorsal area. Long axonal projections of pChAT-positive cells in the tuberomammillary nucleus were shown by retrograde labelling of these cells after injection of cholera-toxin B subunit into the cerebral cortex. This study demonstrates that a splice variant of choline acetyltransferase is expressed in the tuberomammillary nucleus of rat. The results raise the possibility that some of the known diverse projection areas of this nucleus may have a cholinergic component.

Analysis of the gene expression of SPARC and its prognostic value for bladder cancer.

PURPOSE: We analyzed the gene expression of the glycoprotein termed secreted protein, acidic and rich in cysteine (SPARC), also called osteonectin and BM40, in bladder cancer and its relationship with conventional clinical-histopathological manifestations, evaluated its prognostic value for patient outcome and determined the possible mechanism underlying the effect of SPARC on bladder cancer progression. MATERIALS AND METHODS: Tissue samples from 63 patients with bladder cancer were used for analysis. Gene expression levels of SPARC and matrix metalloproteinase-2 were analyzed using reverse transcription-polymerase chain reaction. Correlations of the expression of SPARC with histopathological findings or patient outcome and with matrix metalloproteinase-2 were evaluated. RESULTS: Significantly higher expression of SPARC was observed in grades 3 and 2 than in grade 1 tumors (p <0.001 and <0.05, respectively). Stage T2 or greater invasive tumors expressed a significantly higher level of SPARC than stages T1 or less superficial tumors (p <0.0001). Patients in whom the lesions showed high SPARC expression had a significantly worse prognosis than those with low SPARC expression disease (p <0.0001). Even in those with invasive bladder cancer high SPARC expression was associated with significantly worse survival than low expression (p <0.01). Moreover, gene expression of SPARC significantly correlated with matrix metalloproteinase-2 gene expression (p <0.0001), implying that regulation of matrix metalloproteinase-2 expression may be a possible mechanism underlying the effect of SPARC on bladder cancer progression. CONCLUSIONS: A significant correlation was detected of the gene expression level of SPARC with histological grade, pathological stage and bladder cancer prognosis. SPARC may have an important role in bladder cancer progression and provide some additional information in patients with bladder cancer.

Prognostic significance of immuno-proteosome subunit expression in patients with renal-cell carcinoma: a preliminary study.

Our purpose was to elucidate the clinical roles of the "immuno-proteosome," which is involved in the accelerated pathway of the major histocompatibility complex (MHC) class I-restricted antigen presentation system, in renal cell carcinoma (RCC). The relative expression of six proteosome subunits (existing subunits X, Y, and Z and immunoproteosome subunits LMP7, LMP2, and MECL1) in 54 RCCs was investigated using RT-PCR analysis and was compared with clinicopathological measures, including patient outcome. Expression of the LMP7 and LMP2 genes was significantly low in high-grade tumors, and that of the LMP7 and MECL1 genes was significantly low in high-stage tumors. Low levels of LMP7, LMP2, and MECL1 expression were strongly associated with shortened survival (LMP7: P = 0.0002, LMP2: P < 0.0001, MECL1: P < 0.0047). The levels of subunits X, Y, and Z had no significant correlation with those measures. These findings suggest that RCCs with low level of immuno-proteosome subunit expression have a disorder in their antigen-presentation system. As a consequence, they may escape from immune surveillance and worsen patient outcome.

[Ectopic prostatic tissue in retrotrigone of the bladder: a case report].

We herein report a case of ectopic prostatic tissue in the retrotrigone of the bladder. A 35-year-old man was referred to our hospital because of bladder tumor which was incidentally discovered on abdominal ultrasonography (US). US and computed tomography (CT) showed a tumor in the bladder wall 1.5 cm in diameter. Magnetic resonance imaging (MRI) revealed an invasive bladder tumor. Cystoscopy showed a non-papillary, wide-based tumor in the retrotrigone of the bladder. Transurethral resection of bladder tumor was carried out and pathological findings showed ectopic prostatic tissue. This is the 8th case of ectopic prostatic tissue in the Japanese literature.

[A case of tuberculosis of the prostate presenting as endoscopically cavitary change].

A 62-year-old man was admitted to our hospital with the chief complaint of terminal macroscopic hematuria. He had a history of left tuberculous epididymitis in 1994. On digital rectal examination, the prostate was found to be a normal size and slightly hard with no elasticity. Transcrectal ultrasound showed hypoechoic lesions in the peripheral zone. T1-weighted MRI demonstrated cavitary lesions and T2-weighted MRI demonstrated relatively low signal intensity in the same zone. Urethrography revealed various cystlike lesions in the prostatic urethra. Cystourethroscopy revealed cavitary change with many septa in the left lobe of the prostate. TUR-P was performed and histological findings of the specimen revealed tuberculosis of the prostate. The patient was treated with an antituberculous regimen of INH, RFP and EB.

Secondary amyloidosis of the bladder causing macroscopic hematuria.

Bladder involvement in amyloidosis is unusual. The case of an 80-year-old man with macroscopic hematuria caused by secondary amyloidosis of the bladder is described. Cystoscopic examination revealed only a diffuse edematous area and bleeding. No tumor-like lesions were identified. Transurethral biopsy revealed amyloid deposits. Macroscopic hematuria disappeared spontaneously after cystoscopy and bladder biopsy. The patient has been followed up without treatment and is currently free of symptoms.

The apolipoprotein E genotype influences the risk for vasospastic angina.

It has been suggested that people with the epsilon4 allele of the apolipoprotein E (apoE) polymorphism and the deletion (D) allele of the insertion (I/D) polymorphism of angiotensin-converting enzymes, are at a greater risk for coronary artery disease. However, only a few studies have examined the relationships between vasospastic angina (VSA) and genotype, especially with the apoE polymorphism. In the present study, 76 patients with VSA without significant fixed coronary artery stenosis, 149 patients with ischemic heart disease (IHD) who had 75% or more luminal diameter narrowing and 213 healthy subjects were enrolled. The odds ratio for VSA of the epsilon4 allele carriers relative to the epsilon3/3 allele subjects compared with subjects with IHD and control subjects combined was 0.44 (95% CI 0.21 to 0.93, P=0.021), and that compared with control subjects alone was 0.36 (95% CI 0.17 to 0.78, P=0.005), implying that the presence of the epsilon4 allele indicates resistance to the development of VSA. In contrast, people with the epsilon2 allele showed a tendency to develop VSA more frequently than did patients with IHD (P=0.009), although the frequency of the epsilon2 allele did not differ between patients with VSA and control subjects. On the other hand, no recessive and dominant effects of the D alleles on VSA were found. These findings suggest that the risk of the occurrence of VSA may be reduced by the epsilon4 allele and increased by the epsilon2 allele. The ApoE polymorphism may be associated with IHD and VSA, probably due to the modulation of lipid metabolism.

Matrix metalloproteinases and bladder cancer.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes which degrade the extracellular matrix or components of the basement membrane. They have essential roles in tumor invasion and metastasis. In bladder cancer, elevated MMP-2 and MMP-9 expression in tumor tissues, correlated with tumor stage, grade or prognosis, were reported in several studies. Moreover, high levels of serum or urine MMP and TIMP were observed in patients with bladder cancer especially in advanced cases. However, the true roles of MMPs and TIMPs in bladder cancer progression are not yet clarified. Here, we discuss the roles and clinical implications of MMPs in bladder cancer.

Expression of vascular endothelial growth factor isoforms and platelet-derived endothelial cell growth factor in bladder cancer.

We analyzed the expression of vascular endothelial growth factor (VEGF) messenger ribonucleic acid (mRNA) isoforms and platelet-derived endothelial cell growth factor (PDECGF) mRNA in bladder cancer. We also attempted to determine if correlation exists between their expression level and conventional clinical variables in patients with bladder cancer. Tissues obtained from 60 patients with bladder carcinoma were used for analysis. Expression levels of VEGF isoforms and PDECGF were examined using reverse transcription-polymerase chain reaction (RT-PCR). Correlations between the expression levels of each VEGF isoform and PDECGF and histopathologic findings were evaluated. Four VEGF isoforms corresponding to VEGF121, 165, 189, and 206 were detected in bladder cancer tissue by RT-PCR. Gene expression of all VEGF isoforms as a ratio of the target to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) showed no correlation with pathologic stage of bladder cancer. However, with regard to relative expression levels of VEGF isoform, which is the ratio to the sum of total VEGF isoforms, the levels of VEGF206 and VEGF189 in tumor samples of grade pT2 or higher were significantly lower than those in tumors of grade pT1 or lower (P<.05). In contrast, the levels of VEGF121 in >/=pT2 tumors tended to be higher than those in

[Analysis of serum soluble interferon alpha/beta receptor levels in patients with urological diseases].

PURPOSE: In order to define the clinical significance of serum soluble Interferon alpha/beta receptor (sIFN alpha/beta R) levels, we determined sIFN alpha/beta R concentrations in serum of patients with urological benign and malignant diseases. MATERIALS AND METHODS: Serum sIFN alpha/beta R levels were measured in normal control (n = 22), patients with benign diseases (n = 50) included urolithiasis (n = 16), prostatic hypertrophy (n = 13), and malignant diseases included bladder cancer (n = 49), renal cell carcinoma (n = 30) and prostate cancer (n = 36) by the enzyme linked immunosolbent assay (ELISA) using monoclonal and polyclonal antibodies. The levels of serum sIFN alpha/beta R was correlated with the results of other hematoserological examinations, and clinical or pathological characters of each urological malignancies. RESULTS: The serum sIFN alpha/beta R levels (pg/ml) of patients with urolithiasis (2,370.6 +/- 640.6, p = 0.0002), benign prostatic hypertrophy (2,121.1 +/- 550.6, p = 0.0103), bladder cancer (2,512.3 +/- 1,012.3, p = 0.0006), renal cell carcinoma (2,686.4 +/- 1,510.9, p = 0.0046), prostate cancer (3,188.7 +/- 1,788.0, p = 0.0003) showed significantly higher values than those of controls (1,709.5 +/- 346.7). Moreover, we found statistically significant correlations among serum creatinine (Cr) levels and sIFN alpha/beta R levels. However, there were no correlations between the sIFN alpha/beta R levels and clinical stage, or histological grade in the patients with bladder cancer or prostate cancer, whenever the levels of sIFN alpha/beta R were corrected by serum Cr levels. On the other hand, high level of corrected serum sIFN alpha/beta R was observed in patients with high stage or high grade renal cell carcinoma, but not significant statistically. CONCLUSIONS: Elevated serum sIFN alpha/beta R was observed in patients with urological disease. Further examinations should be necessary to determine the clinical usefulness of serum sIFN alpha/beta R.

The role of the activated form of matrix metalloproteinase-2 in urothelial cancer.

OBJECTIVE: To investigate the expression of matrix metalloproteinase-2 (MMP-2, reportedly associated with cancer cell invasion and metastasis in many human cancers) in urothelial tumours and thus define its role in this disease. Materials and methods The expression of both the activated form of MMP-2 and total MMP-2 (activated + latent form) was measured using gelatine zymography in tissue obtained surgically from 61 patients with urothelial cancer. The correlation between the level of the activated form of MMP-2 and clinical and histological variables was assessed. RESULTS: The expression of activated and total MMP-2 were significantly higher in invasive tumour tissue and both levels were correlated with histological grade. In particular, the level of activated MMP-2 was more closely correlated than that of total MMP-2 in invasive tumour tissue. Moreover, high levels of activated MMP-2 were strongly associated with shorter disease-specific survival (P = 0.0016). CONCLUSION: These findings suggest that activated MMP-2 plays a significant role in invasion of urothelial cancer and that the level of activated MMP-2 expression is a useful prognostic indicator.

Primary pulmonary hypertension with central sleep apnea: sudden death after bilevel positive airway pressure therapy.

An obese 23-year-old man with sleep-disordered breathing and primary pulmonary hypertension (PPH) had been administered oral beraprost sodium, anticoagulant warfarin, and home oxygen therapy, at another hospital as treatment for the PPH, but he had not experienced any symptomatic improvement. The patient had a body mass index of 32.4kg/m2, and complained of fatigue, shortness of breath on exertion, excessive daytime sleepiness, and snoring. Arterial blood gas analysis showed a PaO2 and a PaCO2 of 70.9 and 31.2mmHg, respectively. A polysomnographic study revealed central sleep apnea with an apnea-hypopnea index (AHI) of 29.7episodes/h. The patient showed improvement of daytime sleepiness after starting nocturnal nasal bilevel positive airway pressure (BiPAP) therapy for the central sleep apnea, but his pulmonary hypertension, measured in the daytime, worsened. The patient died suddenly while walking to the bathroom in the morning 1 month after initiation of BiPAP therapy. It is necessary to consider the possibility of sudden death when nasal BiPAP therapy is given to a PPH patient with central sleep apnea.