Efficacy and safety of systemic chemotherapy and intra-arterial chemotherapy with/without radiotherapy for bladder preservation or as neo-adjuvant therapy in patients with muscle-invasive bladder cancer: a single-centre study of 163 patients.

INTRODUCTION: Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear. MATERIALS AND METHODS: The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC + R, n = 79). RESULTS: Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC + R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC + R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC + R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%). CONCLUSIONS: IAC + R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy.

Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer.

Stromal cell-derived factor-1 (SDF-1)/CXCR4 interaction is critical for the trafficking of lymphocytes, homing and retention of hematopoietic stem cells within the bone marrow and is essential in fetal hematopoiesis. Binding of SDF-1 to CXCR4 activates a variety of intracellular signal transduction pathways and effector molecules that regulate cell survival, proliferation, chemotaxis, migration and adhesion. Recently, intensive research has demonstrated that SDF-1/CXCR4 interaction also regulates several key events in wide variety of cancers. Serum-depleted media in the presence of SDF-1 protected the breast cancer cells from apoptosis. CXCR4-low-expressing MCF-7 formed small tumor at inoculated site in SCID mice 8-9 weeks after inoculation while completely failed to metastasis into various organs. In contrast, CXCR4-high-expressing MDA-231 cells were most efficient in the formation of a large tumor and organ-metastasis within 3 weeks in SCID mice. This review briefly focuses on the role of SDF-1/CXCR4 interaction in tumor growth and metastasis of breast cancer cell both in vitro and in vivo.

Natural killer cells in breast cancer cell growth and metastasis in SCID mice.

Natural killer (NK) cell is an important component of the innate immune system and plays a central role in host defense against tumor and virus-infected cells. This review briefly summarizes the role of murine NK cells in tumor growth and metastasis of breast cancer cells in severe combined immunodeficiency (SCID) mice. Conventional SCID and NOD-SCID strains have been used to study for xenotransplantion of human tumors. SCID mice models of cancer mimic human diseases and have provided valuable information. However, these mice strains have some residual immunity such as NK cells that somewhat limit post-transplantation growth and metastasis of human xenografts. In contrast, NOD/SCID/gammac(null) (NOG) mice without common gamma-chain inoculated with breast cancer cells were most efficient in the formation of a large tumor and metastasis. NOG mouse strain without NK activity appears to be more promising as tool for xenotransplantion of human cancer. This new xenotransplant model is relevant and can be recommended for use in clarifying the mechanism of growth of cancer cells as well as for developing new therapeutic strategies against cancer.

Clinicopathological study of vesicoureteral reflux (VUR)-associated pyelonephritis in renal transplantation.

We retrospectively studied the occurrence of vesicoureteral reflux (VUR)-associated pyelonephritis using renal biopsies obtained from the transplanted kidneys, and correlated the histological changes with clinical parameters. Out of a total of 131 renal biopsies performed between 1990 and 2001 on renal transplant patients at the department of Urology of Nagasaki University Graduate School of Biomedical Sciences, 12 patients showed pyuria more than twice in a single year. Seven of these 12 patients were available for determining VUR by voiding cystourethrography (VCUG). Cystoureterography demonstrated VUR in three of seven studied patients with pyuria. A histopathological examination revealed dilatation of both proximal and distal tubules in renal biopsies of transplant patients with VUR, compared to renal biopsies of transplant patients without VUR, or non-transplanted patients with thin membrane disease. One of the patients with VUR showed advanced features of chronic pyelonephritis in four consecutive biopsies at different time points, suggesting a late stage of reflux nephropathy in the transplanted kidney. We conclude from our study that the occurrence of VUR-related pyelonephritis may be one of the important long-term complications in the survival of renal allografts.

Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats.

BACKGROUND: Ghrelin may stimulate gastric motility via the vagal nerve pathway. However, the mechanism of ghrelin-induced changes in gastrointestinal motility has not yet been clearly defined. The present study was designed to investigate whether ghrelin accelerates gastric emptying via capsaicin-sensitive afferent neurones and directly affects the enteric neuromuscular function. METHODS: Gastric emptying of nutrient solids was assessed after intravenous administration of saline or ghrelin in conscious rats. The effects of ghrelin on gastric emptying were also examined in rats pretreated with capsaicin. Gastric emptying and intestinal transit of non-caloric liquids were evaluated using 51Cr solution. The effects of ghrelin on spontaneous contractile activities of isolated strips from stomach and jejunum were also investigated and the influence of ghrelin on motor responses to carbachol and electrical field stimulation was examined. RESULTS: Ghrelin significantly accelerated gastric emptying of both nutrient solids and non-caloric liquids in conscious rats. The intestinal transit of non-caloric liquids was also enhanced by ghrelin. Pretreatment with capsaicin prevented the ghrelin-induced acceleration of gastric emptying of nutrient solids. Ghrelin did not modulate spontaneous and carbachol-induced contractions of strips of gastric body, gastric antrum and jejunum. However, electrical field stimulation-induced contractions were significantly enhanced by ghrelin in the gastric body. CONCLUSIONS: The results suggest that the stimulatory effects of ghrelin on gastric motility are mediated by direct stimulation of the enteric neural pathway and capsaicin-sensitive afferent neurones.

A comparative histological and morphometric study of vascular changes in idiopathic portal hypertension and alcoholic fibrosis/cirrhosis.

AIM: To examine the pathological changes of hepatic arteries in idiopathic portal hypertension (IPH) which is characterized by the obliteration of the intrahepatic portal vein branches and presinusoidal portal hypertension. METHODS AND RESULTS: Liver specimens (biopsied or surgically resected) from 20 patients with IPH, 20 patients with alcoholic fibrosis/cirrhosis (AF/C) and 20 histologically normal livers were used. The vascular lumina of arterial and venous vessels in portal tracts were morphometrically evaluated by an image analysis system. The ratio of portal venous luminal area to portal tract area (portal venous index) of IPH and that of AF/C were significantly reduced compared with normal liver. The portal venous index for IPH was significantly lower than that for AF/C. The ratio of hepatic arterial luminal area to portal tract area for AF/C was significantly higher than that in normal liver; however, that for IPH was similar to normal. The peribiliary vascular plexus was increased in AF/C but not in IPH. In AF/C, the number of mast cells and macrophages known to be the source of angiogenic substances was significantly increased in the portal tract compared with normal liver, while in IPH it was not increased. CONCLUSIONS: In AF/C, a reduction in portal venous lumen was associated with an increase of hepatic arterial lumen and of angiogenesis-related cells in portal tracts. However, such compensatory arterial changes were not evident in IPH, and this compensatory failure may be a feature of IPH.

Previous or occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma without hepatic fibrosis.

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.

Successful treatment of dissemination of hepatocellular carcinoma to the pleura and diaphragm after percutaneous liver biopsy.

BACKGROUND/AIM: Treatment for dissemination of hepatocellular carcinoma to the pleura and diaphragm following percutaneous needle biopsy has not been established. METHODS: The case of a 57-year-old man who underwent percutaneous needle biopsy for liver tumor is presented. RESULTS: Ten months after resection of the tumor (moderately differentiated hepatocellular carcinoma), masses in the right pleural cavity and on the diaphragm were detected by computed tomography. Resections of the masses with surrounding tissue and the diaphragm and wedge resection of the right lung were performed. A wide range of the pleura and the diaphragm was coagulated with an argon beam coagulator. The patient is in good health without recurrence 4 years after the operation. CONCLUSION: Aggressive surgical treatment should be considered for patients with dissemination of hepatocellular carcinoma by needle biopsy when the lesions are limited.

Analysis of inhibition by H89 of UCP1 gene expression and thermogenesis indicates protein kinase A mediation of beta(3)-adrenergic signalling rather than beta(3)-adrenoceptor antagonism by H89.

Although it has generally been assumed that protein kinase A (PKA) is essential for brown adipose tissue function, this has not as yet been clearly demonstrated. H89, an inhibitor of PKA, was used here to inhibit PKA activity. In cell extracts, it was confirmed that norepinephrine stimulated PKA activity, which was abolished by H89 treatment. In isolated brown adipocytes, H89 inhibited adrenergically induced thermogenesis (with an IC(50) of approx. 40 microM), and in cultured cells, adrenergically stimulated expression of the uncoupling protein-1 (UCP1) gene was abolished by H89 (full inhibition with 50 microM). However, H89 has been reported to be an adrenergic antagonist on beta(1)/beta(2)-adrenoceptors (AR). Although adrenergic stimulation of thermogenesis and UCP1 gene expression are mediated via beta(3)-ARs, it was deemed necessary to investigate whether H89 also had antagonistic potency on beta(3)-ARs. It was found that EC(50) values for beta(3)-AR-selective stimulation of cAMP production (with BRL-37344) in brown adipose tissue membrane fractions and in intact cells were not affected by H89. Similarly, the EC(50) of adrenergically stimulated oxygen consumption was not affected by H89. As H89 also abolished forskolin-induced UCP1 gene expression, and potentiated selective beta(3)-AR-induced cAMP production, H89 must be active downstream of cAMP. Thus, no antagonism of H89 on beta(3)-ARs could be detected. We conclude that H89 can be used as a pharmacological tool for elucidation of the involvement of PKA in cellular signalling processes regulated via beta(3)-ARs, and that the results are concordant with adrenergic stimulation of thermogenesis and UCP1 gene expression in brown adipocytes being mediated via a PKA-dependent pathway.

[Complex translocation (8;15;21) (q22;p12;q22) in a child with AML-M2 showing de novo appearance of the short form of AML1-MTG8 chimeric mRNA during the course].

A 4-year-old boy admitted with exophthalmos was diagnosed as having acute myeloblastic leukemia with maturation (AML-M2). Chromosomal analysis (G-banding) showed t(8;15;21). Fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), spectral karyotyping (SKY), and nucleolar organizer region (NOR) staining suggested that this complex translocation might have resulted from stepwise translocation, namely an initial translocation between chromosomes 8 and 21, followed by a second translocation between der(21) and chromosome 15, rather than the other possibility of clockwise translocation. During chemotherapy, RT-PCR demonstrated the short form of AML1-MTG8 mRNA, in addition to chimeric mRNA of the usual length. Sequence analysis revealed that this shorter chimeric mRNA had resulted from deletion of a 250-bp sequence at the 5' end of MTG8. A literature search failed to reveal any similar cases of t(8;21) AML-M2 associated with this deletion of chimeric mRNA.

Synchronized disappearance of serum HCV-RNA, anti-U1 RNP, anti-La/SS-B, and anti-Scl-70 in a patient with chronic hepatitis.

The authors report a rare case of chronic hepatitis in whom normalization of serum aminotransferases was associated with disappearance of serum hepatitic C virus (HCV)-ribonucleic acid (RNA), anti-U1 RNP, anti-La/SS-B, and anti-Scl-70 antibodies without treatment of interferon or corticosteroids. A 27-year-old Japanese woman was diagnosed with chronic hepatitis C, with positive anti-nuclear antibody, anti-U1 RNP, anti-La/SS-B, and anti-Scl-70 antibodies. Histopathologic examination of a liver biopsy specimen showed a periportal interface hepatitis with a predominantly lymphoplasmacytic necroinflammatory infiltrate and lobular hepatitis. After two-year treatment with ursodeoxycholic acid (UDCA), serum aminotransferases normalized and serum HCV-RNA, anti-U1 RNP, anti-La/SS-B, and anti-Scl-70 antibodies disappeared. It was unclear whether disappearance of HCV-RNA was spontaneous, due to some immunomodulating effects of UDCA, or other unknown mechanism, but host immune response may be associated with HCV elimination.

Prevention of hepatic and peritoneal metastases by the angiogenesis inhibitor fr-118487 after removal of growing tumor in mice.

We established a mouse rising dbl quote, left (low)primary tumor resection model" in which a transplanted tumor was resected after an orthotopic transplantation of colorectal cancer tissue to estimate the therapeutic effect of an angiogenesis inhibitor on metastasis. The angiogenesis inhibitor FR-118487 is a member of the fumagillin family. Here, 1 mg / kg / day of FR-118487 was subcutaneously administered to nude mice for 1 week, 2 weeks, or 4 weeks through an osmotic pump. Liver metastasis developed in 7 of 9 control mice, 2 of 6 mice that underwent the tumor resection 2 weeks after transplantation (early resection), and in all 7 of the mice that underwent the tumor resection 4 weeks after transplantation (late resection). In the short treatment trial, the FR-118487 administration immediately after the early resection completely inhibited both hepatic and peritoneal metastases, whereas its administration after the late resection had no effect on liver metastasis. In the prolonged treatment trial, inhibitory effects of prolonged treatment with FR-118487 on both hepatic and peritoneal metastases after the late resection were clearly demonstrated. The mice of the resection-alone group all died within 106 days after tumor inoculation, due to metastases of colon carcinoma. In contrast, half of the mice that underwent resection and then received antiangiogenic therapy were alive at the end of the observation period (160 days after transplantation). In conclusion, the combination of surgery and subsequent antiangiogenic therapy may be useful to prevent the distant metastasis of colorectal cancer and to improve the prognosis of patients with colorectal cancer.

Clinical features and treatment of hepatocellular carcinoma in eight patients older than eighty years of age.

BACKGROUND/AIMS: Most-hepatocellular carcinoma patients are between 40 and 60 years of age, but an increasing number of elderly patients with hepatocellular carcinoma is expected in the future because of the increase in life expectancy seen in many countries. Since elderly patients have a high incidence of comorbid illnesses, it should be useful to examine the clinical features of these patients to select the optimal management strategy for hepatocellular carcinoma. METHODOLOGY: A retrospective review of 111 patients with hepatocellular carcinoma was undertaken to examine the clinical features of 8 patients older than 80 years of age. RESULTS: In the 111 patients with hepatocellular carcinoma, the ratio of males to females was 81:30 and the peak incidence of hepatocellular carcinoma was noted in the seventh and eighth decades in males and females, respectively. Of these, 21 (19%) were type "B" [seropositive for hepatitis B surface antigen (HBsAg) and seronegative for antibody to the hepatitis C virus (anti-HCV)], 69 (62%) were type "C" (seronegative for HBsAg and seropositive for anti-HCV), 3 (3%) were type "B + C" (seropositive for both HBsAg and anti-HCV), and 18 (16%) were type "non-B non-C" (seronegative for both HBsAg and anti-HCV). The peak incidences of type "B" were in the sixth decade, whereas those of type "C" were in the seventh decade in both males and females. Patients with "non-B non-C" were common in their seventies. Of the 111 patients, 6 (5 males and 1 female) were older than 80 years at the time of diagnosis and 2 females became 80 years old during the course of follow-up of hepatocellular carcinoma. All but one of these patients were anti-HCV-positive, stage and clinical stage I or II according to the criteria defined by the Liver Cancer Study Group of Japan, and underwent transcatheter arterial embolization and/or transcatheter arterial infusion chemotherapy. Transcatheter arterial embolization/transcatheter arterial infusion or percutaneous ethanol injection therapy was well tolerated in these patients, and the outcome of these patients was good. However, concomitant underlying diseases other than liver diseases made it impossible or difficult to apply an aggressive management protocol for hepatocellular carcinoma in some patients. CONCLUSIONS: Our results suggest that the overall treatment of hepatocellular carcinoma in the elderly should be similar to that in younger patients, but may be restricted by the concomitant underlying diseases specific to advanced age.

Identification of novel first exons in Ad4BP/SF-1 (NR5A1) gene and their tissue- and species-specific usage.

It has been demonstrated that the mammalian Ad4BP/SF-1 (NR5A1) gene is regulated precisely in sex, tissue, and developmental stage specific manners. To clarify the complex transcriptional regulation, we investigated in the present study whether the gene transcription is regulated by multiple promoters accompanied by noncoding first exons. Novel first exons (Io and Ig) were identified downstream of the already identified exon Ia. Nucleotide sequences revealed that Ia and Ig exons were well conserved, whereas Io exon was less conserved among the mouse, rat, and human genes. Interestingly, the splice donor of the mouse and human Io and human Ig exons do not satisfy the consensus sequence. Transcripts containing Ia, Io, and Ig were detected in all rat tissues examined, while the transcript containing Io was undetectable in the corresponding tissues of mice. The lack of exon Io usage in the mouse was confirmed by transient transfection assays with cultured cells. Quantitative RT-PCR analysis revealed that the transcript containing Ig exon was the main product in the pituitary but significantly less in the spleen, suggesting that the regulation of Ad4BP/SF-1 gene transcription in the pituitary and spleen is distinct from that of other tissues. The above findings, together with the structural abnormality at the splice donor site, suggest that acquisition of the multiple first exons enables the Ad4BP/SF-1 gene to be regulated differentially in different animal species and in different tissues in the same animal.

Combination therapy with vascular endothelial growth factor neutralizing antibody and mitomycin C on human gastric cancer xenograft.

Antiangiogenic therapy has been proposed as a new strategy for the treatment of solid tumors. To enhance the therapeutic effect of antiangiogenic agents, combination with conventional anticancer therapy should be investigated. In the present study, we investigated the therapeutic effect of the combination of vascular endothelial growth factor neutralizing antibody (VEGF Ab) and mitomycin C (MMC) on MT-2, a human gastric cancer xenograft. When small pieces of MT-2 were transplanted orthotopically into 62 nude mice, liver metastasis developed 6 weeks after transplantation. The VEGF Ab (100 micro g / mouse) was administered i.p. in the VEGF Ab group (n = 14) and the combination group (n = 16) twice a week from day 10 after transplantation. MMC (2 mg / kg) was administered in the MMC group (n = 16) and the combination group (n = 16) on days 10, 17 and 24 after transplantation. Compared with the control group, in which saline solution was administered i.p., all three treatments inhibited tumor growth significantly and the effects of MMC and combination therapy were potent. Liver metastases were also inhibited significantly by the administration of VEGF Ab alone, MMC alone or combination therapy. Liver metastasis developed in 9 mice of the control group, 3 of the VEGF Ab group, and 4 of the MMC group, but no mice had liver metastasis in the combination therapy group. However a significant body weight loss and a decrease in spleen weight were observed in the MMC and combination groups, with no significant difference between the two groups. These results suggest that combination therapy with VEGF Ab and MMC may be a potent therapy for human gastric cancer.

Management of pancreatic arteriovenous malformation.

Pancreatic arteriovenous malformations (AVM), while extremely rare, are frequently complicated by gastrointestinal bleeding. The elimination of pancreatic AVM is difficult once portal hypertension has developed. We describe herein a patient with congenital AVM of the pancreatic head presenting with recurrent episodes of melena, in whom pylorus-preserving pancreatoduodenectomy provided a means of definitive management. We also review the literature and focus on the diagnostic and therapeutic approaches. Angiography is always necessary to facilitate tactics of treatment, even if diagnosis has been established by non-invasive imaging modalities. To obtain complete regression, total extirpation of the affected organ, or at least the involved portion, should be performed before this disease leads to the lethal complications of gastrointestinal bleeding and portal hypertension. Transcatheter arterial embolization is the only alternative treatment for the control of hemorrhage.