Estimation of post-therapeutic liver reserve capacity using 99mTc-GSA scintigraphy prior to carbon-ion radiotherapy for liver tumors.

BACKGROUND: There is currently no established imaging method for assessing liver reserve capacity prior to carbon-ion radiotherapy (CIRT) for liver tumors. In order to perform safe CIRT, it is essential to estimate the post-therapeutic residual reserve capacity of the liver. PURPOSE: To evaluate the ability of pre-treatment 99mTc-galactosyl human serum albumin (99mTc-GSA) scintigraphy to accurately estimate the residual liver reserve capacity in patients treated with CIRT for liver tumors. MATERIALS AND METHODS: This retrospective study evaluated patients who were performed CIRT for liver tumors between December 2018 and September 2020 and underwent 99mTc-GSA scintigraphy before and 3 months after CIRT, and gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI within 1 month before CIRT were evaluated. The maximal removal rate of 99mTc-GSA (GSA-Rmax) was analyzed for the evaluation of pre-treatment liver reserve capacity. Then, the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using liver SPECT images fused with the Gd-EOB-DTPA-enhanced MRI. GSA-RL before CIRT and GSA-Rmax at 3 months after CIRT were compared using non-parametric Wilcoxon signed-rank test and linear regression analysis. RESULTS: Overall, 50 patients were included (mean age ± standard deviation, 73 years ± 11; range, 29-89 years, 35 men). The median GSA-RL was 0.393 [range, 0.057-0.729] mg/min, and the median GSA-Rmax after CIRT was 0.369 [range, 0.037-0.780] mg/min (P = .40). The linear regression equation representing the relationship between the GSA-RL and GSA-Rmax after CIRT was y = 0.05 + 0.84x (R2 = 0.67, P < .0001). There was a linear relationship between the estimated and actual post-treatment values for all patients, as well as in the group with impaired liver reserve capacity (y = - 0.02 + 1.09x (R2 = 0.62, P = .0005)). CONCLUSIONS: 99mTc-GSA scintigraphy has potential clinical utility for estimating the residual liver reserve capacity in patients undergoing carbon-ion radiotherapy for liver tumors. TRIAL REGISTRATION: UMIN000038328, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043545 .

Prevalence of sarcopenia in Japanese women with osteopenia and osteoporosis.

Sarcopenia and osteoporosis are both significant health burdens among postmenopausal women. This study examined associations between sarcopenia and osteopenia/osteoporosis in Japanese women and evaluated the prevalence of sarcopenia in women with osteopenia and osteoporosis. A total of 2400 Japanese women aged 40-88 years underwent dual-energy x-ray absorptiometry (DXA) scans of the whole body, lumbar spine, and total hip. Osteopenia and osteoporosis were defined according to World Health Organization criteria using bone mineral density (BMD) of the lumbar spine or hip. Sarcopenia was defined as a relative skeletal muscle index (RSMI) more than 2 standard deviations below the mean for a young adult reference population, calculated as the appendicular skeletal muscle mass (ASM) obtained from whole-body DXA divided by height in meters squared (RSMI = ASM/height(2)). Significant and marginal/moderate positive correlations were observed between RSMI and lumbar spine/total hip BMDs (r = 0.197 and r = 0.274, respectively; p < 0.0001 each). The BMDs of the lumbar spine and total hip showed significant moderate negative correlations with age (r = -0.270 and r = -0.375, respectively; p < 0.0001 each), but RSMI showed no association with age in this population (r = 0.056). When osteopenia/osteoporosis was defined using lumbar spine BMD, prevalences of sarcopenia in subjects with normal BMD, osteopenia and osteoporosis were 10.4, 16.8, and 20.4 %, respectively. When osteopenia/osteoporosis was defined using total hip BMD, the prevalences of sarcopenia in these subjects were 9.0, 17.8, and 29.7 %, respectively. A Chi-square test for independence showed a significant association between sarcopenia and osteopenia/osteoporosis (p < 0.0001). These results indicate that sarcopenia is significantly associated with osteopenia and osteoporosis in Japanese women.

An ultra-high speed Whole Slide Image viewing system.

BACKGROUND: One of the goals for a Whole Slide Imaging (WSI) system is implementation in the clinical practice of pathology. One of the unresolved problems in accomplishing this goal is the speed of the entire process, i.e., from viewing the slides through making the final diagnosis. Most users are not satisfied with the correct viewing speeds of available systems. We have evaluated a new WSI viewing station and tool that focuses on speed. METHOD: A prototype WSI viewer based on PlayStation®3 with wireless controllers was evaluated at the Department of Pathology at MGH for the following reasons: 1. For the simulation of signing-out cases; 2. Enabling discussion at a consensus conference; and 3. Use at slide seminars during a Continuing Medical Education course. RESULTS: Pathologists were being able to use the system comfortably after 0-15 min training. There were no complaints regarding speed. Most pathologists were satisfied with the functionality, usability and speed of the system. The most difficult situation was simulating diagnostic sign-out. CONCLUSIONS: The preliminary results of adapting the Sony PlayStation®3 (PS3®) as an ultra-high speed WSI viewing system were promising. The achieved speed is consistent with what would be needed to use WSI in daily practice.

[Leiomyosarcoma of the scrotum].

A 31-year-old man visited another hospital with a chief complaint of a solid mass in the left scrotum. The diagnosis was a skin cancer of the scrotum, and he was referred to our hospital. We performed surgical resection of the mass, left testis, and bilateral superfical inguinal nodes. Histopathological findings revealed leiomyosarcoma of the scrotum. He is free of disease at 16 months after the operation.

Hierarchical Elemental Odor Coding for Fine Discrimination Between Enantiomer Odors or Cancer-Characteristic Odors.

Odors trigger various emotional responses such as fear of predator odors, aversion to disease or cancer odors, attraction to male/female odors, and appetitive behavior to delicious food odors. Odor information processing for fine odor discrimination, however, has remained difficult to address. The olfaction and color vision share common features that G protein-coupled receptors are the remote sensors. As different orange colors can be discriminated by distinct intensity ratios of elemental colors, such as yellow and red, odors are likely perceived as multiple elemental odors hierarchically that the intensities of elemental odors are in order of dominance. For example, in a mixture of rose and fox-unique predator odors, robust rose odor alleviates the fear of mice to predator odors. Moreover, although occult blood odor is stronger than bladder cancer-characteristic odor in urine samples, sniffer mice can discriminate bladder cancer odor in occult blood-positive urine samples. In forced-choice odor discrimination tasks for pairs of enantiomers or pairs of body odors vs. cancer-induced body odor disorders, sniffer mice discriminated against learned olfactory cues in a wide range of concentrations, where correct choice rates decreased in the Fechner's law, as perceptual ambiguity increased. In this mini-review, we summarize the current knowledge of how the olfactory system encodes and hierarchically decodes multiple elemental odors to control odor-driven behaviors.

Impact of appendicular and trunk skeletal muscle mass and back extensor strength on sagittal spinal alignment in Japanese women without vertebral fracture.

OBJECTIVES: Progressive and generalized loss of skeletal muscle mass (SMM) and strength are characteristics of sarcopenia. However, the impact of appendicular and trunk SMM and back extensor strength (BES) on spinal sagittal alignment remains unclear. Herein, we investigate the relationship between these factors and spinal sagittal alignment. METHODS: In total, 202 women without vertebral fractures (median age, 66.9 years; interquartile range, 61.4-71.9 years) were analyzed at an orthopedic outpatient clinic. Pelvic incidence (PI), lumbar lordosis (LL), sagittal vertical axis (SVA), and pelvic tilt (PT) were measured on whole spine radiographs. Body mass index (BMI), appendicular and trunk relative SMM index, and BES were also evaluated. These measurements were compared between spinal sagittal alignment groups using the Mann-Whitney U test. Finally, the factors contributing to abnormal alignment were analyzed using multiple logistic regression analysis. RESULTS: BES was significantly lower in all abnormal sagittal alignment groups, as defined by PI-LL (≥ 10°), SVA (≥4 cm), and PT (≥20°) (all P < 0.001). On multivariate analysis, BES was a contributing factor for abnormal PI-LL (P < 0.001), SVA (P = 0.001), and PT (P < 0.001). Conversely, a decrease in appendicular and trunk relative SMM index did not statistically affect abnormal spinal sagittal alignment. CONCLUSIONS: BES was associated with changes in spinal sagittal alignment; however, SMM, which is often used for diagnosing sarcopenia, did not affect spinal sagittal alignment.

Enhancement of the sensitivity of renal cell carcinoma cells to fas-mediated cytotoxicity and apoptosis by the selective cyclooxygenase-2 inhibitor JTE-522.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the production of prostaglandins and its inhibitors have been shown to induce apoptosis in a variety of cancer cells. We reasoned that combination treatment of renal cell carcinoma (RCC) cells with COX-2 inhibitors and anticancer agents may result in synergistic apoptosis. We examined whether the selective COX-2 inhibitor JTE-522 synergizes with anticancer agents in cytotoxicity and apoptosis against RCC cells. METHODS: The cytotoxicity of the selective COX-2 inhibitor JTE-522 and other anticancer agents against the RCC cell lines and the normal renal cell line was determined by the microculture tetrazolium dye assay. RESULTS: JTE-522 was cytotoxic against the Caki-1 RCC cell line. JTE-522 and anti-Fas monoclonal antibody (CH-11) exhibited a synergistic cytotoxic effect against Caki-1 cells. In contrast, JTE-522 in combination with 5-fluorouracil, adriamycin, cis-diamminedichloroplatinum, or interferon-alpha, all commonly used clinically, resulted in an additive cytotoxic effect. Synergy achieved in cytotoxicity with JTE-522 and CH-11 was shown to be due to apoptosis. CONCLUSIONS: The present study demonstrated that the selective COX-2 inhibitor JTE-522 had a cytotoxic effect on RCC and that synergistic cytotoxicity against RCC was obtained with JTE-522 in combination with anti-Fas monoclonal antibody. These results suggest that selective COX-2 inhibitors in combination with immunotherapy may be useful in treating patients with RCC.

Cancer death from non-muscle invasive bladder cancer: report of the Japanese Urological Association of data from the 1999-2001 registry in Japan.

OBJECTIVES: Our aim was to clarify the risk factors of cancer death in order to reduce mortality from T1 bladder cancer. METHODS: The Japan registration database (1999-2001) was used for the analysis. Data were collected at least 3years after the initial diagnosis. Cause-specific survival using a Kaplan-Meier survival estimation with the log-rank method was evaluated. Univariate and multivariate analysis using the Cox proportional hazard model was also carried out. The 1997 TNM classification was used for pathological staging, and the 1973 WHO classification was used for pathological grading. RESULTS: There were 76 cancer deaths among a total of 1919 clinical T1 cases. Regardless of the subsequent treatment strategies, non-papillary tumor appearance, non-peduncular tumor stalk, multiple tumors, a tumor size greater than 3cm, positive urinary cytology and pathological grade 3 were found to be statistically significant in cancer death by univariate analysis. By multivariate analysis, non-papillary tumor appearance, positive urinary cytology and a tumor size greater than 3cm were confirmed as significant risk factors. Cancer death cases were found in 47.4% of worst-grade 2 tumors, and in 67.1% of predominantly grade 1 or 2 tumors. CONCLUSION: Non-papillary tumor appearance, positive urinary cytology and a tumor size greater than 3cm should be included to enable the assessment of risk criteria in cancer death from T1 bladder cancer.

[Neuroendocrine differentiation in adenocarcinoma of the prostate during hormonal treatment : a case report].

A case of neuroendocrine (NE) differentiated prostate cancer is reported herein, which was progressed with NE differentiation during hormonal treatment in adenocarcinoma of the prostate. A 65-year-old man was admitted to our department with increased serum prostate specific antigen (PSA) (150 ng/ml). A prostate biopsy was performed and histological examinations indicated poorly differentiated adenocarcinoma with a Gleason score of 5 + 4 = 9. Further examinations showed metastases to systemic bones. The clinical stage was T3bN0M1b and hormonal therapy using leuprorelin was started. Eighteen months after hormonal therapy, the serum PSA level declined to 1.702 ng/ml. He subsequently experienced edema in his legs. Computed tomography (CT) demonstrated enlargement of the prostate and swelling of multiple pelvic lymph nodes. Immunohistochemical examination of a re-biopsy specimen revealed a neuroendocrine carcinoma. The neuron-specific enolase (NSE) level was 50.9 ng/ml. The treatment measure was changed from hormonal therapy to combination chemotherapy comprising cisplatin (CDDP) and irinotecan (CPT-11). Pelvic radiotherapy (50 Gy) was then performed. Two courses of the chemotherapy resulted in a great reduction of the tumor volume. However, he had liver metastases 3 months later. His condition worsened rapidly and he died at 8 months after definite diagnosis.

Validation set analysis to predict postoperative outcomes by technetium-99m galactosyl serum albumin scintigraphy for hepatectomy.

BACKGROUND: The indocyanine green retention rate at 15 min (ICGR15) is a gold standard parameter of liver function when deciding on the extent of hepatectomy. However, ICGR15 is influenced by several hepatic conditions. To evaluate auxiliary preoperative liver functional reserve, we examined the clinical significance of modified parameters by blood tests and technetium-99m galactosyl human serum albumin (Tc-GSA) scintigraphy. METHODS: We measured liver function parameters, including the hepatic uptake ratio (LHL15) and the blood pool clearance index (HH15) of Tc-GSA and their modified formulae [LHL/HH15, LHL minus HH15, and converted ICGR15 (cICGR15) from a preliminary study] in 229 patients, including 18 with biliary obstruction. RESULTS: The mean values of LHL15/HH15, LHL minus HH15, and cICGR15 were 1.646 ± 0.295, 0.347 ± 0.116, and 13.2 ± 5.3%, respectively. These parameters correlated significantly with other liver functions measured by blood tests except for the bilirubin level (P < 0.05) although the actual ICGR15 level correlated positively with the bilirubin level. The difference of ICGR15 (ICGR15 minus cICGR15) in patients with biliary obstruction tended to be higher in comparison with that in patients without biliary obstruction (P = 0.044). Values of LHL/HH15, LHL minus HH15, and the cICGR15 were not significantly associated with postoperative complications. CONCLUSION: The modified parameters of Tc-GSA were useful for evaluating hepatic function in patients with high bilirubinemia due to biliary obstruction. However, it remains difficult to establish a more reliable parameter as a standard hepatic function test instead of ICGR15.

Anti-gout agent allopurinol exerts cytotoxicity to human hormone-refractory prostate cancer cells in combination with tumor necrosis factor-related apoptosis-inducing ligand.

Allopurinol has been used for the treatment of gout and conditions associated with hyperuricemia for several decades. We explored the potential of allopurinol on cancer treatment. Allopurinol did not expose cytotoxicity as a single treatment in human hormone refractory prostate cancer cell lines, PC-3 and DU145. However, allopurinol drastically induced apoptosis of PC-3 and DU145 in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a promising candidate for anticancer agent but its efficacy is limited by the existence of resistant cancer cells. We examined the underlying mechanism by which allopurinol overcomes the resistance of prostate cancer cells to TRAIL. Allopurinol up-regulated the expression of a proapoptotic TRAIL receptor, death receptor 5 (DR5). Allopurinol increased DR5 protein, mRNA, and promoter activity. Using DR5 small interfering RNA (siRNA), we showed that allopurinol-mediated DR5 up-regulation contributed to the enhancement of TRAIL effect by allopurinol. Furthermore, we examined the mechanism of allopurinol-mediated DR5 up-regulation. DR5 promoter activity induced by allopurinol was diminished by a mutation of a CAAT/enhancer binding protein homologous protein (CHOP)-binding site. In addition, allopurinol also increased CHOP expression, suggesting that allopurinol induced DR5 expression via CHOP. Allopurinol possesses the activity of a xanthine oxidase (XO) inhibitor. We used XO siRNA instead of allopurinol. XO siRNA also up-regulated DR5 and CHOP expression and sensitized the prostate cancer cells to TRAIL-induced apoptosis. Here, we show the novel potential of allopurinol in cancer treatment and indicate that the combination of allopurinol with TRAIL is effective strategy to expand the TRAIL-mediated cancer therapy.

Recent advances in molecular targeted therapy for metastatic renal cell carcinoma.

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15-20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.

Post-chemotherapy nerve-sparing retroperitoneal lymph node dissection for advanced germ cell tumor.

OBJECTIVE: To report our experience with post-chemotherapy nerve-sparing retroperitoneal lymph node dissection (RPLND) for advanced germ cell tumor (GCT). METHODS: Between 1994 and 2008, 92 patients with advanced GCT underwent RPLND after multiple treatments with systemic chemotherapy at our institution. A nerve-sparing RPLND was carried out in 78 patients (84.8%; median age 32 years). Of them, 19 had a seminoma and 59 had a non-seminoma. RESULTS: Lumbar splanchnic nerves controlling ejaculatory function were macroscopically preserved during RPLND. Bilateral and unilateral lumbar splanchnic nerves were preserved in 40 patients and 38 patients, respectively. Sixty-five patients could be evaluated for ejaculation. Fifty-four patients (83.1%) achieved antegrade ejaculation with a median postoperative interval of 3 months (range: 1-10 months). Twenty-eight patients (28/30: 93.3%) and 26 patients (26/35: 74.3%) undergoing bilateral and unilateral nerve-sparing RPLND had antegrade ejaculation, respectively (P = 0.041). Only two patients (2.6%) had mediastinal and retroperitoneal recurrences during a median follow-up of 42 months (range: 1-138 months), respectively. However, these patients were cured by chemotherapy and surgery. CONCLUSIONS: Post-chemotherapy nerve-sparing RPLND preserves ejaculatory function in the majority of patients with advanced GCT without increasing the risk of local recurrence.

Bladder cancer develops 6 years earlier in current smokers: analysis of bladder cancer registry data collected by the cancer registration committee of the Japanese Urological Association.

OBJECTIVES: It is generally recognized that cigarette smoking is the most important risk factor for bladder cancer. The present study was undertaken to examine the relationships between smoking history of bladder cancer patients and the age of onset of bladder cancer and tumor characteristics. METHODS: The present study examined the data for 5959 cases (4728 males and 1231 females) collected in the bladder cancer database of the Japanese Urological Association from 1999 to 2001. Patients were divided by smoking history into three categories as current non-smokers, current smokers and unknown smoking history. Relationship between smoking history and the age at diagnosis of bladder cancer, gender, T stage, grade, tumor size, tumor number and initial symptoms was analyzed. RESULTS: In both males and females the onset of bladder cancer is about 6 years (6.1 years in males and 5.9 years in females) earlier for current smokers than for current non-smokers. At the time of diagnosis, tumor stage was significantly higher in the current smokers group. The current smokers group tended to have larger tumor size. CONCLUSIONS: The finding of 6-year-earlier onset of bladder cancer among current smokers is of great importance to both health care and medical economics. It is essential to make people better informed concerning the need to quit smoking.

Clinical outcome of tumor recurrence for Ta, T1 non-muscle invasive bladder cancer from the data on registered bladder cancer patients in Japan: 1999-2001 report from the Japanese Urological Association.

OBJECTIVE: To characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent transurethral bladder tumor resection with or without intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) therapy. METHODS: We developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes from a Japanese bladder cancer registry between 1999 and 2001 and identified a study population of 3237 consecutive patients who had complete data based on pathological features. Median patient age was 69.9 years. RESULTS: The 1-year, 3-year, and 5-year overall recurrence-free survival rates were 77.0%, 61.3%, and 52.8%, respectively. In multivariate analyses, the multiplicity of bladder tumors, tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Overall, 1710 patients (52.8%) received intravesical instillation; chemotherapy in 1314 (76.8%) and BCG treatment in 396 (23.2%). In patients treated with intravesical chemotherapy in which an anthracycline chemo-agent was used in 90.5% of the cases, multivariate analyses demonstrated that male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were associated with tumor recurrence. CONCLUSIONS: The accumulation and analysis of data from the Japanese National Bladder Cancer Registry made it possible to determine the clinical characteristics, management trends, and survival rates for the period studied. Further study with a dataset created from longer follow-up data would be warranted to analyze tumor progression and disease survival.

Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles.

One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.

Significance of the preoperative regional maximal removal rate of technetium-99m-galactosyl human serum albumin in the future remnant liver: a sequential study of regional maximal removal rate of technetium-99m-galactosyl human serum albumin in the whole liver.

BACKGROUND: The relationship between posthepatectomy complications and liver functional parameters was preliminary reported in a pilot study. The present study sequentially evaluated the clinical significance of maximal removal rate of technetium-99m-galactosyl human serum albumin (GSARmax) in the future remnant liver (rGSARmax) in patients to predict posthepatectomy complications. METHODS: Between 2010 and August 2017, GSARmax, rGSARmax, their difference (Dif), and the rGSARmax to GSARmax ratio were examined in 247 additional patients who underwent hepatectomy for liver and biliary diseases. Hepatectomy-related postoperative complications (i.e. long-term ascites, intra-abdominal infection, and hepatic failure) occurred in 73 (29.6%) patients. RESULTS: The median and mean preoperative GSARmax values were 0.477 and 0.498±0.166 mg/min, respectively; rGSARmax values were 0.341 and 0.366±0.145 mg/min, respectively; Dif values were 0.105 and 0.132±0.111 mg/min, respectively; and the rGSARmax to GSARmax ratio values were 0.774 and 0.746±0.177, respectively. Among these, the GSARmax and rGSARmax values were significantly correlated with the liver functional parameters ICGR15, LHL15, HH15, prothrombin activity, serum hyaluronic acid level, and platelet count (all P<0.01). The rGSARmax values were significantly lower in patients with long-term ascites (P<0.05), and the predictive cutoff values of rGSARmax were 0.290 mg/min; however, the multivariate logistic regression analysis showed that rGSARmax was not independently related to long-term ascites. CONCLUSION: When accompanied by other functional liver reserve parameters, rGSARmax seemed to be an alternative liver functional parameter related to ascites.

Significant antitumor activity of cationic multilamellar liposomes containing human interferon-beta gene in combination with 5-fluorouracil against human renal cell carcinoma.

Immunotherapy is one of the most effective treatments against metastatic renal cell carcinoma (RCC). However, the response rate is not high. Therefore, more effective therapies are necessary for patients with metastatic RCC. We previously reported on the significant antitumor activity of cationic multilamellar liposome containing human interferon-beta (huIFN-beta) gene (IAB-1) against RCC. We then examined the antitumor effect of IAB-1 in combination with anticancer drugs against RCC. The cytotoxicity of IAB-1 alone, and in combination with anticancer drugs, cisplatin, adriamycin, 5-fluorouracil, gemcitabine, paclitaxel and irinotecan hydrochloride against the human RCC cell line NC65 was examined by the colorimetric method using tetrazolium salt. For the in vivo study, we used NC65 cells inoculated into the severe combined immunodeficiency mouse. The results showed that the in vitro combination therapy with IAB-1 and 5-FU was more cytotoxic than IAB-1 alone. However, synergistic cytotoxicity was not observed when combined with IAB-1 and other anticancer drugs. NC65 tumors transfected with IAB-1 in mice were smaller than those receiving an injection of empty liposome or the recombinant huIFN-beta protein. Treatment with IAB-1 in combination with 5-FU resulted in significant anticancer activity. IAB-1 enhanced the activity of thymidine phosphorylase (TP), which converts 5-FU to the active metabolite, FdUMP. In contrast, IAB-1 decreased the activity of thymidylate synthase (TS), which is a target enzyme of 5-FU. In conclusion, these findings indicate that a combination of IAB-1 and 5-FU may have enhanced antitumor activity against human RCC, suggesting its potential clinical application. The mechanism of enhanced cytotoxicity by combination therapy with IAB-1 and 5-FU may up-regulate TP activity and down-regulate TS activity.

The growth-inhibitory effects of dexamethasone on renal cell carcinoma in vivo and in vitro.

BACKGROUND: Recently, several kinase inhibitors have been reported to exert stronger growth inhibitory effects on metastatic renal cell carcinomas (RCCs) than cytokines such as interferons (IFNs) and interleukin-2 (IL-2). On the contrary, the adverse effects of these drugs are also severe. The aim of this study is to analyze the growth-inhibitory effects of DEXamethasone (DEX) on RCC in vivo and in vitro. METHODS: The MTT assay was performed using three RCC cell lines, OUR-10, Caki-1, and NC65. OUR-10 cells were subcutaneously transplanted to the dorsal area of nude mice. The nuclear translocation of glucocorticoid receptor (GR) and NF-kappa B was examined using appropriate antibodies. Concentrations of interleukin-6 (IL-6), IL-8, and vascular endothelial cell growth factor (VEGF) in the conditioned media and cytosol were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: All three RCC cell lines responded to DEX treatment. The growth of OUR-10 xenografts was significantly inhibited by administration of DEX. GR was translocated into the nucleus on DEX treatment. Intracellular IL-6, as well as IL-6 in the conditioned medium, decreased in OUR-10 cells following treatment with increasing amounts of DEX. Concentrations of IL-8 and VEGF in the conditioned medium of OUR-10 and NC65 cells also decreased following DEX treatment, with the inhibition of nuclear translocation of NF-kappa B. CONCLUSION: DEX treatment is a candidate for advanced RCC therapy by inhibiting the activation of NF-kappa B and its downstream products such as IL-6, IL-8 and VEGF.

Expression of X-linked inhibitor of apoptosis protein is a strong predictor of human prostate cancer recurrence.

PURPOSE: The X-linked inhibitor of apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We examined the expression patterns of XIAP with regard to human prostate cancer, predicting that XIAP status may predict cancer recurrence and/or clinical outcome. EXPERIMENTAL DESIGN: Immunohistochemistry was done on tissue microarrays constructed from 226 primary prostate cancer specimen. The protein expression distribution was examined across the spectrum of epithelial tissues and its association with standard clinicopathologic covariates and tumor recurrence was examined in 192 outcome-informative patients. RESULTS: The mean XIAP expression was significantly higher in prostate cancer compared with prostatic intraepithelial neoplasia (PIN), normal, and benign prostatic hyperplasia. We observed that XIAP is an independent predictor of tumor recurrence in multivariate Cox proportional hazards analysis in all patients as well as after substratifying by Gleason score. Interestingly, patients with high XIAP levels had a much lower probability of tumor recurrence than those with lower XIAP expression. Even patients with high-grade tumors who had higher XIAP levels had a lower risk of recurrence compared with any patient whose tumors express lower XIAP. CONCLUSIONS: XIAP is expressed at higher levels in prostate cancers compared with matched normal tissues. High XIAP expression is strongly associated with a reduced risk of tumor recurrence and is not directly associated with Gleason score, tumor stage, capsular involvement, or preoperative prostate-specific antigen status, suggesting that it is a novel prognosticator and a potential target for prostate cancer diagnosis and therapy. Significantly, these findings provide important and extensive validation of previous results.