Difference in the Electromyographic Behavior of the Masticatory and Swallowing Muscles During Cued Versus Spontaneous Swallowing.

The risk of dysphagia and/or aspiration is determined using screening tests, such as the repeated saliva swallowing test and modified water swallowing test, which evaluate cued swallowing. However, humans masticate and swallow foods with various consistencies, forms, and amounts, without conscious awareness. Therefore, this study aimed to examine the difference in the behavior of masticatory and swallowing muscles during spontaneous versus cued swallowing through a series of mastication and swallowing processes by evaluating surface electromyogram (sEMG) signals. The effect of the consistency and amount of food on the behavior of these muscles was also investigated. The sEMG recordings of the masseter muscles and anterior belly of the digastric muscle for 12 subjects, and genioglossus muscle for 5 subjects were obtained. The genioglossus activity was recorded using custom-made ball electrodes. The test foods were cookies and tofu, in amounts of 2 g and 4 g. The normalized muscle activity (integrated EMG), duration of the muscle activity, initial activation timepoint of each muscle, and total duration of swallowing were compared among four conditions. The activity of each muscle was significantly higher during the swallowing of cookies than tofu, for 4 g vs 2 g, and for cued versus spontaneous swallowing. The duration of each muscle activity, initial activation timepoint, and total duration of swallowing were significantly longer for cookies versus tofu, for 4 g vs 2 g, and for spontaneous versus cued swallowing. These results suggest that the behavior of the masticatory and swallowing muscles is affected by cued swallowing and by the consistency and amount of food.

Na18F accumulates on the compressive side of peri-implant bone under immediate loading.

This study aimed to examine the dynamic change in bone metabolism by immediate loading in several sites around implants using high-resolution Na18F-PET scan. Two titanium implants (Ø 1.2 mm) were inserted parallel to each other in the right tibiae of Wistar rats (n = 4). The left tibia was set as control side. One day after insertion, closed coil springs of 4.0 N were attached to the expose superior portions of the implants to apply a continuous mechanical stress. The rats with fluorine-18 (18F) ion (5 mCi/rat) intravenously injected were scanned by PET scanner at 4, 7, 14, 28 days after load application. Round region of interests (ROIs) were set around the distal implant of the right tibia (loaded side) and same site (control) of the left tibia. Furthermore, four rectangular ROIs were set at the superior and inferior parts of traction side (mesial) and opposite side (distal) of the distal implant. Longitudinal dynamic changes in bone metabolism were evaluated by examination of the accumulation count of 18F ion at each ROI. The uptake values of ROIs (loaded side) initially increased until 7 days, and they gradually decreased from the peak level to the pre-loading level despite a static force being applied to the implants. In cancellous bone, the uptake values at the superior part of traction side and inferior part of opposite side showed significantly high value compared with those at other parts. In conclusion, immediate loading to the implant initially enhanced bone metabolism around it, especially at the part with compressive stress. Peri-implant bone metabolism varies according to different loading conditions.

Evaluation of peri-implant bone metabolism under immediate loading using high-resolution Na18F-PET.

OBJECTIVE: This study aimed to examine the influence of immediate loading on the dynamic changes of bone metabolism around dental implants using a high-resolution semiconductor sodium 18F-fluoride (Na18F)-PET. METHODS: Tibiae of 12 adult male rats were divided into 4 groups: immediate loading (IL), no loading (NL), bone defect (BD), and control (CTR). For the IL group, a 4.0-N load was applied continuously by two closed-coil springs attached between two implants in tibia. Each rat received an intravenous injection of Na18F and was scanned by high-resolution Na18F-PET at day 1 and then at weeks 1, 2, 3, 4, 5, 6, and 8 after surgery. Bone metabolism around the implant was evaluated by standardized uptake value (SUV), which indicates the outcome of Na18F accumulation. CT scanning was also performed, and PET and CT images were superposed to determine the anatomical orientation in PET images. RESULTS: Bone metabolism peaked at 7 days after surgery and then gradually decreased in all three test groups (IL, NL, and BD). SUVs of all three test groups were significantly higher than the baseline at 1, 2, 3, and 4 weeks after surgery, with SUVs in the IL group returning to baseline levels earlier than those in the NL and BD groups. CONCLUSIONS: Fluorine integrates preferentially with the initial low-calcified bone; thus, our results suggest that immediate loading promotes the calcification of the bone tissue in the early stage on peri-implant bone formation. CLINICAL RELEVANCE: Na18F-PET allows for an estimate of bone metabolism change around the implant.

Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer.

AIM: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. METHODS: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. RESULTS: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. CONCLUSION: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients.

Fluorodeoxyglucose positron emission tomography/computed tomography for diagnosis of upper urinary tract urothelial carcinoma.

BACKGROUND: The purpose of this study was to assess the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to detect upper urinary tract urothelial carcinomas (UTUC) compared with pathological examination of tissues obtained by ureteroscopic biopsy and split cytologic analysis of urine obtained after retrograde pyelography. METHODS: Clinicopathological records of patients at our institution were retrospectively reviewed. Fifty patients with clinically suspected UTUC, who were histologically diagnosed by nephroureterectomy, partial ureterectomy, or endoscopic biopsy, were included. The patient cohort included 42 men and 8 women, with a median age of 73 (range 54-92) years. RESULTS: Only 27 % of 49 patients with UTUC had positive voided urine cytology, and 33 % of 40 patients had positive split urine cytology. In addition, 40 % of 10 patients had a positive endoscopic biopsy. However, 83 % of 48 patients with UTUC had positive results from FDG-PET/CT examination. The positive predictive value of FDG-PET/CT was 95 %. There were no correlations between sensitivity and tumor stage or tumor grade. Sensitivity of FDG-PET/CT for patients with and without diabetes mellitus was 60 and 89 %, respectively. CONCLUSIONS: These preliminary results from a small number of patients revealed that FDG-PET/CT enabled effective detection of UTUC.

Long­term exposure to leptin enhances the growth of prostate cancer cells.

Obesity correlates with an increased risk of developing prostate cancer (PCa) and leptin plays an important role in PCa progression. Since leptin is produced by adipocytes, the serum leptin level is higher in obese than in non-obese individuals. However, the effects of leptin remain controversial and unclear. The aim of the present study was to investigate the effect of leptin on PCa cell aggressiveness. Three human PCa cell lines (LNCaP, DU145 and PC-3) were treated with recombinant leptin for 28 days. Cell proliferation, migration, and invasion were estimated using the WST assay, a wound-healing assay, and a BD Matrigel invasion assay, respectively. The mechanism underlying the proliferative effect of leptin was investigated by cell transfections with small interfering RNA (siRNA) against the leptin receptor (ObR) or forkhead box O1 (FOXO1), and by immunocytochemistry. Long-term exposure of PCa cells to leptin enhanced their proliferation, migration and invasion. Leptin increased ObR expression and enhanced Akt phosphorylation constitutively. Leptin also increased the phosphorylation of FOXO1 via PI3K signaling and FOXO1 gene silencing enhanced PCa cell proliferation. Leptin induced the translocation of FOXO1 from the nucleus to the cytoplasm. Furthermore, the PI3K inhibitor, LY294002 suppressed this translocation. These results suggested that leptin regulated the subcellular localization of FOXO1 and induced Akt phosphorylation. Additionally, we revealed that leptin increased the expression of cyclin D1 and decreased the expression of p21 protein. In conclusion, long-term exposure to leptin increased the cell proliferation, migration, and invasion of PCa cells through inactivation of FOXO1. This inactivation resulted from exclusion of FOXO1 from the nucleus and its restriction to the cytoplasm through PI3K/Akt signaling. Our findings contribute to an understanding of the association between obesity and PCa aggressiveness.

Genome-wide association study identified SNP on 15q24 associated with bladder cancer risk in Japanese population.

Through genome-wide association analysis and an independent replication study using a total of 1131 bladder cancer cases and 12 558 non-cancer controls of Japanese populations, we identified a susceptibility locus on chromosome 15q24. SNP rs11543198 was associated with bladder cancer risk with odds ratio (OR) of 1.41 and P-value of 4.03 × 10(-9). Subgroup analysis revealed rs11543198 to have a stronger effect in male smokers with OR of 1.66. SNP rs8041357, which is in complete linkage disequilibrium (r(2) = 1) with rs11543198, was also associated with bladder cancer risk in Europeans (P = 0.045 for an additive and P = 0.025 for a recessive model), despite much lower minor allele frequency in Europeans (3.7%) compared with the Japanese (22.2%). Imputational analysis in this region suggested CYP1A2, which metabolizes tobacco-derived carcinogen, as a causative candidate gene. We also confirmed the association of previously reported loci, namely SLC14A1, APOBEC3A, PSCA and MYC, with bladder cancer. Our finding implies the crucial roles of genetic variations on the chemically associated development of bladder cancer.

[Clinicopathologic characteristics and prognosis of patients with adrenocortical carcinoma].

PURPOSE: Adrenocortical carcinoma (ACC) is a rare condition associated with poor prognosis. This study aimed to evaluate the clinicopathologic characteristics and prognosis of 7 patients with ACC. PATIENTS AND METHODS: The clinicopathologic characteristics, treatment, and survival of 7 patients with pathologically confirmed ACC treated at our institution between January 2002 and December 2012 were retrospectively examined. RESULTS: The study cohort comprised 4 male and 3 female patients (median age at diagnosis, 63 years [range, 36-71 years]). The median tumor size was 7.0 cm (range, 4.0-13.0 cm), and the median follow-up duration was 22 months (range, 9-107 months). One patient had stage I ACC, 4 had stage III, and 2 showed metastasis. The patient with stage I disease underwent laparoscopic adrenorectomy and those with stage III disease underwent adrenorectomy with the excision of adjacent organs. Four of these 5 patients are alive without recurrence at a median of 55 months (range, 22-107 months) after surgery. Of the 2 patients with metastases, 1 received combined chemotherapy with etoposide, adriamycin, and cisplatin plus mitotane without surgical resection but died 19 months later, and the other, with a solitary lung metastasis, underwent adrenorectomy and metastatectomy followed by adjuvant treatment with mitotane and is alive without recurrence at 9 months after treatment. The 3-year cause-specific survival rate was 56%. CONCLUSIONS: Patients with advanced-stage tumors showed long-term survival with complete tumor resection at diagnosis; hence, this seems to be most beneficial treatment option for patients with ACC.

Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells.

Cisplatin is currently the most effective anti-tumor agent available against bladder cancer. To clarify the mechanism underlying cisplatin resistance in bladder cancer, the present study examined the role of the aldo-keto reductase family 1 member C2 (AKR1C2) protein on chemoresistance using a human bladder cancer cell line. The function of AKR1C2 in chemoresistance was studied using the human HT1376 bladder cancer cell line and the cisplatin-resistant HT1376-CisR subline. AKR1C2 was expressed in HT1376-CisR cells, but not in the parental cells. The effect of small interfering (si) RNAs and an inhibitor targeting AKR1C2 was examined to determine whether cisplatin sensitivity can be rescued by blocking AKR1C2 expression or function. Silencing of AKR1C2 mRNA or inhibition of AKR1C2 by 5ß-cholanic acid resulted in a decrease in the survival of cells following cisplatin exposure. Intracellular accumulation of reactive oxygen species (ROS) was determined using a 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescent probe. Cisplatin exposure increased the level of intracellular ROS in HT1376 cells in a dose-dependent manner. The ROS levels in HT1376-CisR cells were significantly lower than those in HT1376 cells and knockdown of AKR1C2 mRNA significantly restored ROS levels. Cisplatin exposure did not increase intracellular ROS in HT1376-CisR cells, although the level of intracellular ROS increased in HT1376 cells following cisplatin exposure. Silencing of AKR1C2 mRNA restored the ROS increase response to cisplatin and menadione as an oxidative stressor in HT1376-CisR cells. Menadione has the function of an oxidative stressor. The silencing of AKR1C2 mRNA restored the increased ROS response to cisplatin and menadione in HT1376-CisR cells. These results indicate that induction of AKR1C2 in human bladder cancer cells aids in the development of cisplatin resistance through antioxidative effects. The results of this study indicate that AKR1C2 may be an effective molecular target for restoring cisplatin resistance.

Influence of immediate and early loading on bone metabolic activity around dental implants in rat tibiae.

OBJECTIVES: The aim of this study was to examine the influence of immediate and early loading on dynamic changes in bone metabolism around dental implants using bone scintigraphy. MATERIAL AND METHODS: Two titanium implants were inserted in the right tibiae of 21 rats. Closed coil springs with 4.0-N loads were applied parallel to the upper portion of the implants for 35 days. According to the load application timing, rats were divided into three groups: immediate loading (IL) group, early loading 1 day after implant insertion (1-D early loading [EL]) group, and loading 3 days after implant insertion (3-D EL) group. Rats were intravenously injected with technetium-99 m-methylene diphosphonate (Tc99 m-MDP) (74 MBq/rat) and scanned by bone scintigraphy at 1, 4, 7, 11, 14, 21, 28, and 35 days after load application. The ratio of accumulation of Tc99 m-MDP around the implants to that of a reference site (uptake ratio) was calculated to evaluate bone metabolism. RESULTS: In every group, the uptake ratio increased until 7 days after load application and then gradually decreased. It was significantly higher than baseline at 4, 7, 11, and 14 days (P < 0.001). The uptake ratio in the 1-D EL and 3-D EL groups were significantly higher than that in the control group and also that in the IL group (P < 0.001). CONCLUSIONS: Bone metabolism initially increased and then gradually decreased to baseline despite differences in load timing. Increases in bone metabolic activity differed according to load application timing; the later the load application, the more enhanced the bone metabolism.

Combined chemotherapy with gemcitabine and carboplatin for metastatic urothelial carcinomas in patients with high renal insufficiency.

BACKGROUND: This was a retrospective study to evaluate the activity and toxicity of a combined chemotherapeutic regimen of gemcitabine and carboplatin (GCa) in patients with metastatic urothelial carcinomas (UCs) with special regard to patients with highly impaired renal function. METHODS: Eleven patients whose creatinine clearance was 30 ml/min or under and who had been diagnosed with metastatic UC were treated with GCa. The patient cohort comprised 4 males and 7 females, with a median age of 74 (range 67-84) years. The median follow-up was 19 (range 1-58) months. RESULTS: Five of the 11 patients (45%) showed an objective response, with 2 achieving a clinically complete response and 3 a partial response with GCa. The grade 3/4 toxicity of the regimen was primarily hematological, including anemia (55%), neutropenia (45%), and thrombocytopenia (45%). Four patients (36%) could not complete the treatment in total. Grade 3 pneumonitis was found in one patient, and the treatment was terminated. Grade 4 febrile neutropenia occurred in the patient on hemodialysis, and the patient was forced to discontinue the chemotherapy. Another 2 patients also called off the treatment due to a pulmonary adverse event and an elevation of serum creatinine, respectively. CONCLUSIONS: GCa appears to be effective for the treatment of metastatic UCs in patients with impaired renal function, but it is necessary to pay attention to the occurrence of severe adverse events.

Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer.

BACKGROUND: To improve the prognosis of patients with urachal cancer and establish an effective chemotherapeutic regimen for distant metastases. METHODS: We conducted a retrospective study to evaluate the efficacy and safety of a modified combination of 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) therapy in patients with metastatic urachal cancer. RESULTS: Five patients were treated with mFOLFOX6. Their median age was 65 years (range 41-80). The median follow-up time was 42 months (range 18-46). Two of the 5 patients (40%) showed an objective response: 1 achieved a clinically complete response and 1 a partial response. The grade 3/4 toxicity associated with this regimen was primarily neutropenia, but febrile neutropenia was not observed. Oxaliplatin treatment was discontinued because of a grade 2 allergic reaction in 1 patient. Grade 2 peripheral sensory neuropathy caused by oxaliplatin was observed in 2 patients, and the OPTIMOX (stop and go) approach had to be adopted. CONCLUSIONS: mFOLFOX6 appears to be effective for the treatment of metastatic urachal cancer.

Time course of bone metabolism at the residual ridge beneath dentures observed using ¹8F-fluoride positron emission computerized-tomography/computed tomography (PET/CT).

OBJECTIVE: Excessive pressure due to wearing mal-adapting dentures is well known to cause residual bone resorption beneath the denture. X-rays have been commonly utilized to evaluate the changes in the bone beneath the denture. However, X-ray images merely detect bone density and relatively large changes in the bone shape and structure, whereas nuclear medicine imaging can detect functional changes, which occur prior to structural changes. This article aimed to describe the time course of the bone metabolism at the residual ridge beneath the denture following denture use by (18)F-fluoride positron emission computerized-tomography (PET)/computed tomography (CT) scanning. METHODS: Three subjects, who had a free-end edentulous mandible, were treated with a denture replacing the edentulous region of the dental arch. The metabolic changes in the residual bone beneath the denture were assessed by (18)F-fluoride PET/CT imaging. (18)F-fluoride PET/CT scanning was performed at baseline, and 4-6 and 13 weeks after denture use. A volume of interest (VOI) was placed on their mandibles at the edentulous region beneath the denture on the PET/CT image. CT value and mean standardized uptake value (SUV) of the VOI were calculated. The difference in the time variation between the CT value and SUV was analyzed. RESULTS: The adaptation of the denture base to the residual ridge was successful, and there was no trouble such as pain at the residual ridge beneath the denture. The SUVs of each VOI significantly increased at 4-6 weeks after denture use and then decreased at 13 weeks in all three subjects (P < 0.05; two-way ANOVA, Dunnett test). On the other hand, the CT images showed no obvious changes in the bone shape or structure beneath the dentures, and the CT values of each VOI remained static after denture use in all three subjects. CONCLUSIONS: This study indicates that in the present first-time removable partial denture (RPD) users, wearing of a well-adapted RPD initially increased bone metabolism beneath the denture and then decreased it at around 13 weeks after RPD use without any bone structural changes detectable by clinical X-rays. These metabolic changes are a mechanobiological reaction to the pressure induced by RPD use.

Adseverin: a novel cisplatin-resistant marker in the human bladder cancer cell line HT1376 identified by quantitative proteomic analysis.

Cisplatin is currently the most effective antitumor agent available against bladder cancer. However, a majority of patients eventually relapse with cisplatin-resistant disease. Chemoresistance thus remains a major obstacle in bladder cancer therapy. To clarify the molecular mechanisms underlying cisplatin resistance in bladder cancer, we established a cisplatin-resistant subline from the human bladder cancer cell line HT1376 (HT1376-CisR), and conducted large-scale analyses of the expressed proteins using two-dimensional (2D) gel electrophoresis coupled with mass spectrometry (MS). Comparative proteomic analysis of HT1376 and HT1376-CisR cells revealed 36 differentially expressed proteins, wherein 21 proteins were upregulated and 15 were downregulated in HT1376-CisR cells. Among the differentially regulated proteins, adseverin (SCIN), a calcium-dependent actin-binding protein, was overexpressed (4-fold upregulation) in HT1376-CisR, with the increase being more prominent in the mitochondrial fraction than in the cytosol fraction. SCIN mRNA knockdown significantly reduced cell proliferation with mitochondria-mediated apoptosis in HT1376-CisR cells. Immunoprecipitation analysis revealed voltage-dependent anion channels (VDACs) to be bound to SCIN in the mitochondrial fraction. Our results suggest that the VDAC-SCIN interaction may inhibit mitochondria-mediated apoptosis in cisplatin-resistant cells. Targeting the VDAC-SCIN interaction may offer a new therapeutic strategy for cisplatin-resistant bladder cancer.

Bone metabolism of residual ridge beneath the denture base of an RPD observed using NaF-PET/CT.

PATIENT: A 66-year-old woman, who had a bilateral free-end edentulous mandible and no experience with dentures, was examined for the chief complaint of masticatory dysfunction on left side of dental arch. A unilateral distal extension removable partial denture (RPD) replacing lower-left molars was selected. Tomographic images were obtained using Fluorine-18 NaF positron emission computerized tomography (NaF-PET)/computed tomography (CT) before the RPD use and at 1, 6, and 13 weeks after the RPD use to observe the metabolic changes in residual bone caused by the RPD use. PET standardized uptake values (SUVs) and CT values were calculated for lower-left edentulous site (test side) and lower-right edentulous site (control side). As a result, SUVs on the control side remained static after the RPD use, whereas those on the test side increased at 1 and 6 weeks after the RPD use and then decreased. However, CT images showed no obvious changes in the bone shape and structure beneath RPD, and CT values both on the control and test sides did not change either. DISCUSSION: This report shows that NaF-PET could detect bone metabolic changes soon after the RPD use, which cannot be detected by clinical X-rays. The SUV changes may be a mechanobiological reaction to the pressure due to the RPD use, and wearing of the RPD may increase the bone turnover beneath denture. CONCLUSION: This report demonstrates that wearing of an RPD increases bone turnover beneath denture immediately after the RPD use without clinically detectable changes in bone structure or volume.

Potential of histone deacetylase inhibitors for bladder cancer treatment.

Bladder cancer incidence increases with age, presumably reflecting a cumulative exposure to carcinogens and ever-increasing life expectancy. While aberrant protein expression due to DNA mutations is an essential step during oncogenesis, one recent interest has been the role of epigenetic changes in regulating bladder tumor development. Because aberrant histone acetylation has been linked to malignant diseases in several cases, histone deacetylase inhibitors have great potential as new anticancer drugs owing to their ability to modulate transcription and induce differentiation and apoptosis. We herein review the current knowledge on epigenetic issues in bladder cancer, particularly regarding histone acetylation, and discuss its implications for understanding the molecular basis and treatment of this disease.

[Low-dose docetaxel in combination with dexamethasone for hormone-refractory prostate cancer].

PURPOSE: Efficacy and tolerability of docetaxel-based chemotherapy against hormone-refractory prostate cancer (HRPC) has been shown lately. The objective of this study was to evaluate retrospectively the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. PATIENTS AND METHODS: Sixteen patients, with a median age of 69.5 years (range 54-85 years), diagnosed with HRPC were administered a treatment regimen consisting of docetaxel (60-80 mg/body or 50 mg/m2) once every 3 or 4 weeks and dexamethasone 1 mg daily at our institution between November, 2004 and March, 2010. RESULTS: The patients received a median of 11.5 cycles of treatment (range, 2-35 cycles). Eleven of 16 patients (68.8%) had a > or = 50% decrease in serum prostate-specific antigen. The median progression-free survival and overall survival times were 7.1 and 20.3 months, respectively. Grade 3 neutropenia occurred only in 2 patients. Infective endocarditis, gastrointestinal or cerebral hemorrhage, and compressive fracture were occurred in each patient. CONCLUSIONS: The combination of low-dose docetaxel every 3-4 weeks and dexamethasone daily was effective and well tolerated in patients with HRPC. However, it is necessary to pay continuous attention to side effects due to the frequent presence of comorbid diseases particularly in the elderly.

Treatment of metastatic renal cell carcinoma and renal pelvic cancer.

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of molecular targeted drugs have revolutionized the treatment for patients with metastatic RCC (mRCC). Multi-targeted tyrosine kinase inhibitors (sorafenib and sunitinib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have recently shown superiority over interferon-α or placebo. However, while the molecular targeted drugs have demonstrated encouraging results, these drugs have also sometimes induced unexpected adverse events. Control of adverse events is important to obtain the maximum effectiveness and sustain quality of life for patients. Because renal pelvic cancer has many similarities in pathogenesis with urinary bladder cancer, the same chemotherapeutic regimen is often proposed for patients with metastatic renal pelvic cancer. Combined chemotherapy with gemcitabine and cisplatin is now widely considered to be first-line chemotherapy against these metastatic diseases; however, there are still unresolved problems with this treatment, including the limited survival benefit. To select new therapeutic modalities, a more profound understanding of the molecular biology of renal pelvic cancer is crucial. The purpose of this review is to summarize the current evidence supporting the role and activities of new chemotherapeutic agents and to reveal potential future directions in the management of mRCC and renal pelvic cancer.

Combined chemotherapy with gemcitabine and cisplatin for metastatic urothelial carcinomas in patients 80 years of age and over.

BACKGROUND: This retrospective study aimed to determine the efficacy and toxicity of a combined chemotherapeutic regimen of gemcitabine and cisplatin (GC) for the treatment of metastatic urothelial carcinomas (UCs) in patients 80 years of age and over. PATIENTS AND METHODS: Twelve patients who were at least 80 years old and had been diagnosed with metastatic UC were treated with GC. The patient cohort consisted of 9 men and 3 women, with a median age of 83 (range 80-84) years. The median follow-up was 54 (range 14-80) months. RESULTS: Five out of the 12 patients (42%) showed an objective response, with two achieving a clinically complete response and three a partial response with GC. The median time to progression was 6 months, and the median overall survival was 14 months. The grade 3 and 4 toxicities of the regimen were primarily hematological, including anemia (33%), neutropenia (58%), and thrombocytopenia (50%). No grade 3 or 4 non-hematological toxicities were found. CONCLUSION: GC appears to be an effective and well-tolerated regimen for the treatment of metastatic UCs in very old patients.

Knockdown of Akt isoforms by RNA silencing suppresses the growth of human prostate cancer cells in vitro and in vivo.

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers.