Association Between Interdialytic Weight Gain, Perception About Dry Weight, and Dietary and Fluid Behaviors Based on Body Mass Index Among Patients on Hemodialysis.

OBJECTIVE: This study aimed to identify dietary and fluid behaviors associated with relative interdialytic weight gain (RIDWG) (divided by the respective dry weight [DW]) by stratifying the patients according to body mass index (BMI). DESIGN AND METHODS: This was a cross-sectional, multicenter investigation. Between July 2016 and March 2017, data were collected from 4 Japanese dialysis centers in 3 cities. The patients (n = 577) were asked to reply to a self-completed questionnaire, including questions on perception about DW and dietary and fluid behaviors. The differences in perception about DW and dietary and fluid behaviors were compared between RIDWG nonadherence (average RIDWG ≥5％ a month) and adherence subgroups. RESULTS: The 360 participants were stratified into thin (<20; 28.6%), normal low (≥20 and <22; 22.5%), normal high (≥22 and <25; 31.7%), and overweight (≥25; 17.2%) groups on the basis of BMI. In the thin and normal low BMI groups, the RIDWG nonadherent patients were more likely to identify their DW as "looking to increase." Although the difference was less prominent between the adherence subgroups in the thin BMI group, the RIDWG nonadherent patients in normal low BMI group seemed to generally take less care to intentionally regulate their behaviors as a representative of sodium-intake/fluid management. Although patients with a larger body size (overweight and normal high BMI groups) were not associated with this perception about DW, they were associated with some demographic characteristics; regarding the normal high BMI group, a higher proportion of RIDWG nonadherent patients worked full-time, and they more frequently reported an irregular eating pattern. CONCLUSION: Dietary and fluid behaviors associated with RIDWG differed according to the BMI group. Assessing more specific types of patient behaviors, focusing on the underlying factors associated with dietary and fluid behaviors, and taking BMI into consideration are required.

Acute Kidney Injury Due to Nephrolithiasis in Autosomal Dominant Polycystic Kidney Disease Treated With Tolvaptan: A Case Report.

A 61-year-old asymptomatic female with autosomal dominant polycystic kidney disease (ADPKD) on tolvaptan therapy was hospitalized for acute kidney injury (AKI). Nephrolithiasis had already been diagnosed; however, the patient had not undergone any interventions. She also presented with hyponatremia possibly caused by overhydration. Because the estimated glomerular filtration rate (eGFR) decline was significantly higher than the predicted rate, we considered a possible case of postrenal AKI and examined computed tomography (CT), which revealed left hydronephrosis with a 9.4-mm ureteric stone at the level of L3/L4. We restricted fluid intake, which resulted in an increase in sodium levels. She was treated with transurethral lithotripsy (TUL) twice, which successfully improved her kidney function. Although the serum sodium levels increase because of aquaresis in almost all patients treated with tolvaptan, our case was unique in that the patient presented with hyponatremia. We should pay more attention to the periodical follow-up of nephrolithiasis in addition to the increase in total kidney volume and decide the appropriate time to treat nephrolithiasis depending on the case. We should also keep in mind that ADPKD patients have a high frequency of nephrolithiasis and, even if asymptomatic, investigate urinary tract obstruction and hydronephrosis in case of AKI.

Long-term outcomes of the Japanese hemodialysis patients with prostate cancer detected by prostate-specific antigen screening.

We investigated the long-term outcomes of the Japanese hemodialysis patients with prostate cancer detected by prostate-specific antigen (PSA) screening. Clinical data of 646 male hemodialysis patients aged 55 years or older who started yearly PSA testing in the period from January 1, 2004 to December 31, 2012 and were followed until December 31, 2017 were analyzed retrospectively. The median follow-up period was 10.4 years. Nineteen (2.9%) patients were diagnosed with prostate cancer, of whom one patient died of the disease. Androgen-deprivation therapy (ADT) was selected for primary prostate cancer treatment in 17 (89.5%) of these 19 patients. Of six prostate cancer patients who underwent primary ADT (PADT) and died of other causes, three died of infectious disease, each one died of cardiovascular disease, liver cancer, and chronic renal failure. No significant difference was observed in regard to overall survival between the prostate cancer patients with PADT and non-prostate cancer patients. Prognosis of hemodialysis patients who were diagnosed with prostate cancer during yearly PSA screening examination and mainly treated with ADT was favorable without increasing cardiovascular events. This result indicates that PSA screening may be useful for detection and management of prostate cancer even in hemodialysis patients. J. Med. Invest. 68 : 42-47, February, 2021.

Pulmonary sarcoidosis as a cause of intermittent fever of unknown origin in a hemodialysis patient with renal cell carcinoma: A case report and literature review.

Hemodialysis patients have weakened immune systems and can exhibit fever due to various causes. Herein, we describe the case of a 61-year-old hemodialysis patient who exhibited intermittent low-grade fever after a pacemaker had been implanted 2 months before due to sick sinus syndrome. She had a medical history of subcutaneous sarcoidosis and uveitis. Active pulmonary sarcoidosis was diagnosed based on elevated soluble interleukin-2 receptor, elevated lysozyme level, and gallium-67 scintigraphy uptake in hilar and mediastinal lymph nodes. She was also diagnosed with renal cell carcinoma via contrast computed tomography. However, because her C-reactive protein level remained normal, the possibility of neoplastic fever was considered low. After the initiation of prednisolone administration, her fever gradually disappeared. Her serum soluble interleukin-2 receptor and lysozyme level improved in parallel with the enlargement of the mediastinal lymph node and gallium-67 scintigraphy uptake.

Strategy for repeat prostate biopsy: predictors of positive biopsy and additional biopsy location.

PURPOSE: We analyzed patterns of tumor distribution in radical prostatectomy specimens from patients with repeat biopsies to determine additional appropriate biopsy locations for repeat biopsy. METHODS: Between January 2000 and June 2005, a total of 382 patients underwent transrectal ultrasound-guided prostate biopsy. Of these, 47 patients underwent repeat biopsy. Radical prostatectomy was performed for 7 of 22 cancer-positive cases. The 7 specimens were superimposed to create an idealized prostate gland at 3 levels: apex, mid-prostate, and base. We compared these tumor maps with those from 35 initial biopsy positive patients. RESULTS: Prostate cancer was detected in 22 of 47 patients who underwent repeat biopsy. Tumor mapping showed that tumors detected on repeat biopsy in comparison with tumor maps of initial biopsy were dense at the periurethral area of the apex in prostate. CONCLUSIONS: Additional biopsy cores taken from periurethral area of the apex on repeat biopsy might further enhance the detection of cancers.

Phase I trial of personalized peptide vaccination for cytokine-refractory metastatic renal cell carcinoma patients.

The aim of this clinical trial was to investigate the toxicity and immunological responses of personalized peptide vaccination for cytokine-refractory metastatic renal cell carcinoma patients. Patients were confirmed to be human leukocyte antigen (HLA)-A24 or HLA-A2 positive and had histologically confirmed renal cell carcinoma. Ten patients were enrolled in the present study. The peptides to be administered were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors in peripheral blood mononuclear cells (PBMC) and peptide-specific IgG in the plasma of cancer patients. Patients received subcutaneous injections of four different peptides (3 mg/peptide) every 2 weeks. Vaccinations were well tolerated without any major adverse events. A minimal increase in peptide-specific interferon-gamma production in postvaccination PBMC was observed, regardless of higher levels of cytotoxic T lymphocyte activity in prevaccination PBMC. In contrast, an increase in peptide-specific IgG levels of postvaccination (sixth) plasma was observed in the majority of patients. After progression, five patients received interleukin-2 therapy and continuous vaccination, with survival of 31, 25, 23, 17, and 15 months, but interleukin-2 did not impede humoral responses boosted by the vaccination. These results encourage further clinical trials of personalized peptide vaccinations.

Differences in gene expression between noninvasive and invasive transitional cell carcinoma of the human bladder using complementary deoxyribonucleic acid microarray: preliminary results.

This study was performed to identify differences in gene expression between superficial noninvasive and invasive transitional cell carcinoma (TCC) of the bladder in human beings. We used complementary deoxyribonucleic acid microarrays containing 14,551 different genes to analyze gene expression among 6 cases of superficial and 6 cases of invasive TCC of the bladder to identify differences in gene expression, which might explain differences in the biology and clinical outcomes of these histologic subtypes of TCC. Quantitative real-time polymerase chain reaction was performed for selected genes to validate the microarray data. Significant up-regulation of 40 genes was associated with cases of superficial noninvasive, but not in invasive, TCC of the urinary bladder. This effect included genes involved in epithelial cell dedifferentiation and keratinization, as well as genes related to cell cycle, cell adhesion, transcription, and apoptosis. Conversely, significant up-regulation of 34 genes was associated with cases of invasive TCC, but not in superficial TCC, including genes related to extracellular matrix degradation, immune responses, cell cycling, and angiogenesis. This study shows the usefulness of complementary deoxyribonucleic acid microarray technology for identifying differences in gene expression among different histotypes of bladder cancer.

[A case of renal capsular hemangiosarcoma].

We report herein a case of renal capsular hemangiosarcoma. A 68-year-old man was admitted to our hospital for treatment of a retroperitoneal tumor identified incidentally on abdominal computed tomography (CT) for follow-up of superficial bladder tumor. The tumor was about 7cm in diameter, positioned between the right kidney and the liver. Right nephrectomy was performed under a diagnosis of renal capsular tumor. Pathological diagnosis was hemangiosarcoma and positive surgical margins were suspected. Radiotherapy was performed postoperatively to a total dose of 50 Gy. Hemangiosarcoma frequently occurs in the skin, but is rare in the retroperitoneal cavity. Neither metastasis nor recurrence has been seen as of 19 months postoperatively.

[A non-seminomatous extra-gonadal germ cell tumor responding to intensive treatment: a case report].

A 23-year-old man presented with lumbago as a chief complaint. Computed tomographic (CT) scan revealed multiple lung tumors, multiple liver tumors, bulky retroperitoneal tumors with marked elevation of serum lactic dehydrogenase (LDH), alpha-fetoprotein, and beta subunit of human chorionic gonadotropin (HCG-beta). The patient was referred to our hospital for treatment. Scrotal ultrasonography and physical examination revealed bilateral normal testes. Because of bulky retroperitoneal masses with elevated specific tumor markers as well as bilateral normal testes, our diagnosis led to extra-gonadal germ cell tumor. Because the pulmonary lesion had increased rapidly, chemotherapy was performed without the tumor biopsy. After multiple chemotherapy regimens including BEP (bleomycin, etoposide, cisplatin), high-dose chemotherapy, and TIN (paclitaxel, ifosfamide, nedaplatin), all tumor marker levels fell into within the normal range. The tumor size was decreased remarkably on CT. Then, retroperitoneal lymphadenectomy were performed to confirm whether they still contained viable tumor cells. They contained only necrotic tissues without viable cancer cells by pathological examination. Consequently, the patient has been free of recurrence for 18 months after intensive treatment.

[Chemotherapy-resistant germ cell cancer of the testis treated by salvage surgery: a case report].

A 38-year-old patient who had a non-seminomatous testicular cancer was treated by resection of the retroperitoneal metastatic mass that had proven refractory to bleomycin, etoposide and cisplatin (BEP) and paclitaxel, ifosfamide and cisplatin (TIP) chemotherapies. Although salvage chemotherapy was given against the chemorefractory metastatic lesions in the retroperitoneum, the serum alpha-fetoprotein level elevated to 3,252 ng/ml. Retroperitoneal lymph node dissection was performed, and viable cells were identified histopathologically in the resected tissues. The serum AFP level normalized after surgery. No recurrence has been observed for 22 months postoperatively. This experience indicates that salvage surgery even under high serum marker levels may have a beneficial outcome for selected cases of chemotherapy-resistant germ cell tumors.

Reduction or discontinuation of antibiotic prophylaxis in vascular access surgery, tendon sheath incision and PD catheter placement.

PURPOSE: Immune response in dialysis patients is suppressed and these patients are susceptible to bacterial infections. Therefore, minimal use of antibiotics in dialysis patients is recommended to avoid generating drug-resistant bacteria. However, minor surgeries including vascular access surgery, tendon sheath incision and peritoneal dialysis (PD) catheter placement are inevitable in dialysis patients and evidence-based recommendations on the judicious use of antibiotics are not currently available for these procedures. In this study, the optimal antibiotic prophylaxis for minor surgeries was evaluated. METHODS: This is a retrospective study. In dialysis patients at Kawashima Hospital, a three-step reduction of antibiotic use was performed in 651 cases of arteriovenous fistula (AVF) and tendon sheath incision surgeries from July 2009 through October 2012. Moreover, general surgical guidelines-recommended dose of preoperative antibiotics only were used in 532 cases of arteriovenous graft (AVG) and PD catheter placement from January 2010 through October 2012. The surgical site was observed for 2 weeks after the surgery. RESULTS: In only one case of AVF surgery, redness of the skin around the stitches was noticed 5 days after the surgery, which was healed with antibiotics taken orally for 3 days. Neither AVG nor PD catheter placement demonstrated any infection at the surgical site during the 2-week observation period. CONCLUSIONS: Even in dialysis patients, neither pre- nor postoperative antibiotics are necessary for AVF and tendon sheath incision surgeries. AVG and PD catheter placement surgeries require only a small amount of antibiotics preoperatively.

Roles of NKT cells in resistance against infection with Toxoplasma gondii and in expression of heat shock protein 65 in the host macrophages.

We investigated the roles of gamma delta T, NK, and NK1.1(+) T-like (NKT) cells in protective immunity against infection with Toxoplasma gondii. gamma delta T cells, NKT and NK cells, and NK cells in BALB/c mice were depleted by treatment with anti-TCR-gamma delta monoclonal antibody (mAb), anti-interleukin-2 receptor beta chain (IL-2R beta) mAb, and anti-asialoGM1 Ab, respectively, and these mice were infected with T. gondii. Treatment of mice with anti-TCR-gamma delta mAb aggravated toxoplasmosis, while treatment with anti-asialoGM1 Ab had no effects. Treatment with anti-IL-2R beta mAb enhanced the expression of heat shock protein 65 (HSP65) and gamma interferon (IFN-gamma) mRNA, while it inhibited interleukin-4 (IL-4) mRNA expression, ameliorating toxoplasmosis. In addition to NK cells, anti-IL-2R beta mAb eliminated cells expressing IL-2R beta and intermediate levels of CD3 (IL-2R beta(+) CD3(int)). Mice treated with anti-IL-2R beta mAb decreased the number of DX5(+) CD3(int) cells, which are considered to be equivalent to NK1.1(+)T cells in NK1.1 allele-negative strains. IL-2R beta(+) CD3(int) cells isolated from splenic and hepatic lymphoid cells were confirmed to express the TCR-V alpha 14 transcript. The magnitude of HSP65 induction in macrophages correlated with the protective potential against T. gondii infection after treatment with the antibodies, supporting our previous finding that gamma delta T cells play an essential role in the induction of HSP65 in host macrophages. Interestingly, NKT cells suppressed the expression of gamma delta T cell-induced HSP65 and IFN-gamma. Furthermore, depletion of IL-2R beta(+) CD3(int) cells suppressed the IL-4 mRNA expression. These results suggest that NKT cells may be the cells responsible for suppression of protective immunity against T. gondii infection by interfering with the gamma delta T cell-induced HSP65 expression, possibly through the generation of IL-4.

A convenient cancer vaccine therapy with in vivo transfer of interleukin 12 expression plasmid using gene gun technology after priming with irradiated carcinoma cells.

We studied interleukin (IL)-12 gene therapy using a gene gun as a new autologous vaccination strategy for cancer. In the first experiment, BALB/c mice were inoculated with syngeneic murine renal cancer cells (Renca) intradermally in the abdomen. This was followed by an injection of IL-12 expression plasmid using the gene gun. About 40% of the mice exhibited rejection of the tumor after the treatment and these mice also acquired immunological resistance against a secondary challenge with Renca cells. Based on these results, we examined whether antitumor activity can be potentiated when mice undergo combination treatment with intradermal inoculation of irradiated Renca cells and transfection with IL-12 gene. Inoculation of irradiated Renca cells alone was partially effective in inducing antitumor immunity, whereas the combined treatment remarkably intensified this effect. Moreover, this combined treatment inhibited tumor establishment and enhanced survival of the mice with tumor infiltration by CD4(+) and CD8(+) T cells, even when the treatment was started after tumor-implantation at a distant site. This antitumor effect was antigen specific and we confirmed the induction of antitumor cytotoxic T cells by this treatment. These results show that local cutaneous transfer of IL-12 expression plasmid using gene gun technology enhances systemic and specific antitumor immunity primed by irradiated tumor cells.

Changes in levels of prostate-specific antigen and testosterone following discontinuation of long-term hormone therapy for non-metastatic prostate cancer.

INTRODUCTION: We evaluated changes in levels of prostate-specific antigen (PSA) and testosterone following discontinuation of long-term hormone therapy for non-metastatic prostate cancer. PATIENTS AND METHODS: Treatment was discontinued in 31 patients with non-metastatic prostate cancer (clinical stage B-C) after ≥ 5 years of hormone therapy, during which time PSA level had been maintained less than 0.5 ng/ml. PSA and testosterone levels were measured after discontinuation of therapy. PSA > 4.0 ng/ml was defined as PSA relapse in this study. RESULTS: Mean age at discontinuation of hormone therapy was 78.7 years (range, 66-90). Mean duration of follow-up after discontinuation of therapy was 25.5 months. PSA non-relapse rate was quite high (87.1%). 4 of the 31 patients showed PSA relapse, after 12-24 months. Testosterone level exceeded castration level (< 1.0 ng/ml) in 3 patients, each of whom developed PSA relapse. CONCLUSIONS: During follow-up, the PSA relapse rate was relatively low. These results suggest that treatment may be safely discontinued in many prostate cancer patients. In addition, rate of testosterone recovery after treatment discontinuation may be associated with PSA relapse. When considered the adaptation of discontinued, or intermittent hormone therapy for aged people, these findings may be useful.

Bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through hepatocyte growth factor.

OBJECTIVES: To examine the effects of fibroblast-derived humoral factors, especially hepatocyte growth factor (HGF), on the invasive potential of bladder cancer cells. Stromal cells in cancer tissue are thought to play an important role in the transformation and invasion of cancer cells. METHODS: The influence of fibroblast cells (TIG-1 cells) and HGF on the invasive potential of bladder cancer cells (5637, T24, J82, HT1376, and MGHU-1 cells) was evaluated by in vitro cell invasion assay. The expression of HGF and c-Met, which is the receptor of HGF, was examined by reverse transcriptase-polymerase chain reaction. To clarify the relationship between the serum HGF level and invasive bladder cancer, we measured the serum concentrations of HGF in patients with bladder cancer without metastatic disease and normal controls, using an enzyme-linked immunosorbent assay. RESULTS: The in vitro cell invasion assay showed that the number of invading bladder cancer cells was significantly increased by the conditioned medium (CM) of the fibroblast cells. HGF neutralization antibody partially inhibited the enhancement of invasiveness by fibroblast CM. The CM of fibroblasts cultured with bladder cancer CM stimulated cancer cell invasion more strongly (with increased HGF secretion) than did the CM of fibroblasts cultured without bladder cancer CM. The serum HGF levels were significantly greater in patients with muscle-invasive bladder cancer (regardless of tumor size) than in patients with non-muscle-invasive bladder cancer. CONCLUSIONS: The present results have suggested that bladder cancer cell invasion is enhanced by cross-talk with fibroblasts through humoral factors, including HGF. Elucidation of this mechanism could lead to novel therapeutic strategies for bladder cancer.

Clinical research of renal vein control using Hem-o-lok clips in laparoscopic nephrectomy.

Control of the renal vein represents a crucial step in laparoscopic nephrectomy. Although endovascular gastrointestinal anastomosis (GIA) staplers have generally been used for renal vein control because of the large diameter of the vessel, Hem-o-lok clips have recently been used for renal artery control. GIA staplers are expensive and can malfunction on rare occasions, resulting in severe complications. We evaluated renal vein control using Hem-o-lok clips (adaptive vascular width 7-16 mm) in laparoscopic nephrectomy. Since April 2004, we have ligated renal arteries using Hem-o-lok clips. From June 2004, this method was applied for renal vein control in 40 laparoscopic nephrectomies. After renal pedicle dissection, renal pedicle ligation was accomplished using extra large (XL) Hem-o-lok clips on both the renal arteries and veins by placing two clips on the patient side and one clip on the specimen side. Ligation times for obtaining renal vein control were compared between XL Hem-o-lok clips and GIA staplers in 40 cases before June 2004. Vascular control using XL Hem-o-lok clips was successful in all 40 cases, without any slipping of clips or uncontrolled bleeding. After renal pedicle dissection, ligation time for achieving renal vein control was 167.0 +/- 48 s (range: 122-295 s) using XL Hem-o-lok clips (mean, three clips) and 68 +/- 24.0 s (range: 54-150 s) using a GIA stapler. XL Hem-o-lok clips allow safe and reliable control of renal veins in laparoscopic nephrectomy. Ligation time is only 100 s longer than using a GIA stapler. In addition, costs are reduced by more than 90% compared to GIA stapling.

Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy.

AIM: Laparoscopic adrenalectomy is currently indicated for biochemically and clinically functional adrenal tumors and potentially malignant tumors of the adrenal glands. Non-functional adenomas greater than 5 cm in diameter of the adrenal gland are generally considered to represent potentially malignant tumors. The present study shows indications of laparoscopic adrenalectomy for non-functional adrenal tumors with hypertension in a retrospective fashion. METHODS: Between 1994 and 2004, 110 laparoscopic adrenalectomies were performed at Tokushima University Hospital. All 110 patients underwent detailed endocrinological examination before surgery. Medical and operative records of these 110 patients (57 men, 53 women), including operative parameters, histopathological findings and pre- and postoperative hypertension, were reviewed. Forty-five patients underwent laparoscopic adrenalectomy for non-functional adrenal tumors, and [(131)I]6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (NP-59) scintigraphy was performed for patients with preoperative hypertension. RESULTS: Mean patient age was 55.0 years (range, 22-77 years). Mean maximum tumor diameter was 42 mm (range, 20-105 mm). All adrenal tumors were removed successfully by laparoscopic surgery. Hypertension was postoperatively improved in seven of the 11 patients with preoperative hypertension, without subclinical Cushing syndrome. Importantly, all patients who improved hypertension after adrenalectomy displayed strong accumulation in adrenal tumors with visualization of the contralateral gland on NP-59 scintigraphy. Conversely, blood pressure did not improve in four patients for whom scintigraphy yielded negative results. CONCLUSIONS: The indication of laparoscopic adrenalectomy for non-functional adrenal tumors is generally considered for lesions more than 5 cm diameter. However, the present study suggests that laparoscopic surgery should be considered even in patients with tumors less than 5 cm in diameter, if both hypertension and accumulation in tumors on NP-59 scintigraphy are present.

Prostate stem cell antigen predicts tumour recurrence in superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: To evaluate the relationship between prostate stem cell antigen (PSCA) expression level in transitional cell carcinoma (TCC) of the urinary bladder and various clinicopathological features, including stage and grade; and to determine whether PSCA mRNA expression predicts disease recurrence in superficial (not muscle-invasive) TCC of the bladder. PATIENTS AND METHODS: Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on 97 TCC tissue samples and in 36 samples of normal bladder urothelium; the findings were analysed in relation to clinicopathological factors. Immunohistochemical expression was examined using light and confocal immunofluorescence microscopy to validate the RT-PCR data. RESULTS: Twenty-seven patients developed disease recurrence, while the remaining 22 had no evidence of recurrence of superficial TCC of the bladder. There was significantly higher PSCA mRNA expression in TCC than in normal urothelium samples (P = 0.008). Superficial (TaT1) tumours had significantly higher PSCA expression than muscle-invasive (> or = pT2) tumours (P < 0.001). There was no significant difference between patients with G1-2 tumours and those with G3 tumours (P = 0.109). Immunohistochemical analysis showed markedly greater PSCA expression in superficial than invasive TCC. Notably, from a multivariate analysis, the expression level of PSCA was an independent predictor of disease recurrence in superficial TCC (P = 0.012). CONCLUSIONS: These findings suggest that the PSCA expression level measured by real-time RT-PCR could be a valuable prognostic marker for tumour recurrence in superficial TCC of the bladder.

Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand.

TRAIL/Apo2L is a pro-apoptotic cytokine that is capable of inducing apoptosis in a wide variety of cancer cells but not in normal cells. Among various molecular strategies by which cancer cells evade apoptosis, PI3K/Akt signaling represents a dominant survival pathway. In this report, we investigated the role of PI3K/Akt pathway in TRAIL-induced apoptotic death in human bladder cancer cells. We observed that RT4 cells had very low level of constitutively active Akt and were sensitive to TRAIL, whereas UM-UC-3 and T24 cells had higher levels of constitutively active Akt and were resistant to TRAIL. Downregulation of constitutively active Akt by PI3K inhibitors, wortmannin and LY294002, reversed cellular resistance to TRAIL. However, transfecting constitutively active Akt into RT4 cells increased Akt activity and inhibited TRAIL-induced apoptosis. These results suggest that elevated Akt activity protects UM-UC-3 and T24 cells from TRAIL-induced apoptosis, and the PI3K/Akt signaling might inhibit apoptotic signals. Thus, the modulation of Akt activity by combining pharmacological drugs or genetic alterations of the Akt expression could induce cellular responsiveness to TRAIL and PI3K/Akt signaling pathway could serve as a novel target for therapeutic intervention in bladder cancer.