Age-dependent prognostic value of body mass index for non-metastatic clear cell renal cell carcinoma: A large multicenter retrospective analysis.

BACKGROUND AND OBJECTIVES: The prognostic value of obesity is unestablished for renal cell carcinoma. We assessed the age-dependent prognostic value of body mass index (BMI) in a large multicenter cohort of patients with non-metastatic clear cell renal cell carcinoma (nm-cRCC). METHODS: This study evaluated 2092 patients with nm-cRCC who underwent surgery with curative intent at five Korean institutions between 2001 and 2014. RESULTS: There was no significant difference in BMI between the young (<45 years) and older patients (≥45 years) (P = 0.398). Among older patients, high BMI (≥25 kg/m2 ) was associated with better 5-year rates of recurrence-free survival (RFS) and cancer-specific survival (CSS) (P = 0.003 and 0.004, respectively), and multivariate analysis confirmed that high BMI was independently associated with better RFS and CSS (RFS hazard ratio [HR]: 0.617, P = 0.005; CSS HR: 0.588, P = 0.024). However, among young patients, there were no significant BMI-related differences in the 5-year RFS and CSS rates (P = 0.457 and 0.420, respectively), and high BMI was not independently associated with RFS or CSS (P = 0.822 and 0.749, respectively). CONCLUSIONS: Among patients with nm-cRCC, high BMI was associated with a favorable prognosis among older patients but not among young patients. Therefore, the relationship between obesity and nm-cRCC prognosis might vary according to age.

Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand.

CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137-/- mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103+ DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8+ cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103+ DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103+ DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989-6000. ©2017 AACR.

Influence of nutritional deficiency on prognosis of renal cell carcinoma (RCC).

OBJECTIVE: To evaluate the prognosis of patients with renal cell carcinoma (RCC) by nutritional status defined by body mass index (BMI), serum albumin and cholesterol. PATIENTS AND METHODS: This study retrospectively enrolled 1437 patients who underwent radical nephrectomy (932) or partial nephrectomy (505) for RCC. We assigned nutritional status according to the presence of none or one nutritional risk factor (control group) and two or all three of the following nutritional risk factors (nutritional deficiency group). The nutritional factors and thresholds were preoperative albumin level (<3.5 g/dL), preoperative cholesterol level (<220 mg/dL), and preoperative BMI (<23 kg/m(2) ) RESULTS: The patients' mean (sd) age was 55.23 (12.41) years and BMI was 24.36 (3.17) kg/m(2) . The mean (sd) serum cholesterol level was 180.07 (38.24) mg/dL, and the albumin level was 4.2 (0.45) g/dL. In all, 141 (9.8%) patients had none of the nutritional deficiency criteria, 802 (55.8%) had one, 429 (29.9%) had two, and 65 (4.5%) had all three. Clinicopathological variables, i.e. female gender, high tumour stage, positive lymph node metastasis, positive distant metastasis, high nuclear grade and non-clear cell type histopathology were associated with the nutritional deficiency group. In multivariate Cox analysis, nutritional deficiency was an independent predictor for RCC recurrence (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.05-1.83, P = 0.020) and RCC-related mortality (HR 2.06, 95% CI 1.39-3.03, P < 0.001). CONCLUSION: Nutritional deficiency defined by BMI, serum albumin and cholesterol is an important factor that predicts postoperative prognosis of patients with RCC who have undergone radical or partial nephrectomy.

Application of simplified Fuhrman grading system in clear-cell renal cell carcinoma.

OBJECTIVE: To investigate the efficacy of simplified (two- or three-tiered) Fuhrman grading systems as prognostic indicators in clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: By reviewing records, various clinicopathological factors were assessed in 431 patients who received surgical management for clear-cell RCC. A conventional four-tiered Fuhrman grading system was compared with a modified two-tiered grading system (Fuhrman grades I and II were combined as one class, and grades III and IV as another) and also with a three-tiered grading system (only grades I and II were combined). Efficacies of grading systems were assessed via univariate analyses and multivariate models for prediction of cancer-specific survival. RESULTS: In univariate analysis, the four-tiered and three-tiered grading systems showed similar accuracies (76.5 vs 76.2%, P =0.614) for predicting cancer-specific survival, which were greater than that of the two-tiered system (72.5%; both P < 0.05). Of the three grading systems, only the three-tiered system was an independent predictor of cancer-specific survival in multivariate analysis (P = 0.046). When receiver operating characteristic-derived areas under the curve (AUCs) of multivariate models for predicting cancer-specific survivals were assessed, AUCs for models including the three-tiered Fuhrman grading system and the conventional four-tiered Fuhrman grading system were the same (95.3%), followed by that of a model incorporating the two-tiered grading system (95.1%). CONCLUSION: A modified, three-tiered Fuhrman grading system can be considered an appropriate option in the application of a nuclear grading system to the prognostication of clear-cell RCC in both univariate analysis and multivariate model setting.

Comparison of laparoscopic radical nephrectomy and open radical nephrectomy for pathologic stage T1 and T2 renal cell carcinoma with clear cell histologic features: a multi-institutional study.

OBJECTIVES: To assess the oncologic efficacy of laparoscopic radical nephrectomy (LRN) compared with open radical nephrectomy (ORN) in patients with clear cell renal cell carcinoma (RCC). METHODS: We analyzed the data from 2561 patients who had undergone radical nephrectomy for RCC at 26 institutions in Korea from June 1998 to December 2007. The clinical data of 631 patients with clear cell RCC in the LRN group were compared with the clinical data of 924 patients in the ORN group. The patients with Stage pT3 or greater and those with lymph node or distant metastases were excluded to avoid a selection bias. To evaluate the technical adequacy and oncologic outcome, we compared the perioperative parameters and 5-year overall and disease-free survival rates. RESULTS: The operative time was significantly longer in the LRN group than in the ORN group (219 ± 77 vs 182 ± 62 minutes, P < .001), but the estimated blood loss and complication rate were significantly lower in the LRN group than in the ORN group (P < .001 and P < .001, respectively). On univariate analysis, the LRN group had 5-year overall (93.5% vs 89.8%, P = .120) and recurrence-free (94.0% vs 92.8%, P = .082) survival rates equivalent to those of the ORN group. Even after adjusting for age, sex, T stage, tumor grade, and body mass index in a Cox proportional hazards model, statistically significant differences between the 2 groups were not found for the 5-year overall (hazard ratio 1.523, P = .157) and recurrence-free (hazard ratio 0.917, P = .773) survival rates. CONCLUSIONS: Our large multi-institutional data have shown that LRN provides survival outcomes equivalent to those of ORN in patients with Stage pT1-T2 clear cell RCC.

Cytotoxicity and apoptosis by survivin small interfering RNA in bladder cancer cells.

OBJECTIVE: To investigate the effects of survivin gene RNA interference on cell growth and the cell cycle in the human bladder cancer cell line T24. MATERIALS AND METHODS: A small interfering RNA (siRNA) targeting survivin was transfected into T24 cells using a liposome approach. Reverse transcription-polymerase chain reaction and Western blot analysis were used to examine survivin gene expression in T24 cells. Cells densities were determined by haematocytometer counts and flow cytometry was used for cell cycle analysis. Caspase-3 activity was quantified. RESULTS: After treatment with survivin siRNA, the survivin gene expression in T24 cells was almost completely absent. The survivin siRNA treatment caused a profound decrease in survivin protein, which was correlated with a decrease in cell growth, G2/M arrest, and an increase in the fraction of cells undergoing apoptosis. The inhibition of survivin expression increased caspase-3 activity in T24 cells, which led to apoptosis. CONCLUSIONS: RNA interference can efficiently suppress survivin expression in T24 cells. Targeting survivin by siRNA may be a promising approach to block proliferation of bladder cancer cells and may provide a suitable adjuvant therapy for treatment of bladder cancer.

Reduction of oxidative stress in cultured renal tubular cells and preventive effects on renal stone formation by the bioflavonoid quercetin.

PURPOSE: We investigated the effects of quercetin on renal tubular cell injury induced by oxalate and the inhibitory effects of quercetin on urinary crystal deposit formation in an animal model. MATERIALS AND METHODS: MDCK cells (American Type Culture Collection, Manassas, Virginia) were incubated with different concentrations of oxalate with and without quercetin. MTT (Sigma) assays for cell viability, malondialdehyde and catalase activity were measured to investigate the antioxidant effect of quercetin. Male Sprague-Dawley rats were divided into 3 groups. Group 1 was fed standard rat chow. Groups 2 and 3 rats were fed standard chow supplemented with 3% sodium oxalate for 4 weeks. For the first 8 days in 4 weeks each rat in groups 2 and 3 also received gentamicin intramuscularly. Additionally, group 3 rats were administered quercetin for 4 weeks. Rats were sacrificed after 4 weeks, after which 24-hour urine collections and kidney removal were performed. In the renal tissue malondialdehyde, superoxide dismutase and catalase activity was measured. Bisected kidneys were examined under microscopy to determine the number of crystals. RESULTS: The viability of MDCK cells significantly decreased and malondialdehyde production increased in the presence of oxalate. However, co-exposure to quercetin inhibited the decrease in cell viability and inhibited the lipid peroxidation production induced by oxalate. In the animal study malondialdehyde production in group 3 significantly decreased compared to that in group 2. Catalase and superoxide dismutase activity was increased in group 3 compared to that in group 2. The number of crystals in kidneys in group 3 was decreased significantly compared to that in group 2. CONCLUSIONS: Quercetin has an inhibitory effect on urinary crystal deposit formation.

Effects of ovariohysterectomy on reactivity in German Shepherd dogs.

This study investigated the effects of ovariohysterectomy on reactivity of German Shepherd dogs. Fourteen healthy dogs ranging in age from 5 to 10 months were assigned to an ovariohysterectomy or a sexually intact group. Their behaviours were digitally video recorded 4-5 months after treatment and analysed for treatment effects on reactivity. Responses to the approach of an unfamiliar human leading an unknown dog were assigned the following reactivity scores: severe reactivity, 3; moderate reactivity, 2; defensive or mild reactivity, 1; attentive or no reactivity, 0. Median reactivity scores in response to the approach of an unfamiliar human walking with an unknown dog were calculated for each observation period. Dogs in the ovariohysterectomized group showed more reactivity, and median reactivity scores were higher in the ovariohysterectomy group compared with those of the sexually intact group. Ovariohysterectomy of 5-10 month old German Shepherd bitches specifically, and perhaps bitches of any breed generally, may induce an increase in reactivity. Practitioners may benefit from recognizing that a range of behavioural changes may occur post-ovariohysterectomy.

Laparoscopic adrenalectomy for functioning and non-functioning adrenal tumors: analysis of surgical aspects based on histological types.

BACKGROUND: The aim of this study was to evaluate whether hormonal functions of the tumor influence the operative results of laparoscopic adrenalectomy, and to analyse the clinical outcomes in patients with various hormonally active adrenal tumors. METHODS: Clinical and pathological records of 68 patients were reviewed. The average age of patients was 40 years (range 20-75); 39 were women and 29 men. For the comparison, patients were divided into the non-functioning tumor group (n = 22) and the functioning tumor group (n = 46). RESULTS: All laparoscopic adrenalectomies were finished successfully, and no open surgery was necessary. The median operative time and blood loss in the two groups were similar; however, in subgroup analysis, operative time for pheochromocytoma was significantly longer than that for non-functioning tumor (P = 0.044). No difference was noted in intra- and postoperative data between the groups. Of the 22 patients with aldosteronoma, 18 (81.8%) became normotensive and no longer required postoperative blood pressure medications. Adrenalectomy led to an overall reduction in the median number of antihypertensive medications (P < 0.001). All patients with Cushing adenoma had resolution or improvement of the signs and symptoms during follow-up periods. There was no evidence of biochemical or clinical recurrence in any patient with pheochromocytoma. CONCLUSION: The results of this retrospective review document that laparoscopic adrenalectomy is a safe and effective treatment for functioning as well as non-functioning adrenal tumors, although endocrinologic features may play a significant role.