Background
The decline of health-related quality-of-life (QOL) during the year after radical prostatectomy is severe. General self-efficacy (GSE) is an effective psychological factor for long-term ...regulation of patient behavior and emotions. GSE is expected to facilitate enhanced health-related quality of life. We evaluated changes in GSE and analyzed the relationship between GSE and prostate cancer-specific and general health-related QOL.
Methods
We conducted a longitudinal survey with 104 patients who underwent radical prostatectomy and administered the General Self-efficacy Scale (GSES), Expanded Prostate Cancer Index Composite (EPIC), and SF8 Health Survey (SF-8). ANCOVA was performed to compare EPIC and SF-8 between GSES high and low-medium groups.
Results
GSES scores increased significantly after 6 months. Regarding EPIC urinary summary scores, high GSES group was significantly higher than low-medium group at 1 month (mean score difference MSD, 7.3; 95% CI 1.1–13.2,
P
= 0.016), 3 months (MSD, 6.8; 95% CI 0.7–12.8,
P
= 0.028), and 6 months (MSD, 6.3; 95% CI 0.9–11.7,
P
= 0.022). High GSES group had significantly higher SF-8 physical component summary score at 6 months (MSD, 3.2; 95% CI 1.4–5.0,
P
= 0.001), and significantly higher SF-8 mental component summary score at 1 month (MSD, 2.6; 95% CI 0.4–4.9,
P
= 0.022), 3 months (MSD, 2.7; 95% CI 0.8–4.6,
P
= 0.007), and 6 months (MSD, 2.8; 95% CI 1.0–4.6,
P
= 0.003).
Conclusion
This study suggests that high GSE was associated with better prostate cancer-specific and general health-related QOL after radical prostatectomy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
► Sorafenib treatment upregulated GSK-3β levels in RCC cells. ► Pharmacologic inhibition of GSK-3 suppressed xenograft RCC tumor growth. ► Inhibition of GSK-3 enhanced antitumor effect of sorafenib ...in vitro and in vivo.
Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) is phosphorylated and activated by mammalian target of rapamycin complex 1, which serves as a regulator of cell growth, cell ...survival, metastasis and angiogenesis in many types of cancer. The aim of this study was to evaluate the role of phosphorylated 4EBP1 (p4EBP1) in primary renal cell carcinoma (RCC) as a biomarker in metastatic RCC (mRCC) and non-mRCC cohorts. Primary tumor tissue from 254 non-mRCC and 60 mRCC patients were immunohistochemically stained for t4EBP1 and p4EBP1. The disease-free interval (DFI) categorized by the expressions and clinical parameters were assessed by univariate and multivariate analysis in the non-mRCC cohort. Then, the cause-specific survival (CSS) was assessed in the mRCC cohort by the same methods as used in the non-mRCC cohort. In the non-mRCC cohort, patients with t4EBP1 expression had no RCC recurrence. Patients with p4EBP1 expression had the shorter DFI in univariate analysis (P=0.037). p4EBP1 and pT1b-4 expression levels were independent predictors for
metastasis. In the mRCC cohort, intermediate/poor MSKCC risk, non-clear cell RCC, and no p4EBP1 expression were correlated with poor CSS on multivariate analysis. Expression of p4EBP1 could be a predictive biomarker for
metastasis in non-mRCC patient cohort. By contrast, mRCC patients showing no p4EBP1 expression had shorter CSS than patients with p4EBP1 expression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Data on the outcomes of third- or fourth-line therapy for metastatic renal cell carcinoma (mRCC) are limited. The aim of our study was to evaluate the efficacy of therapy beyond the second line. We ...retrospectively analysed data of mRCC patients who underwent systemic therapy at Yamagata University Hospital. The best objective response (BOR), response rate (RR), and progression-free survival (PFS) were assessed for each line of treatment. To investigate the correlation between overall survival (OS) and the number of treatment lines during a patient's lifetime, the median OS was assessed using univariate and multivariate analyses. In the first-, second-, and third-line therapies, approximately 20% of patients had long PFS of >15 months. In targeted treatments beyond the third line, only one treatment suppressed disease progression for >10 months. Among patients who died during the follow-up period, those treated with triple and quadruple lines had similar OS (42.5 months vs. 48.4 months, respectively). Multivariate analysis showed that patients with triple or more lines of therapy had better OS; however, quadruple or more lines of therapy was not an independent prognostic factor. We concluded that third-line systemic therapy could improve OS; however, fourth-line therapy could not.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Introduction & objectives
Activation of Akt/mTOR pathway induces 4EBP1 phosphorylation, and enhances cell proliferation, anti-apoptotic effect, and angiogenesis in many types of cancers ...including renal cell carcinoma (RCC). As mTOR and angiogenetic proteins are main targets in metastatic RCC (mRCC) treatment. We assessed the correlation with survivals and phosphorylated 4EBP1 (p4EBP1) expression.
Materials & methods
We enrolled 254 non-mRCC patients who underwent primary surgery in Yamagata University between 2003 and 2010, and 59 mRCC patients whose resected primary lesion was available. Immunohistochemistry for p4EBP1 was performed on their FFPE samples. We assessed correlations between p4EBP1 expression manners and clinical features (disease-free interval DFI for non-mRCC patients, cause-specific survival CSS and progression-free survival PFS for mRCC patients). The CSS was calculated from mRCC diagnosis to death or last follow-up date. The PFS was calculated based on the durations patients were medicated. Univariate analysis was calculated by log-rank test and multivariate analysis was calculated by Cox-regression analysis.
Results
Non-mRCC patients with highly p4EBP1 expression were shorter DFI than those without high expression (p = 0.036). Their 5-year disease-free rates were 83.4% and 93.4%, respectively. The independent poor DFI factors were high p4EBP1 expression (HR; 3.4, p = 0.0054), grade (p = 0.0055), and pT stage (p < 0.0001).
In contrast, mRCC patients with p4EBP1 expression was longer CSS than those without expression (median CSSs; 56.7 and 32.2 months, p = 0.0246). The independent poor CSS factors were no p4EBP1 expression (hazard ratio HR; 3.3, p = 0.0409), grade 4 (HR; 8.7, p = 0.0006), and poor prognostic group on MSKCC criteria (HR; 4.2, p = 0.02770). Expression of p4EBP1 showed statistically longer PFS in mRCC patients with axitinib (median PFS; 9.2 and 2.5 months, p = 0.0255). The similar trends were shown in patients with other TKIs and mTOR inhibitors.
Conclusion
Since non-mRCC patients with the highly p4EBP1 expression had shorter DFI, expression of p4EBP1 should indicate aggressive RCC in nature. Nevertheless, mRCC patients with p4EBP1 expression had longer survival. These results mean that expression of p4EBP1 might be a predictive biomarker for TKIs and mTOR inhibitors.
Citation Format: Sei Naito, Osamu Ichiyanagi, Hiromi Ito, Hidenori Kanno, Tomoyuki kato, Yuuta Kurota, Atsushi Yamagishi, Mayu Yagi, Toshihiko Sakurai, Hayato Nishida, Hisashi Kawazoe, Tomohiro Shibasaki, Akira Nagaoka, Norihiko Tsuchiya. The potential of p4EBP1 expression as predictive biomarker of mRCC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2017-2782
A 62‐year‐old male patient with end‐stage renal disease and metastatic renal cell carcinoma (RCC) was referred to our hospital. Sequential targeted therapy consisting of sorafenib, sunitinib, and ...everolimus was administered, but the patient's disease gradually progressed. Axitinib was subsequently administered at a decreased dose of 6 mg/day for 2 weeks, after which the dose was escalated to 10 mg/day. Axitinib therapy was maintained for a total of 6 months without severe adverse effects. Sequential molecularly targeted drug therapy including axitinib, with careful monitoring, is one possible treatment option for patients with metastatic RCC with renal impairment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Introduction: Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase, as a positive regulator of several cancer cell survival and proliferation. We previously showed that ...nuclear accumulation of GSK-3beta indicates high grade, high stage, and poor survival in bladder urothelial cancer (UC). And inhibition of GSK-3beta suppresses UC cell proliferation and induces apoptosis via NF-kappaB down-stream genes viz. BCl-2 and XIAP (Clin Cancer Res 2010). Here we were to identify the interaction between cisplatin and GSK-3 inhibitor, AR-A014418 in UC.
Experimental Procedures: We added cisplatin (0, 1, 3, 6 μg/ml) and AR-A014418 (0, 10, 20 μM) to medium in T24 and HT1376 human UC cells and assessed their viability by MTS assay. Furthermore, we intraperitoneally administrated PBS 5 time per week, 2.5 mg/kg body weight cisplatin once per week, 20 mg/kg body weight AR-A014418 5 time per week, or cisplatin and AR-A014418 into each 6 mice with subcutaneous xenografts of HT1376 for 3 weeks.
Result: Treatment of cisplatin and AR-A014418 showed synergistic effect in cell lines. Cisplatin did not change expression level of GSK-3beta, and AR-A014418 suppressed XIAP for cell lines with cisplatin. The average tumor volume of the mice treated by cisplatin was equivalent to one by PBS within treatment period. However, the tumors treated by cisplatin grew bigger than ones by PBS after withdrawal of treatment. AR-A014418 inhibited the growth of tumor compared to PBS and cisplatin. And combine use of cisplatin and AR-A014418 prevented the tumor from re-growth by cisplatin after treatment. Body weight did not vary between mice by each treatment methods.
Conclusion: Cisplatin and AR-A014418 synergistically suppressed UC cells viability. And AR-A014418 cancelled re-growth of low-dose cisplatin in xenograft model.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2011-2419
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