Pretreatment assessment of tumor enhancement on contrast-enhanced computed tomography as a potential predictor of treatment outcome in metastatic renal cell carcinoma patients receiving antiangiogenic therapy

BACKGROUND: Tumor vascularity is a potential predictor of treatment outcomes in metastatic renal cell carcinoma (mRCC), and contrast enhancement of tumors in computed tomography (CT) is correlated significantly with microvessel density. In this study, the authors investigated whether tumor enhancement in contrast-enhanced CT (CECT) is useful for predicting outcomes in patients with mRCC who are receiving antiangiogenic therapy. METHODS: Attenuation values were reviewed retrospectively on CECT images of all metastatic lesions in 66 patients from February 2007 to November 2008. All patients received a tyrosine kinase inhibitor (either sunitinib or sorafenib). Tumor response was evaluated on CECT studies every 12 weeks. The authors analyzed the association between contrast enhancement and treatment outcomes, including objective response, tumor size reduction rate, time to response, and time to progression. RESULTS: In 46 patients, 198 metastatic lesions were assessed. Tumor size was reduced in 140 lesions (70.7%) and was increased in 58 lesions (29.3%). The mean reduction in size was 23.8%. The overall mean time to response and the time to progression were 8.6 months and 16.4 months, respectively. In multivariate analyses, tumor enhancement and enhancement pattern were associated with objective responses (P = .003 and P = .028, respectively). In addition, tumor enhancement was associated with tumor size reduction (P = .004). In Cox proportional hazards models, only tumor enhancement was associated significantly with the time to size reduction and progression-free survival (P = .03 and P = .015, respectively). CONCLUSIONS: Tumor enhancement on CECT images was associated with treatment outcomes and was identified as a potential predictor of treatment outcomes after antiangiogenic therapy in patients with mRCC.ope

Management of BCG Failures in Non-Muscle-Invasive Bladder Cancer

PURPOSE: Bacillus Calmette-Guerin (BCG) intravesical therapy is the standard treatment in high-risk patients with non-muscle-invasive bladder cancer, but a significant number of patients experience recurrence after BCG therapy. Although several treatment options are available for recurrence after BCG therapy, the optimal treatment strategy is still controversial. We reviewed current and promising treatment options after BCG failure. MATERIALS AND METHODS: search of published literature using PubMed and meeting abstracts was performed. RESULTS: BCG failures are further subdefined as BCG refractory, BCG resistant, BCG relapsing, and BCG intolerance. Several predictors for BCG response have been studied, but prediction or stratification before therapy seems to be difficult in clinical practice. Novel biomarkers associated with immunologic mechanisms appear to be promising to predict BCG failure. Radical cystectomy is the standard treatment for BCG-refractory disease, but the timing of cystectomy is controversial. BCG maintenance or combination with interferon-alpha is a promising therapy for BCG resistance or relapse. Some salvage therapies or device-assisted instillations have been also promising, but the efficacy and safety of these novel therapies should be confirmed by large prospective studies before their clinical use in BCG failure. CONCLUSIONS: Patients with BCG failure are not a homogeneous group and need to be stratified. Radical cystectomy should be performed without delay in patients with BCG-refractory status, but salvage intravesical therapies may be an alternative in cases without true refractory status. Although BCG and interferon intravesical therapy is promising, more efficient salvage therapy after BCG failure is required.ope

Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma

Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.ope

Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78 potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/eIF2α pathway

Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC.ope

Exponential rise in prostate-specific antigen (PSA) during anti-androgen withdrawal predicts PSA flare after docetaxel chemotherapy in patients with castration-resistant prostate cancer

PURPOSE: To investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: This study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1. RESULTS: There were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034). CONCLUSION: An exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.ope

Predicting the response of patients with advanced urothelial cancer to methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) after the failure of gemcitabine and platinum (GP)

BACKGROUND: Platinum-based systemic chemotherapy is the treatment of choice for patients with advanced urothelial carcinoma (UC). Although no chemotherapeutic regimen is established as a second-line therapy, recent studies reported that methotrexate, vinblastine, Adriamycin and cisplatin (MVAC) elicited a significant response in patients who failed gemcitabine and platinum (GP) chemotherapy. We investigated the clinical factors useful for predicting a favourable response to MVAC in UC patients who failed GP. METHODS: Forty-five patients with advanced UC who received second-line MVAC chemotherapy after failure with first-line GP chemotherapy were enrolled in this study. Univariate and multivariate analyses based on Cox's regression were performed to identify independent prognostic factors for progression-free survival (PFS) after second-line MVAC chemotherapy. RESULTS: The median follow-up period after the first MVAC administration was 10.0 months. The median PFS and overall survival (OS) were 6.5 months (95% confidence interval [CI]: 5.1-7.9) and 14.5 months (95% CI, 7.4-21.4), respectively. The overall response rate was 57.8%. The response to first-line GP chemotherapy (hazard ratio [HR], 2.500; p = 0.012) and patient age (HR, 1.047; p = 0.033) were predictors of PFS after MVAC chemotherapy. CONCLUSIONS: The response to first-line GP chemotherapy and age were independent predictors of PFS in patients who received second-line MVAC chemotherapy. This report is the first to describe independent predictors of PFS after MVAC chemotherapy.ope

Estramustine Phosphate Based Chemotherapy for Hormone Refractory Prostate Cancer

Purpose We wanted to evaluate the efficacy and side effects of estramustine monotherapy and estramustine plus etoposide or dexamethasone combined therapies for patients with hormone refractory prostate cancer (HRPC). Materials and Methods Between 2000 and 2004, 33 patients who were diagnosed with HRPC and treated with estramustine-based chemotherapy were evaluated. Eleven patients had oral estramustine monotherapy (group 1), 12 patients had oral estramustine plus oral etoposide (group 2), and finally 10 patients had oral estramustine plus oral dexamethasone (group 3). The prostate-specific antigen (PSA) response, progression-free survival and disease-specific survival were evaluated. Results The median patient age was 71 years and the median PSA was 97.3ng/ml. The median follow-up period was 17 months (range: 5-47). The overall response rate was 45.5%, and the response rate for each group was 36.4% for group 1, 41.7% for group 2 and 70.0% for group 3, respectively. The median time to progression (TTP) was 5 months (range: 1-16) overall and it was 5 months, 5.5 months and 5 months in groups 1, 2 and 3, respectively. Regarding the response rate, progression-free survival and disease specific survival, there were no statistically significant differences between the three groups (p>0.05). The most common hematologic complication was anemia that occurred in 28 patients and deep vein thrombosis occurred in 2. Severe toxicities (≥grade 3) occurred in only 2 patients. Conclusions Estramustine phosphate showed over a 45% response rates with less morbidities. Estramustine-based chemotherapy can be considered as an option for the treatment of HRPC. However, larger randomized controlled trials for regimens combined with other efficacious agents are necessary to elucidate the efficacy of chemotherapy for HRPC.ope

The novel histone deacetylase inhibitor, N-hydroxy-7-(2-naphthylthio) hepatonomide, exhibits potent antitumor activity due to cytochrome-c-release-mediated apoptosis in renal cell carcinoma cells

BACKGROUND: Epigenetic modifications play a critical role in the regulation of all DNA-based processes, such as transcription, repair, and replication. Inappropriate histone modifications can result in dysregulation of cell growth, leading to neoplastic transformation and cell death. Renal tumors have been shown to have a higher global methylation percentage and reduced histone acetylation. Preclinical models have revealed that histone gene modifiers and epigenetic alterations play important roles in renal cell carcinoma (RCC) tumorigenesis. Recently, a novel HDAC inhibitor, N-hydroxy-7-(2-naphthylthio) heptanomide (HNHA), has been introduced as an example of a new class of anti-cancer agents. The anti-cancer activity of HNHA and the underlying mechanisms of action remain to be clarified. METHODS: The MTS assay using a panel of RCC cells was used to evaluate the anti-proliferative effects of HNHA. The established HDAC inhibitors, SAHA and TSA, were used for comparison. Western blotting analysis was performed to investigate the acetylation of histone H3 and the expression of apoptotic markers in vitro and in vivo. Subcellular fractionation was performed to evaluate expression of Bax and cytochrome c in the cytosol and mitochondria, and also translocation of cytochrome c from the cytoplasm to the nucleus. A confocal microscopic evaluation was performed to confirm inhibition of cell proliferation, induction of apoptosis, and the nuclear translocation of cytochrome c in RCC cells. RESULTS: In this study, we investigated the apoptosis-inducing activity of HNHA in cultured kidney cancer cells. Apoptosis in the HNHA-treated group was induced significantly, with marked caspase activation and Bcl-2 suppression in RCC cells in vitro and in vivo. HNHA treatment caused cytochrome c release from mitochondria, which was mediated by increased Bax expression and caspase activation. HNHA also induced nuclear translocation of cytochrome c, suggesting that HNHA can induce caspase-independent nuclear apoptosis in RCC cells. An in vivo study showed that HNHA had greater anti-tumor and pro-apoptotic effects on RCC xenografts than the established HDAC inhibitors. CONCLUSIONS: HNHA has more potent anti-tumor activity than established HDAC inhibitors. Its activities are mediated by caspase-dependent and cytochrome-c-mediated apoptosis in RCC cells. These results suggest that HNHA may offer a new therapeutic approach to RCC.ope

A Case of von Hippel-Lindau Disease with Colorectal Adenocarcinoma, Renal Cell Carcinoma and Hemangioblastomas

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome associated with mutations of the VHL tumor suppressor gene located on chromosome 3p25. The loss of functional VHL protein contributes to tumorigenesis. This condition is characterized by development of benign and malignant tumors in the central nervous system (CNS) and the internal organs, including kidney, adrenal gland, and pancreas. We herein describe the case of a 74-year-old man carrying the VHL gene mutation who was affected by simultaneous colorectal adenocarcinoma, renal clear cell carcinoma, and hemangioblastomas of CNS.ope

Impact of clinical trial participation on survival in patients with castration-resistant prostate cancer: a multi-center analysis

BACKGROUND: Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC). METHODS: This multi-center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated. RESULTS: An Eastern Cooperative Oncology Group performance status (ECOG PS) >/=2 at CRPC diagnosis was found in a lower proportion CT participants than in non-participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score >/= 8, ECOG PS >/=2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS. CONCLUSIONS: Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre-established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated.ope