bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of neoadjuvant ABI-007, carboplatin, and gemcitabine (ACG) in patients with locally advanced carcinoma of the bladder.
Authors: Smith D. C. , Grivas P. , Daignault S. , Hafez K. , Wood D. P. , Lee C. T. , Montie J. E. , Weizer A. Z. , Montgomery J. , Hussain M.
Published: February 2017

244

Background: Neoadjuvant cisplatin-based chemotherapy benefits patients with bladder cancer, particularly in the 30% with pathologic complete response (pCR) at cystectomy. Many patients with bladder cancer are not candidates for cisplatin. Taxane-based regimens have activity in urothelial cancer. ABI-007 is an albumin-bound paclitaxel with increased activity and decreased toxicity compared to standard paclitaxel preparations.

Methods: Eligible pts have T2-4,N0,M0 or Tany,N1- 3,M0 bladder cancer with ECOG PS 0-1, and adequate marrow (granulocyte count > 1,500/mm3, platelet > 100,000/mm3, and hemoglobin > 9.0 g/dl), hepatic (transaminases < 2.5 X upper limit of normal, alkaline phosphatase < 2.5 X upper limit of normal, and bilirubin < 1.5 mg/dl) and renal function (serum creatinine < 2.0 mg/dl and/or creatinine clearance > 40 ml/min). Pts are treated with intravenous ABI-007 260 mg/m2 and carboplatin (target area under the curve=5) on day 1 with gemcitabine 800 mg/m2 on days 1 and 8, followed by radical cystectomy after three cycles of therapy. The primary study endpoint is the proportion of patients with pCR at cystectomy.

Results: 27 patients have been enrolled. By clinical staging, 20 had T2 disease, 5 had T3, 2 had T4, and 2 had nodal enlargement. All are evaluable for toxicity with 22 evaluable for response (exclusions-3 for change in dose schedule, 1 each for refusal of cystectomy and withdrawal from study). 25/27 patients received all three cycles (78 total cycles) with doses reduced in 26 cycles for toxicity. All patients had transient grade 3-4 neutropenia and 17 received filgrastim, but only two had febrile neutropenia. Six pts had pCR with an additional 5 having residual carcinoma in situ (CIS) and 1 with T1 disease at cystectomy. 54% of evaluable patients had no muscle invasive disease at cystectomy.

Conclusions: Neoajuvant ACG is active in bladder cancer with pCR rate nearing 30% and nearly as many patients with CIS but no residual invasive disease. Marrow toxicity is significant but manageable.

[Table: see text]
DAB389 EGF for the treatment of superficial urothelial cancer.
Authors: Flaig T. W. , Su L. , Thorburn A. , Frankel A. E. , Li Y. , Woo J. H. , Varella-Garcia M. , La Rosa F. G. , Li C. , Yang X.
Published: February 2017

255

Background: Intravesical BCG has remained the standard treatment for superficial bladder cancer for decades, despite frequent recurrences after its use. Toxic fusion proteins are a novel class of agents containing both a targeting and a treatment component; correspondingly, DAB389EGF contains an EGF and a diphtheria element, thereby targeting any cell expressing EGFR. Notably, the normal urothelium has little or no luminal EGFR expression in contrast to urothelial cancers, which frequently overexpress EGFR.

Methods: DAB389EGF was tested in vitro to determine the effect of DAB389EGF on cell viability in culture. Tests of clonogenicity were performed by treating plated cells for 2 hours and following colony counts over 14 days. DAB389EGF was tested in an orthotopic murine model of bladder cancer with implanted HTB9 cells modified to express luciferase. DAB389EGF was administered intravesically via catheterization of the murine bladder and held in place for 2 hours with a temporary suture to close the urethra. Treatments were continued twice weekly for 2 weeks, with DT-GMCSF used as a control.

Results: Treatment with DAB389EGF yielded IC50's ranging from 0.5 to 15.7 ng/ml in 8 tested bladder cancer cell lines, but the IC50 was > 500ng/ml in the EGFR- negative H520 control cell line. A single 2-hour exposure to DAB389EGF (50ng/ml) decreased colony formation in all of the bladder cancer cell lines, with complete suppression in HT1376 and T24 cells. In the animal model, luciferase activity was lost in 5 of 6 mice treated with DAB389EGF, versus 1 of 6 mice treated with control. After the 2 week treatment period, histological assessment of the treated mice was undertaken and was consistent with the luciferase findings. FISH was used to detect human or murine-originated cells in order to confirm the presence or absence of xenograft tissue histologically.

Conclusions: Targeted-toxin fusion proteins represent a novel treatment approach for superficial bladder cancer. By capitalizing on the differential expression of EGFR between cancerous and normal urothelium, DAB389EGF selectively targets bladder cancer cells. Preliminary animal studies support the efficacy and tolerability of this approach with additionally animal work currently underway.

No significant financial relationships to disclose.
Urinary Met level as a novel biomarker for urothelial carcinoma of the bladder.
Authors: Sorbellini M. , McNeil B. , Cohen B. , Athauda G. , Giubellino A. , Coleman J. , Netto G. J. , Getzenberg R. H. , Linehan W. , Bottaro D. P.
Published: February 2017

257

Background: To determine whether urinary soluble Met (sMet) can differentiate between benign conditions and bladder cancer (CaB), and in cases of bladder cancer, between different stages of transitional cell carcinoma (TCC).

Methods: Urinary samples from patients with (Total: 63, pTa: 12, pTis: 22, pT1: 13, ≥ pT2: 16) and without (Total: 27) CaB from three different institutions were prospectively collected prior to cystosopy, TURBT or cystectomy. sMet levels were determined by electrochemiluminescence immunoassay and normalized to urinary creatinine values. Normalized sMet values were compared to final pathologic stage. AUC values were obtained comparing patients with and without TCC.

Results: Urinary sMet levels accurately differentiated between patients with and without CaB (AUC: 78%, sensitivity, specificity and negative predictive value were: 68%, 78% and 95%, respectively), patients with no CaB and those with lamina propria invasion (AUC: 79%, sensitivity, specificity and negative predictive value were: 65%, 81% and 95%, respectively) and patients with no CaB and those with muscle invasive CaB (AUC: 85%, sensitivity, specificity and negative predictive value were: 75%, 83% and 97%, respectively).

Conclusions: Urinary sMet levels accurately distinguish patients with CaB from those without, and between patients with different CaB stages. These results suggest that urinary sMet may have utility as a bladder cancer marker for screening, treatment follow-up and clinical trial design.

No significant financial relationships to disclose.
Use of a MET-specific photoprobe to identify bladder tumors in an orthotopic xenograft model of bladder cancer.
Authors: Sorbellini M. , Giubellino A. , Srivastava G. , Sourbier C. , Jagoda E. , Williams M. , Choyke P. L. , Pinto P. A. , Linehan W. , Bottaro D. P.
Published: February 2017

260

Background: Met over-expression has been found in bladder cancer (CaB). Stage and grade increases in urothelial carcinoma have been found to correlate with increases in Met expression. To assess whether molecular optical imaging could enhance the detection of bladder tumors, we used a Met-specific soluble photoprobe in an orthotopic xenograft model of bladder transitional cell carcinoma (TCC).

Methods: An orthotopic xenograft murine model of CaB was developed with T24-Luciferase-positive bladder cancer cells. Presence of tumor was confirmed by luciferase optical imaging (Xenogen IVIS) of mice, 4 weeks after TCC cell implantation. Mice were euthanized and their bladders removed and bivalved. Bladders were incubated for 30 minutes with unbound fluorophore (Cy5**, Peak emission at 675 nM) and subsequently for another 30 minutes with Cy5** bound to a Met-specific peptide. Fluorescence imaging (Maestro) was performed before and after each incubation period. Following imaging, presence of tumor was confirmed histologically.

Results: Cy5**-Met- peptide bound in sufficient density to tumor tissue in bladders for visualization by optical imaging. The tumor to normal bladder imaging ratio ranged from 2:1 to 8:1. Bladder regions with high uptake of Cy5**-Met-peptide corresponded to tumor areas confirmed by histological analysis.

Conclusions: Cy5**-Met-peptide successfully targets Met in an orthotopic xenograft model of bladder cancer. Our results suggest that this agent maybe useful for the enhanced visualization of bladder cancer tumors during cystoscopy.

No significant financial relationships to disclose.
Synergistic potentiation of anti-tumor immunity with light-activated drug therapy and anti-CTLA4 antibody treatment.
Authors: Bromley E. , Waitz R. , Wang S. , Allison J. P.
Published: February 2017

27

Background: Talaporfin sodium (TS) is a light-activated, locally cytoreductive drug in phase III clinical trials for several different cancers. It is activated intratumorally with a thin, flexible LED array. TS treatment has been shown in preclinical studies to activate CD8+-dependent anti-tumor immunity in a model of metastatic breast cancer. Anti-CTLA4 antibody is an immunotherapy that acts by suppressing negative regulation of immune effectors. It has recently completed a successful phase III clinical trial in melanoma patients in which it was shown to prolong survival. TS and anti-CTLA4 antibody have great potential to synergistically reduce primary tumor burden and generate systemic anti-tumor immunity.

Methods: This study examined combination treatment with these two therapies in a murine prostate cancer tumor model (C57BL/6 + TRAMP C2). A large, established tumor on the left side of each mouse was treated with light-activated TS (or light- only control). One day after treatment, mice were injected intradermally with 0.5 × 106 TRAMP C2 cells on the opposite flank. Anti-CTLA4 (or vehicle control) was given on days 1, 4, 7 and 10. Progression of the untreated tumor was measured.

Results: Growth of untreated tumors was prevented or significantly delayed in 55% and 33% of combination-treated animals, respectively (n = 9). In addition, contralateral tumor growth was prevented in 1 of 9 animals given talaporfin sodium alone while another animal's tumor showed growth delay. None of the untreated controls or anti-CTLA4 only animals showed a similar response. Individual combination-treated mice with delayed tumor growth often showed an atypical tumor growth curve in which progression either tapered off or began to reverse between 30 and 40 days post treatment.

Conclusions: Reduction of tumor using local treatment with a light-activated drug could potentiate the anti-tumor immune response resulting from anti-CTLA4 treatment and prevent growth of secondary tumors in a preclinical prostate cancer model.

[Table: see text]
Multimodality therapy including surgical resection (SR) and intraoperative electron radiotherapy (IOERT) for locoregionally recurrent (LRR) or advanced primary malignancies of the urinary bladder (UB) or ureter.
Authors: Hallemeier C. L. , Karnes R. J. , Pisansky T. M. , Davis B. , Gunderson L. L. , Leibovich B. C. , Haddock M. G. , Choo R.
Published: February 2017

277

Background: For patients (pts) with LRR or advanced primary tumors of the UB or ureter, limited therapeutic options exist. Outcomes of combined SR and IOERT are reported here.

Methods: From 1983 to 2009, a total of 17 pts with urothelial (16 pts) or squamous cell carcinoma (1 pt) of the UB (n=13) or ureter (n=4) were treated with SR and IOERT. Pts had LRR after radical cystoprostatectomy or nephroureterectomy (n=15) or advanced primary tumor (n=2). Extent of SR was R0 (microscopic negative margins), R1 (microscopic positive margins), and R2 (gross residual tumor) in 7, 1, and 9 pts, respectively. After maximal SR, IOERT was delivered to the tumor bed. Median IOERT dose and energy delivered were 12.5 Gy (range; 10-20) and 9 MeV (range; 6-18), respectively, with 1 (n=15), 2 (n=1), or 3 (n=1) IOERT fields. Sixteen pts also received perioperative external beam radiotherapy (EBRT) with a median dose of 50.4 Gy (range; 21.6- 60). Five pts received concurrent chemotherapy (CT) with perioperative EBRT. Overall (OS), disease-free survival (DFS) and relapse patterns were estimated from the date of SR and IOERT using the Kaplan-Meier method.

Results: The median pt age was 63 years (yrs) (range; 51-76). The median follow-up of surviving pts was 3.6 yrs (range; 1.1-10.0). OS and DFS at 1, 2, and 5 yrs were 53%, 31%, and 16%, and 24%, 18%, and 18%, respectively. Central (within the IOERT field), locoregional (tumor bed or first echelon draining lymphatics), and distant relapse at 2 yrs were 15%, 49%, and 67%, respectively. Seven pts received systemic CT after relapse. Mortality within 30 days of SR and IOERT was 0%. Two pts (12%) experienced grade 4-5 (NCI-CTCAE v. 4) toxicity potentially related to the multimodality therapy.

Conclusions: For pts with LRR or advanced primary tumor of the UB or ureter, this multimodality therapy including SR and IOERT resulted in durable OS and DFS in a small but significant number of pts. Both LRR and distant relapse were common, indicating a need for more effective systemic therapy along with more refined locoregional therapy.

No significant financial relationships to disclose.
A phase II trial of gemcitabine (G), carboplatin (C), and sorafenib (S) in patients (pts) with transitional cell carcinoma (TCC): Preliminary safety and outcome.
Authors: Mehnert J. M. , Mortazavi A. , Stein M. N. , Donadio A. C. , Zelterman D. , McDonough J. A. , Rowen E. , Hoimes C. J. , Gibney G. , Kelly W. K.
Published: February 2017

278

Background: Sorafenib is an oral tyrosine kinase inhibitor with anti-angiogenic properties that may enhance the antitumor activity of GC and when administered as maintenance therapy after GC may delay disease recurrence. This study investigated the safety and clinical outcome of adding S to GC for pts with advanced TCC and the role of S maintenance after GC.

Methods: Metastatic/unresectable chemotherapy naive TCC pts ECOG PS 0-1 received G 1,000 mg/m2 d1, 8 and C AUC = 5 d1 with S 400 mg bid d2-19 q21 d for 6 cycles. Pts with stable disease or PR/CR continued on 400 mg bid of S. The primary endpoint was proportion of pts free of progression at 5 months with secondary endpoint of proportion of pts with PR/CR. A Simon two-stage design would enroll 30 pts; if 8 of the initial 17 followed for 5 months or more post treatment showed disease progression, the trial would terminate.

Results: 17 pts enrolled, 14 male, 3 female; median age 64 (47-86); ECOG 0 (7)/1 (10). The median number of cycles of GC + S given was 4.4 with multiple dose reductions in 71%. 7 pts (47%) experienced grade (gr) 3/4 neutropenia and 4 (24%) gr 3/4 anemia during GC + S; no neutropenic fever was seen. Gr 3/4 thrombocytopenia occurred in 59% with 2 events of hematuria, 1 epistaxis, and 1 bleeding colitis. Gr 3 nonhematologic toxicities: hypophosphotemia (29%), diarrhea (6%), fatigue (24%), anorexia (6%), dehydration (6%), hand foot syndrome (6%), rash (12%), hypertension (6%). Responses: 1 CR (6%), 4 PR (24 %), 8 SD (47%); 3 pts with evaluable disease showed tumor shrinkage, including 1 with resolution of bone metastases. 9 (53 %) were progression free at 5 months; 7 (41%) came off trial due to > 3 dose reductions (1 prior to first restaging) and 1 withdrew consent. 7 (41%) that achieved CR, PR or SD after a minimum of 4 cycles GC + S received maintenance S for a median of 8 cycles.

Conclusions: GC + S showed clinical activity in advanced TCC similar to GC alone but prolonged progression-free intervals were observed in patients treated with S maintenance. GC + S was associated with increased hematologic toxicity although S maintenance was well tolerated. Further studies exploring the role of S maintenance after chemotherapy are warranted.

[Table: see text]
Oncologic outcomes for node-positive patients undergoing robotic radical cystectomy.
Authors: Mmeje C. , Nunez-Nateras R. , Pruthi R. , Nielsen M. E. , Wallen E. , Humphreys M. , Castle E. P.
Published: February 2017

290

Background: Previous studies have shown robot assisted radical cystectomy (RARC) to have equivalent perioperative outcomes to open radical cystectomy. There are few reports that have examined the oncologic results of RARC specifically with respect to node-positive patients. We report the outcomes of node-positive patients who have undergone RARC with medium-term (at least 1 year) follow-up.

Methods: A total of 275 patients underwent RARC at two institutions for invasive bladder cancer between 2005-present. We examined the 50 patients with node-positive disease that had a minimum of one year follow-up. Oncologic outcomes, recurrence free survival (RFS), and disease specific survival (DSS) were analyzed and compared to the open literature.

Results: Mean clinical follow up in this case series was 29 months (range 12–64 months). The mean number of lymph nodes removed was 18 (range 5–35), and mean number of positive LNs was 3.1 (range 1–12). Overall rate of LN positivity was 26%. Mean LN density was 18%. Seventeen (34%) patients had ≤ pT2 disease and 33 (66%) pT3/T4 disease. At this follow-up, 29 patients have recurred, 21 patients died of disease, giving a RFS and DSS of 42% and 58%, respectively. Mean (median) time to recurrence was 10.2 months (9 months). A total of 60% of patients received peri-operative chemotherapy in this cohort. These findings are consistent with prior reports of such oncologic outcomes in node-positive patients in open series.

Conclusions: The oncologic follow-up of patients undergoing RARC with LN positive disease appears to have acceptable outcomes during medium term (mean 29 months) follow-up. As our follow-up increases, we expect to continue to accurately define the long-term clinical suitability and oncologic success of this procedure in this high-risk population.

No significant financial relationships to disclose.
The role of PET-CT in the follow-up of patients with urothelial cancer diagnosis.
Authors: Jankilevich G. , Ogresta F. , Gennari L. , Ominetti A. , Bermudez M. , Peña F. , Eleta M.
Published: February 2017

291

Background: Positron emission tomography (PET) is an imaging technique whose principle is the detection of metabolic activity of tumor cells but in urology its use had been restricted due to urinary excretion of the radiotracer and overlap with urological structures, the use of hybrid PET (PET-CT) would allow its use for monitoring patients with urothelial tumors.

Methods: Between 2007 and 2010 we performed PET-TC images in consecutive patients with suspected recurrences in CT scan or MRI. All patients had renal, bladder and uretral cancer and were treated with urothelial cancer diagnosis. We evaluate the usefulness of FDG PET-CT and its impact on behavior therapy in suspected recurrence in patients with urothelial carcinoma, compared with conventional studies.

Results: 17 patients were studied for suspected recurrence. All patients had positive images previously on CT scan and MRI; positive PET-TC was observed in 14 and 3 studies were negative. The positive PET-CT showed more number of lesions and change the medical and surgical strategy. Of the three studies negative on PET- CT none had recurrence and remain disease free. PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool.

Conclusions: PET/CT is in a great benefit to the detection recurrence in the follow up of patients with urothelial cancer diagnosis. These results showed an increased sensitivity and specificity over previous work with conventional PET technology. In the series studied, the implementation of PET-CT (FDG) in the follow up of patients with urothelial tumors were an useful tool. However, multicenter studies and more patients are required to define its role.

No significant financial relationships to disclose.
Does bladder urothelial cancer behave differently in young patients?
Authors: Wang Z. , Li Y. , Lu H. , Zeng X. , Zhuang Q. , Zhu H. , Hu Z.
Published: February 2017

294

Background: From 2000 to 2008, the incidence of bladder urothelial cancer in the young adults was diagnosed at an increasing trend at the Tongji Hospital, China. To investigate whether bladder urothelial cancer in patients under the age of 40 years behaves significantly differently from the bladder urothelial cancer in elder patients.

Methods: From 1994 to 2008, the records of 4,568 patients with pathological diagnosis of bladder urothelial cancer presented to the Tongji Hospital were retrospectively reviewed. 82 patients were younger than 40 at the time of diagnosis. The clinicopathologic parameters were compared between this group and a serial of 164 older patients during the same time period. The Kaplan-Meier and Cox regression analyses were performed for the survival analysis.

Results: 2.05% of patients with pathological diagnosis of bladder urothelial cancer presented to the Tongji Hospital were younger than 40 years (median age 32.93). Compared to the older group, young adults group had a lower sex ratio (male-to-female ratio, 3.4:1vs.6.5:1, p<0.05); much less likely with advanced stages (the percentage of invasive tumor, i.e., T1 or above, 28.1% vs. 52.4%, p<0.01); less with a high grade (the percentage of high grade tumor, 14.6% vs. 22.6%, p<0.05); lower recurrence rate (23.2% vs. 39.6%, p<0.05); less with big tumor size (the percent of tumor size greater than 3 cm, 18.3% vs. 22.0%, p<0.05); and less with multifocal (12.2% vs. 50.6%, p<0.01). Kaplan-Meier method and the log-rank test showed a significantly better cancer specific and overall survival for the group of young patients (p<0.01). The multivariate Cox regression analyses showed the following criteria were independent prognostic factors of overall survival: bladder tumor multiplicity, size greater than 3 cm, T2 or above stage, and high grade.

Conclusions: Despite an increasing trend of diagnosis, both the pathologic features and clinical outcomes were significantly better in the young patients with bladder urothelial cancer when compared to their elderly counterparts. These findings suggested that more consevertive management approaches may be warranted for this group of patients even under the circumstances of extensive bladder involvement.

No significant financial relationships to disclose.
Evaluation of the role of second TUR for transurethral resection of bladder tumor in one piece (TURBO).
Authors: Ikeda H. , Nomura M. , Shou T. , Ishikawa K. , Kashiwagi E. , Dejima T. , Sanefuji H. , Okumura K.
Published: February 2017

298

Background: Since transurethral resection of bladder tumor in one piece (TURBO) was reported in the Journal of Urology in 2000 by Ukai, some urologists carried out TURBO. We analyzed treatment results of TURBO in our hospital and examined the value of this procedure, especially for the pathological findings, recurrence and necessity of second TUR for TURBO.

Methods: A total of 14 patients with bladder tumors carried out TURBO under spinal anesthesia, in some cases blocking the obtulater nerve, from April 2006 to June 2009 in our hospital. All cases were followed for over 1 year. The procedure is 1. point marking; 2. circular incision; 3. level incision; and 4. specimen retrieval using a needle electrode in accordance with the Ukai's method. We investigated pathological findings (margin situation), operation time, complications and recurrence.

Results: It is possible to diagnose the precise pathlogical findings by TURBO. We judged the width and depth ew in sequential section. There were no complications during and after the operation. Operation time of TURBO (35–170 min) was longer than TUR-BT. Urethral catheter holding period and hospitalization period after TURBO was the same as TUR-BT. TURBO is a relatively safe procedure even for beginners. 5 cases had a recurrence in 13 cases. 2 cases had a recurrence in under 1 year, but the locations were other places. One case had a same place recurrence after 13 months. There were no cases of same place recurrence in under 1 year among margin-negative cases. Therfore we judged that ew-negative cases had no residual cancers.

Conclusions: TURBO is a safe and useful procedure that provides precise pathological findings with minimal complications. Second TUR is not necessary for TURBO. TURBO has a possibility to be gold standard of the treatment for non-muscle invasive bladder cancer.

No significant financial relationships to disclose.
Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): Clinical characteristics, risk factors, and subsequent therapy.
Authors: Heng D. Y. , MacKenzie M. J. , Vaishampayan U. N. , Knox J. J. , Bjarnason G. A. , Tan M. , Wood L. , Donskov F. , Rini B. I. , Choueiri T. K. ,   International mRCC Database Consortium
Published: February 2017

305

Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population are poorly understood.

Methods: Data from patients with mRCC treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers.

Results: One thousand fifty-six evaluable patients were treated with VEGF-inhibitors as their first-line antiangiogenic therapy. Of those, 272 (26%) patients had PD as best response. Their initial treatment was sunitinib (n=203), sorafenib (n=51), or bevacizumab (n=18). Six percent of patients were favorable risk, 55% intermediate risk, and 39% poor risk as per Heng et al JCO 2009 prognostic factors. On multivariable analysis, predictors of PD at first restaging were KPS < 80% (OR 2.3, p < 0.0001), diagnosis to treatment < 1 year (OR 2.1, p < 0.0001), neutrophilia (OR 1.9, p = 0.0021), thrombocytosis (OR 1.7, p = 0.0068), and anemia (OR 1.6, p = 0.0058). The median progression-free survival (PFS) and overall survival (OS) in patients with primary refractory disease vs. patients without (i.e., partial response or stable disease) was 2.4 vs. 11 months (p<0.0001) and 6.8 vs. 29 months (p<0.0001), respectively. Only 108 (40%) VEGF-refractory patients proceeded to receive 2nd line VEGF inhibitors (sunitinib (n=32), sorafenib (n=44), axitinib (n=2), bevacizumab (n=4)), mTOR inhibitors (temsirolimus (n=14), everolimus (n=11)), or interferon (n=1). The response rate, PFS and OS of this second-line therapy was 9%, 2.5 months and 7.4 months, respectively. The response rate, PFS and OS of those receiving second-line VEGF vs. mTOR inhibitors was 10% vs. 6% (p=NS), 2.8 vs. 2.0 months (p=0.069) and 7.9 vs. 4.7 months (p=0.40), respectively.

Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR agents may not be better than alternate anti-VEGF agents after primary anti-VEGF failure. Investigation into the mechanism of primary resistance and alternative therapeutic strategies are needed.

[Table: see text]
A phase I trial of combined tivozanib (AV-951) and temsirolimus therapy in patients (pts) with renal cell carcinoma (RCC).
Authors: Kabbinavar F. F. , Srinivas S. , Hauke R. J. , Amato R. J. , Esteves B. , Dhillon R. , Cotreau M. M. , Al-Adhami M. , Bhargava P. , Fishman M. N.
Published: February 2017

330

Background: Tivozanib, a potent and selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has demonstrated antitumor activity in a phase II study in RCC (Proceedings of ASCO 2009, Abstract 5032). Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for treatment of advanced RCC. This phase Ib open-label study examined combination tivozanib and temsirolimus therapy in pts with advanced RCC to determine the safety and tolerability, maximum tolerated dose (MTD), and clinical activity of this drug regimen.

Methods: Pts with advanced RCC (with clear cell component) who had failed up to 1 prior VEGF-targeted therapy received daily oral tivozanib (3 wks on, 1 wk off = 1 cycle) and intravenous temsirolimus (once weekly). A standard 3+3 dose escalation design was used at four levels: 0.5 mg/d tivozanib and 15 mg/wk temsirolimus; 1.0 mg/d and 15 mg/wk; 1.5 mg/d and 15 mg/wk; and 1.5 mg/d and 25 mg/wk.

Results: As of 9/15/10, 28 pts had been treated and accrual was closed. Demographic features were: 26 male/2 female; 89% Caucasian; median age 62 years (range, 43–71); Karnofsky Performance Status of 100/90/80 for 16, 7, and 4 pts respectively (1 pt missing data). Twenty of 28 pts (71%) had received prior VEGF-targeted therapy. Median duration of treatment was 21.1 wks (range, 0.3–94.0). Treatment-related adverse events seen in ≥10% of pts were (number of pts with all grades/grade 3 toxicity): fatigue (14/3), decreased appetite (9/0), stomatitis (7/1), thrombocytopenia (6/1), diarrhea (6/0), nausea (6/1), vomiting (3/0), and decreased weight (3/0). There were no grade 4 events. The MTD of this combination was tivozanib 1.5 mg/d and temsirolimus 25 mg/wk, and no dose limiting toxicities were encountered. Clinical activity was observed, including tumor responses in pts who had failed VEGF targeted therapies.

Conclusions: The combination of tivozanib with temsirolimus was well tolerated and showed clinical activity in patients with advanced RCC. Tivozanib is the first VEGFR TKI that can be combined with temsirolimus at the full dose and schedule of both agents.

[Table: see text]
Phase I study of high-dose interleukin (HD-IL2) and sorafenib in patients with metastatic clear cell renal cell carcinoma (RCC) and melanoma.
Authors: Lam E. T. , Lesinski G. , Mortazavi A. , Kendra K. L. , Carson W. E. , Tahiri S. , Liersemann R. , Clinton S. K. , Olencki T. , Monk J. P.
Published: February 2017

337

Background: HD-IL2 has demonstrated activity for immune therapy of RCC and melanoma. Sorafenib is a multitargeted kinase inhibitor with antiangiogenic activity and may also modulate antitumor immunity. This ongoing phase I study assesses the safety, tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose of the combination of HD-IL2 and sorafenib in patients with unresectable or metastatic clear cell RCC and melanoma.

Methods: Eligible patients with ECOG PS 0-1, adequate organ function, and favorable or intermediate Motzer status (RCC patients) received up to two series of therapy. Each 82-day series consisted of two cycles of bolus HD-IL2 and 8 weeks of sorafenib. HD-IL2 (600,000 IU/kg IV q8h x 8-12 doses) was given on days 1-5 (cycle 1) and 15-20 (cycle 2). Sorafenib was given on days 29-82 and discontinued 48-72 hours prior to the next series. Dosing levels for sorafenib were (1) 200mg daily, (2) 200mg BID, (3) 200mg qAM and 400mg qPM, and (4) 400mg BID. Patients who achieved stable disease (SD), partial response (PR), or complete response (CR) after Series 1 proceeded to Series 2.

Results: Fourteen patients (8 RCC, 6 melanoma) have been treated. Nine patients completed Series 1 (5 patients came off study due to poor tolerance of HD-IL2, prior to receiving sorafenib). Six patients had SD or better (3 PR, 3 SD) after Series 1. Of these, five have completed Series 2 and one patient progressed during sorafenib treatment in the second series. No DLTs were observed at the first 3 dose levels. All observed grade 3 and 4 AEs were transient and attributable to the known toxicities of HD-IL2 or sorafenib, and were not considered DLT. Adverse events occurring more frequently in Series 2 (HD-IL2 after sorafenib) included proteinuria and dry skin. One death occurred in a patient with melanoma who received only the first cycle of HD- IL2 (never received sorafenib) and one week later experienced sudden death at home, an event reported as possibly related to the HD-IL2.

Conclusions: No DLT was seen in this study of HD-IL2 and sorafenib and the toxicity was predictable and manageable. Both RCC and melanoma patients experienced PR and SD, but not CR. Enrollment to cohort 4 is ongoing.

[Table: see text]
Chromosome 14q imbalances and pathways associated with resistance to antiangiogenic therapy in clear cell renal cell carcinoma.
Authors: Jonasch E. , Alvarez K. , Peterson L. , Tannir N. M. , Sircar K. , Tamboli P. , Monzon F. A.
Published: February 2017

339

Background: Antiangiogenic agents are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy for these agents. Hypoxia inducible factor (HIF) alpha ratios have been linked to phenotypically distinct ccRCC subpopulations. The HIF1 alpha gene is located on chromosome 14q. In this study, the goal was to determine whether chromosomal imbalances identified with SNP arrays are linked to HIF ratios, and to clinical outcome.

Methods: We obtained archival FFPE tumor specimens from 56 patients with mRCC treated with sorafenib or bevacizumab. DNA from the FFPE blocks was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain virtual karyotypes. We then evaluated candidate genes in gain/lost chromosomal regions by qPCR and immunohistochemistry (IHC) in the bevacizumab treated specimens.

Results: In the bevacizumab cohort, HIF1-alpha containing14q loss showed a significant association with worse response to treatment (CR/ PR vs. SD/PD, Fisher exact test, p = 0.0473). In addition, HIF1A mRNA expression was significantly reduced in all samples with 14q loss and was associated with PFS (HR = 2.29, 95% CI = 1.01-5.16, p = 0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss.

Conclusions: Chromosomal imbalances are associated with outcomes in ccRCC patients treated with antiangiogenic agents, and can lead to changes in gene expression. Low HIF1A expression was strongly correlated with shorter PFS. We hypothesize that loss of 14q could lead to an imbalance in HIF-1alpha/HIF-2alpha activity, leading to increased HIF-2alpha and enhanced c-Myc expression, which improves tumor cell viability and engenders resistance to cellular stress induced by antiangiogenic therapy.

No significant financial relationships to disclose.
Relationship between the loss of the retinoblastoma tumor suppressor and radiosensitivity.
Authors: Den R. B. , Ciment S. , Sharma A. , Mellert H. , Mc-Mahon S. , Dicker A. , Knudsen K. E.
Published: February 2017

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Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation. Loss of RB has been observed in 25–30% of prostate cancers and is correlated with increasing tumor stage and grade. The clinical consequences of RB loss are unknown. We have previously shown that RB loss results in a castrate resistant phenotype. We hypothesized that RB loss would downregulate the G1-S cell cycle arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to mitotic catastrophe.

Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts.

Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in all cell lines (p<0.05). Cell death was not mediated through increased apoptosis, however, there was increased cell cycling despite the presence of DNA damage in the RB knockdown cells. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05).

Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. RB status is integral to determining which therapeutic modality should be employed in the management of prostate cancer.

No significant financial relationships to disclose.
Lipid profiles and the risk of kidney cancer in the Swedish AMORIS study.
Authors: Van Hemelrijck M. , Garmo H. , Hammar N. , Walldius G. , Lambe M. , Jungner I. , Holmberg L.
Published: February 2017

342

Background: Since multiple epidemiologic studies showed a link between obesity and kidney cancer (KCa), the lipid metabolism is thought to play a role in development of KCa. With the exception of cholesterol and total fat intake, the association between changes in lipid biomarkers and KCa has not often been researched. We assessed the link between lipid profiles and KCa risk in a large prospective cohort study.

Methods: A cohort based on 85,261 persons (> 20 years old) with baseline measurements of glucose, triglycerides (TG), total cholesterol, HDL, LDL, apolipoprotein A-I and apoB was selected from the Swedish Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards models were used to analyze associations between quartiles and dichotomized values of these lipid components and KCa risk. All models were adjusted for age, gender, socioeconomic status, fasting status, history of kidney disease prior to baseline (ICD9: 580-93), and glucose, cholesterol, and TG levels (depending on the covariate of interest).

Results: During a mean follow-up of 12 years, 161 persons developed KCa (58% men). The mean age at baseline was 46 years. TG were the only lipid component for which a statistically significant association was found with risk of KCa (Hazard Ratio (HR): 1.05 (95%CI: 0.59-1.87), 1.77 (1.05-2.98), and 1.77 (1.04-3.02) for the second, third, and fourth quartile, compared to the first, with p-value for trend: 0.008). The lipid ratio of TG and HDL also showed a statistically significant positive association with risk of KCa (HR: 1.21 (0.71-2.08), 1.56 (0.94-2.58), and 1.92 (1.17-3.17) for the second, third, and fourth quartile, compared to the first, with p-value for trend: 0.004). No other associations were found between lipid components and KCa risk.

Conclusions: This detailed analysis of lipid components and risk of KCa found a relation between levels of TG and KCa risk. In contrast to previous studies, we did not find an association between cholesterol levels and KCa risk. Lipid profiles based on the markers used in this study do not seem to reflect the etiological pathway that has previously been shown between obesity and KCa. Further mechanistic studies are required to assess the link between lipid deregulation and KCa.

No significant financial relationships to disclose.
An evaluation of the role of Src in renal cancer.
Authors: Qayyum T. , McArdle P. A. , Seywright M. , Mcmillan D. C. , Aitchison M. , Edwards J. E.
Published: February 2017

358

Background: The aim of the current study was to assess the expression levels of c-Src, phosphorylated Src, dephosphorylated c-Src at 530 and the downstream marker Fak 861 in renal cancer.

Methods: In all, 60 patients undergoing potentially curative nephrectomy for localised renal cancer were included. Imunohistochemical staining was utilised to assess expression of c-Src, dephosphorlated c-Src at 530, phosphorylated Src at the Y416 site, and Fak 861. Expression was assessed using the weighted histoscore method.

Results: High membrane c-Src was associated with increased cancer specific survival (p=0.032). In addition, increased cancer-specific survival was associated with high levels of cytoplasm and membrane expression of c-Src (p=0.039). When assessed individually, membrane, cytoplasm and nuclear expression of phosphorylated Src was not significantly associated with cancer specific survival. However when membrane and cytoplasm expression was combined, high expression was associated with decreased cancer specific survival (p=0.001). Low cytoplasm Fak expression was associated with increased cancer specific survival (p=0.029). When expression of Fak was combined with phosphorylated Src, high expression was associated with decreased cancer specific survival (p=0.003). When taking together high membrane c-Src and phosphorylated Src expression, this was associated with increased cancer specific survival (p=0.029). On multivariate analysis, combined expression of membrane c-Src and phosphorylated Src (HR 0.49, 95% CI 0.24-0.99, p=0.047) and combined Fak and phosphorylated Src expression (HR 1.88, 95% CI 1.06-3.34, p=0.030) were significant independent predictors of cancer specific survival.

Conclusions: The results suggest that activated c-Src is associated with improved survival and activated Src family members are associated with decreased survival. This would suggest that another member of the Src family maybe associated with decreased survival. Further work is required to identify which of the Src family members are expressed in renal cancer and would therefore allow specific inhibitors for these Src family members to be developed.

No significant financial relationships to disclose.
Use of CXCR4 expression to predict the efficacy of sorafenib treatment in patients with metastatic renal cell carcinoma.
Authors: Guo J. , Tang B. , Sheng X. N. , Cui C. L.
Published: February 2017

359

Background: CXCR4, a chemokine receptor, is implicated in the metastastic process. Higher expression of CXCR4 in renal cell carcinoma predicts shorter disease-free survival and poorer prognosis. This study aims to investigate the relationship of CXCR4 expression with the efficacy of target drugs in treatment of metastatic renal cell carcinoma (mRCC).

Methods: A total of 58 patients with mRCC treated with target drugs (26 with sorafenib, 23 with sunitinib, 5 with pazopanib, 2 with CCI-779, and 2 with axitinib) as the first-line therapy in Beijing Cancer Hospital between 2006 and 2010 were investigated. CXCR4 expression in tissue was detected by immunohistochemistry. Survival curves were estimated according to the Kaplan-Meier method and evaluated with the Log-rank test. The correlation of CXCR4 expression with Memorial Sloan-Kettering Cancer Center criteria (MSKCC) was assessed with χ2 test. p < 0.05 was considered statistically significant.

Results: CXCR4 expression was negative in 6.9% (4/58) of patients, low in 19.0% (11/58) of patients, intermediate in 56.9% (33/58) of patients and high in 17.2% (10/58) of patients, which was not correlated with MSKCC (p = 0.143). The PFS of patients with negative or low CXCR4 expression (20.0 ± 5.9 months) was longer than those with intermediate or high expression (8.5 ± 1.3 months), which, however, was not statistically different (p = 0.131). The PFS of sorafenib-treated patients with negative or low CXCR4 expression was 20.0±8.0 months while the patients with intermediate or high CXCR4 expression was 6.0 ± 0.8 months (p = 0.038). No such correlation existed in the group of patients treated with sunitinib (p = 0.947). And median OS had not been achieved yet.

Conclusions: CXCR4 can predict the efficacy of sorafenib treatment in mRCC patients. Patients with negtive or low CXCR4 expression are more likely to obtain longer PFS than those with intermediate or high CXCR4 expression.

[Table: see text]
Use of TMPRSS2-ERG gene rearrangement and quantitative ERG expression to predict clinical recurrence after radical prostatectomy.
Authors: Klein E. A. , Falzarano S. M. , Maddala T. , Cherbavaz D. , Novotny W. F. , Millward C. , Magi-Galluzzi C.
Published: February 2017

36

Background: The association of TMPRSS2-ERG fusions and ERG expression in prostate cancer (PC) with adverse clinical outcomes has been controversial, with mixed results in the literature. We conducted a study to test whether tumor-derived gene expression profiles, including the presence of TMPRSS2-ERG fusions and ERG gene expression, are associated with clinical recurrence (cR) after radical prostatectomy (RP).

Methods: All patients with clinical stage T1/T2 prostate cancer treated with RP at CC from 1987 to 2004 were identified (n∼f2,600). A cohort sampling design was used to select 127 patients with cR and 374 patients without cR after RP. For each patient a primary Gleason pattern (GP) sample, secondary (or highest) GP sample, and an adjacent nontumor tissue sample were evaluated. Surgical Gleason Score (GS) and clinical data were centrally reviewed. RNA was extracted from 6 manually dissected 10 μ m formalin-fixed paraffin-embedded sections obtained from RP specimens and expression of TMPRSS2-ERGa, TMPRSS2-ERGb, ERG and reference genes were quantified using RT-PCR. Times to cR, PSA recurrence, and PC death were analyzed using Cox PH regression.

Results: Blocks from 441 patients were evaluable. Median F/U was 5.8 years. Patients were mostly Caucasian (83%), clinical stage T1 (66%), had baseline PSA <10 ng/mL (82%), and had surgical Gleason score ≤7 (87%). 848 tumor samples and 410 non-tumor samples were assessed. TMPRSS2-ERGa and/or TMPRSS2-ERGb fusions were present in 51.8% of tumor samples and 7.5% of non-tumor samples. There was 89% concordance (95% CI: 86%, 92%) for TMPRSS2-ERG fusion status between the 2 tumor samples for each patient. High ERG expression was strongly associated with the presence of TMPRSS2-ERG fusions (p <0.01). We did not find an association between TMPRSS2-ERG a/b gene rearrangement or ERG expression with cR, PSA recurrence, PC death, or surgical GS (p > 0.2).

Conclusions: This study was notable for the large number of cR events, use of a standardized quantitative assay, and rigorous central review of pathology and clinical data. We did not find an association of TMPRSS2-ERG gene rearrangements or ERG expression with aggressiveness of prostate cancer post RP.

[Table: see text]