bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of overall survival and the frequency of performing transrectal ultrasound-guided biopsy of the prostate in those patients with low-risk tumors electing active surveillance.
Authors: Buethe David D. , Russell Christopher , Yue Binglin , Lin Hui-Yi , Pow-Sang Julio M.
Published: February 2017

238

Background: Limited derived benefit from definitive treatment has been observed with respect to prostate cancer−specific mortality (PCSM) in those low−risk disease and only small absolute risk reductions in both overall PCSM and incidence of metastasis have been demonstrated. Thus, active surveillance (AS) strategies have been adopted to monitor for disease progression with intent for intervention at time of disease reclassification. Yet, the timing and frequency of surveillance remain without evidence-based standardization. We assessed the relationship between the frequency of surveillance prostate biopsies and the oncologic outcomes in those patients with low−risk prostate cancer (CaP) managed by AS. Methods: An IRB approved retrospective chart review identified 114 patients placed on AS for their CaP between November of 1997 and November of 2000. Of those, 96 patients meet study inclusion criteria mandating a Gleason sum of < 7, tumor presence in < 4 sextets, involvement of <50% of any single biopsy core. Eligible patients were surveyed by serum PSA, DRE, and surveillance TRUS−guided biopsies at physician determined intervals. Results: At diagnosis, the mean age was 70.3 (SD±5.3) years with a mean PSA value of 8.2 (SD±8.2) ng/dL. While on AS, patients underwent a median of 3.5 (SD±2.02) TRUS−guided biopsies; at a frequency approaching 1 biopsy every 18 months. At a median follow−up of 134.8 months (95%CI: 114.5, 148.7), multivariate analysis found more frequent prostatic biopsy acquisition to be inversely associated a worse prognosis with respect to both progression−free (p<0.0001) and overall survival (p=0.0002). Both progression−free (p<0.0001) and overall survival (p=0.0207) were progressively shorter as the interval between biopsies declined from greater than 2 years, to 1−2 years, and then less than 1 year. Conclusions: No survival advantage was achieved by frequent re−biopsy of the prostate. Patients biopsied more frequently were paradoxically found have poorer survival outcomes.
Genomic characterization of metastatic urothelial carcinoma.
Authors: Bambury Richard M. , Riester Markus , Bellmunt Joaquim , Stack Edward C. , Werner Lillian , Park Rachel , Iyer Gopa , Loda Massimo , Kantoff Philip W. , Michor Franziska , Rosenberg Jonathan E.
Published: February 2017

247

Background: The genetic profile of primary urothelial carcinoma (UC) has been well documented but no reports analyze specific chromosomal alterations in metastatic disease. We performed molecular inversion probe array (MIP) analysis to compare chromosomal gains or losses in metastatic and primary UC samples. Methods: 33 samples of metastatic UC and 30 primary samples were analyzed from 48 patients (pts), of which paired primary and metastatic tissue was available for 14 pts. DNA from all samples was subjected to molecular inversion probe array analysis to identify focal areas of copy number gain (CNG) or loss (CNL). We focused this analysis on 21 genes from signaling pathways known to be of interest in UC (Table). CNG or CNL was defined as a log2 copy number ratio ≥ 0.8 or ≤ -0.8. GISTIC 2.0 was used to identify significantly altered regions. Results: In the loci analyzed, there were significantly more alterations in metastases than primary samples (8.4% vs 4.3% p=0.002). In particular, there was a significantly higher frequency of E2F3CNG in metastases (27% vs 7% p=0.046). There was frequent discordance in alterations when comparing primary and metastatic tissue from the same patients: 7 of 14 pts harbored potentially oncogenic CNG/CNL in their metastases that were not present in the primary. Conclusions: More alterations in UC-relevant genes were identified in metastases compared with primary tumors, in keeping with the multistep model of cumulative genetic change in cancer progression. More frequent CNG of the E2F3 gene was noted and may represent a mechanism of UC progression. Frequent discordance in alterations between primaries and metastases may be of significant clinical relevance in the future when selecting patients for appropriate molecularly targeted therapy. [Table: see text]
Impact of the USPSTF D recommendation: Early assessment of referrals for elevated PSA and prostate biopsies in a LUGPA following statement revision.
Authors: McGinley Kathleen F. , Brown Gordon Andrew
Published: February 2017

25

Background: In October 2011, the U.S. Preventative Services Task Force (USPSTF) posted for public comment the draft of their recommendation against prostate cancer screening. Extensive media coverage and discussion within the medical community ensued. The USPSTF released their formal statement of a D recommendation in May 2012. While the potential implications of the USPSTF recommendation upon prostate cancer screening will take years to manifest, the early impact of their recommendations upon the market is evaluable. Methods: The electronic medical record of a large urology group practice composed of 32 physicians was queried for two variables: the number of referrals for an elevated PSA and the number of individuals who underwent a prostate biopsy. A control period of October 2010-September 2011 was selected and compared to October 2011-September 2012, the twelve month period beginning with release of the USPSTF draft against prostate cancer screening. Results: From October 2010 to September 2011, 28698 patients were evaluated for an elevated PSA by 32 urologists; from October 2011 to September 2012, 25075 patients were evaluated by the same number of physicians, a difference of 12.6% following release of the USPSTF recommendations. From October 2010 to September 2011, 2465 patients underwent a prostate biopsy; from October 2011 to September 2012, 1989 had a biopsy, a difference of 19.3%. Conclusions: A marked decrease in the number of patients referred to a large urology group practice for evaluation of an elevated PSA, and an even greater decrease in the number of prostate biopsies performed, occurred in the 12 months following release of the USPSTF recommendations against prostate cancer screening.
Progression-free survival as an endpoint for clinical trials in first-line metastatic urothelial cancer.
Authors: Galsky Matt D. , Krege Susanne , Lin Chia-Chin , Hahn Noah M. , Ecke Thorsten , Moshier Erin L. , Sonpavde Guru , Godbold James H. , Oh William K. , Bamias Aristotelis
Published: February 2017

251

Background: Advances in the first-line treatment of metastatic urothelial cancer (UC) have proven elusive. The lack of appropriate intermediate endpoints to screen the activity of novel regimens may be a barrier to progress, particularly in this disease state characterized by relatively high response rates but short response durations. Progression-free-survival (PFS) at fixed time points may overcome several of the limitations of response rate-based endpoints, but would be further supported by establishing benchmarks and demonstrating a correlation between PFS and overall survival (OS). Methods: Data were pooled from eight phase II and III trials evaluating first-line cisplatin-based chemotherapy in metastatic UC. Landmark analyses for progression at 3, 6, and 9 months after treatment initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. Results: 545 patients were included in the analysis. The median PFS was 7.75 months (95% CI, 7.06, 8.18) and the median OS was 12.35 months (95% CI, 10.97, 13.44). The results of the landmark analysis, adjusted for performance status ≥ 1 and presence of visceral metastases, is shown in the Table. By using the Fleischer model, the estimated correlation between PFS and OS was 0.86 (bootstrap standard error 0.001, 95% CI 0.83, 0.89). Conclusions: PFS at 3, 6, and 9 months predicted OS in this analysis of patients with metastatic UC treated with first-line cisplatin-based chemotherapy. This analysis provides benchmarks, and support, for the use of PFS as an endpoint for phase II trials screening the activity of novel regimens as first-line treatment for metastatic UC. [Table: see text]
Long-term outcome of bacilles Calmette-Guerin perfusion therapy for upper urinary tract urothelial carcinoma in situ.
Authors: Yoneyama Takahiro , Sugiyama Naoki , Suzuki Yuuichirou , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

265

Background: Bacillus Calmette-Guerin (BCG) therapy has already been established as a treatment for muscle noninvasive bladder cancer. Although there are several reports indicating the effectiveness of BCG perfusion therapy for the upper urinary tract urothelial carcinoma in situ (CIS), it is not well established yet. We conducted a retrospective study to assess the long-term outcome of BCG perfusion therapy for the upper urinary tract CIS. Methods: Twenty-six subjects (20 male, 6 female) who received BCG perfusion therapy for the upper urinary tract CIS from December 1997 to December 2011 were enrolled. Ten subjects had the entire urinary tract CIS, seven had bilateral, nine had unilateral CIS of the urinary tract. The average period of observation was 52.6 months (ranging from 5 to 156 months), and the average subject age was 73.6 years (ranging from 56 to 90 years). We used a double-J catheter for 17 cases, a transvesical single-J catheter whose curl was positions in an upper calyx for eight cases, and a straight ureteral catheter inserted for ureterocutaneostomy for one case. We used 80 mg of BCG for the first five cases, 40 mg for the late twenty-one cases. Urine cytology was performed to assess the treatment validity. Results: Of the 26 cases, the treatment protocol was completed in 21 cases. Urine cytology tests became negative in 22 of the 26 subjects (84.6%) who underwent upper urinary tract perfusion. Among these 22 subjects who had negative tests, five subjects had a recurrence in their upper urinary tracts. Side effects were observed in 25 subjects (96.5%), and the most common side effect was bladder irritation. Localized renal tuberculosis which was successfully treated with conservative therapy was seen in two cases. Conclusions: BCG perfusion therapy for the upper urinary tract CIS is active. However, severe side effects are possible, and careful observation is essential while using this therapy.
Proportion of elderly patients with advanced bladder cancer receiving cisplatin-based chemotherapy: A large Medicare database study.
Authors: Chen Guoqing J. , Galsky Matt D. , Latini David M. , Sonpavde Guru
Published: February 2017

276

Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use and pattern of chemotherapy in Medicare fee-for-service elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4b, N0, M0; Any T, N1–N3, M0; Any T, Any N, M1) between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between receiving chemotherapy and patient demographics, and clinical characteristics. Results: A total of 1,031 Medicare FFS elderly patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 40.1% were T4bN0M0, 55.3% were any N1-3M0 and 4.6% were any T, any N, M1. Overall use of chemotherapy occurred in 51.6% of the study patients. Of these patients receiving chemotherapy, carboplatin accounted for 50.6% in the initial treatment, followed by cisplatin in 39.7% and other agents in 9.8%. 37.5% of patients received chemotherapy within 6 months, 14.1% after 6 months, and 48.4% had not receive any chemotherapy over the study period. There were no statistical differences according to gender, race, and age. There were variations in receiving chemotherapy by stage: T4bN0M0 (51%), any T, N1-3, M0 (52.3%) or any T, any N, MI (48.9%), p<0.05. Conclusions: Among elderly patients presenting with ABC in the SEER-Medicare linked database, only 51.6% received chemotherapy and of these only 39.7% received cisplatin. Drug development for this population should focus on chemotherapy-ineligible and cisplatin-ineligible patients. Further analysis will explore practice patterns in prescribing chemo regiments in the initial treatment of ABC and its impacts on patient outcomes.
Radiologic response (RR) by MRI in patients (pts) with muscle-invasive urothelial cancer (MIUC) undergoing neoadjuvant chemotherapy.
Authors: Qu Angela Q. , Choueiri Toni K. , Jacobus Susanna J. , Rosenberg Jonathan E. , Ramaiya Nikhil H. , Krajewski Katherine Maragaret
Published: February 2017

283

Background: Standard response criteria do not always provide a meaningful assessment of treatment benefit in pts with MIUC. We examined the utility of contrast-enhanced imaging in predicting disease free survival (DFS) in MIUC pts, and its correlation with pathological downstaging on radical cystectomy (RC) specimen. Methods: Baseline and post chemotherapy imaging, primarily gadolinium-enhanced pelvic MRI, from pts enrolled on a phase II prospective study of neoadjuvant cisplatin-based chemotherapy were reviewed by 2 oncoradiologists (NR, KK). DFS was defined as time from RC to evidence of disease progression or death. Qualitative (QL) RR was defined by at least moderate decrease in the primary tumor and lymph nodes after chemotherapy, with visually decreased primary tumor bulk by at least half, normalization of node size, and delayed enhancement of residual tumor and nodes. Quantitative (QN) RR was assessed according to anatomic TNM downstaging per AJCC staging criteria 7.0. Fisher’s exact test was used to compare RR with pathological dowstaging. DFS distributions within RR subgroups were estimated with the Kaplan-Meier method and compared using the logrank test. Results: All 39 pts from the original study were included in this analysis. At baseline, 42% of pts had cT2 disease, 42% had cT3, 16% had cT4, and 45% had N1 disease. 91% of pts had bladder primary, and 84% of pts were assessed by MRI. Results showed QL RR in 64% (90% CI 50-77) of pts, QN RR in 61% (90% CI 47-75), and ≤pT1N0M0 in 49% (90% CI 35-63). While there was no association between pathological downstaging and QN RR, there was a modest association with QL RR (p=0.096). 60% of pts with QL RR achieved ≤pT1N0M0 and 71% of pts without QL RR were >pT2. QL RR was also a strong predictor of DFS with an 18-month DFS advantage of 83% (95% CI 56-94) among responders vs. 32% (95% CI 6-63) in non-responders (p=0.036). Conclusions: QL RR post neoadjuvant therapy is modestly associated with pathological downstaging in pts with MIUC and strongly predictive of DFS. Results suggest post-chemotherapy, pre-operative imaging may be a valuable prognostic tool. Confirmation in other UC populations and treatment settings should be explored.
A study of genes and microRNAs that may predict clinical responses to anti-CTLA-4 therapy.
Authors: Gao Jianjun , Chen Hong , Ng Tang Derek , Sharma Padmanee
Published: February 2017

285

Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, Ipilimumab (BMS), has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of Ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+ T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved Phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of Ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+ T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Ipilimumab treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, Ipilimumab significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that Ipilimumab induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Ipilimumab treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.
Association of persistent, unexplained leukocytosis, a paraneoplastic syndrome, with poor prognosis in patients with urothelial carcinoma of the bladder.
Authors: Izard Jason Patrick , Gore John L. , Yu Evan Y.
Published: February 2017

291

Background: Unexplained leukocytosis, thought to be associated with paraneoplastic GCSF, has been described in several malignancies and is linked to a poor prognosis. We sought to define the disease characteristics and outcomes of those patients presenting with urothelial carcinoma and a persistently elevated WBC. Methods: We queried a prospectively maintained database at the University of Washington. Patients were included if they had a histological diagnosis of urothelial carcinoma of the bladder and a WBC of >20 x 103cells/µl. Patient charts were reviewed and were excluded from analysis if the leukocytosis was not persistent in duration or if an underlying cause for the leukocystosis could be identified. Clinical, histological and laboratory data were then collected from the remaining patient cohort. Results: We identified a total of 44 patients who met the inclusion criteria of having urothelial carcinoma of the bladder with a WBC of >20 x 103cells/µl. Of these patients, 7 (16%) patients with a median age of 61.9 (range 34 - 80) yrs at diagnosis had persistent, unexplained leukocytosis. Mixed histologies were present in 3 patients (extensive squamous differentiation in 2 and sarcomatoid differentiation in 1). At the time of presentation with leukocytosis, 5 of 7 had muscle invasive disease and 3 had evidence of metastatic disease. Leukocytosis was frequently associated with hypercalcemia (n = 5), thrombocytosis (n = 5) and anemia (n = 6). All patients died from their disease with the exception of one who is currently alive with locally advanced and unresectable disease 8 months after presentation. Median time from leukocytosis until death was 55 (range 8 - 139) days. Chemotherapy was able to achieve a WBC response in 2 of 4 patients although neither demonstrated a substantial reduction in tumor volume. Both patients ultimately developed a recurrence of their leukocytosis after chemotherapy and progression of their disease. Conclusions: The presence of leukocytosis conveys a poor prognosis. To our knowledge this represents the largest case series of patients with paraneoplastic leukocytosis secondary to urothelial carcinoma.
CEP-11981, a small molecule inhibitor of multiple angiogenic targets, in a preclinical system of urothelial carcinoma (UC).
Authors: Jian Weiguo , Levitt Jonathan M. , Lerner Seth P. , Sonpavde Guru
Published: February 2017

293

Background: The systemic therapy of advanced UC has significant unmet needs. Angiogenesis appears to play a major tumorigenic role in UC, and inhibitors of the VEGF axis have demonstrated activity in clinical trials. Ang/Tie2 and FGFR1 are angiogenic pathways that may collaborate with the VEGF pathway to promote growth. Hence, we sought to examine the preclinical activity of CEP-11981, a small molecule inhibitor of Ang/Tie2, FGFR1 and VEGFR-1-2, in UC. Methods: The in vitro anti-tumor activity of CEP-11981 was evaluated in 4 human cell-lines (5637, TCC-SUP, RT4, RT112). In vivo examination of the anti-tumor activity of different doses of daily oral CEP-11981 for up to 4 weeks was examined in subcutaneous RT4 xenografts. Harvested xenograft tumors were subjected to immunohistochemistry (IHC) to evaluate apoptosis (cleaved-caspase [cc]-3) and angiogenesis (CD31). Results: In vitro activity was not detected at low micromolar concentrations in all 4 cell-lines (attainable in human subjects). Preliminary experiments suggested that both 5 mg/kg and 10 mg/kg orally once daily induced similar regressions of RT4 xenografts, which appeared greater than regressions with 2.5 mg/kg orally once daily. Given that the weight of mice was better maintained with 5 mg/kg dose, we performed the confirmatory experiment comparing placebo with CEP-11981 at 5 mg/kg orally once daily in RT4 xenografts. At this dose, CEP-11981 significantly arrested the growth of UC xenografts compared to control (p<0.05). IHC of harvested RT4 xenografts demonstrated numerically lower angiogenesis (p=not statistically significant) but no change in cc-3. Modulation of Tie2 is being examined. Conclusions: CEP-11981 demonstrated significant preclinical cytostatic anti-tumor activity against human UC xenografts in a murine model, which was attributable to inhibition of angiogenesis. Clinical development of CEP-11981 in tolerable combination regimens and the discovery of tumor and host related biomarkers predictive for benefit are warranted.
Real-world experience with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel (D): Data from PROCEED.
Authors: Sartor A. Oliver , Cooperberg Matthew R. , Vogelzang Nicholas J. , Scholz Mark Creamer , Concepcion Raoul S. , Berry William R. , Pieczonka Christopher , Dakhil Shaker R. , Vacirca Jeffrey L. , Sandler Andrew , McCoy Candice , Whitmore James Boyd , Tyler Robert Claude , Higano Celestia S.
Published: February 2017

30^

Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The phase III IMPACT trial showed a significant improvement in overall survival with sipuleucel-T treatment (tmt). In IMPACT, D use was prohibited within 3 months prior to registration due to the potential immunosuppressive impact of chemotherapy. PROCEED is an ongoing, multicenter, phase 4 registry enrolling pts receiving sipuleucel-T in the real-world setting. Enrollment has no restrictions on D use; thus, data from PROCEED may help determine whether prior D affects sipuleucel-T manufacture. Here we present preliminary results on baseline demographics and product parameters in PROCEED subjects with and without prior D exposure. Methods: Pts who were treated with sipuleucel-T within the prior 6-months at clinical sites were asked to provide informed consent to participate in PROCEED. Results: By September 2012, 560 pts completed sipuleucel-T tmt; 15% previously received D (median 291 days prior to 1st sipuleucel-T infusion). Patients with prior D had higher PSA levels, and those with recent D use tended to have a lower performance status and higher Gleason scores, but product parameters were generally comparable between the groups (see table). Conclusions: Pts enrolled in PROCEED with and without prior D exposure had different baseline demographics and disease characteristics. However, sipuleucel-T product parameters were comparable regardless of prior D exposure. Clinical trial information: NCT01306890. [Table: see text]
Impact of baseline prognostic factors on progression-free survival at 6 months (PFS6) and response in patients receiving second-line therapy for advanced urothelial carcinoma (UC).
Authors: Pond Gregory Russell , Agarwal Neeraj , Bellmunt Joaquim , Choueiri Toni K. , Qu Angela Q. , Fougeray Ronan , Niegisch Guenter , Galsky Matt D. , Wong Yu-Ning , Stadler Walter Michael , Sridhar Srikala S. , Sternberg Cora N. , Sonpavde Guru
Published: February 2017

301

Background: PFS6 was identified to be a robust intermediate endpoint in the setting of second-line therapy for advanced UC (Sonpavde, ESMO Congress, 2012) We studied the impact of second-line prognostic factors (Sonpavde, ESMO Congress 2012) (liver metastasis [LM], anemia [Hb<10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and response rate (RR) to enable comparison of outcomes across phase II trials. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. Results: Data regarding progression, Hb, LM, PS and TFPC were available in 570 patients, who were considered evaluable. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was <6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). PFS6 and RR varied significantly according to risk group (Table). For every unit increase in risk group, the hazard of progression in 6 mo increased by 41% and the odds of response decreased by 48%. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. These data facilitate comparison of outcomes across phase II trials enrolling heterogeneous populations. [Table: see text]
Combining next-gen sequencing of TP53 and FGFR3 for detecting bladder cancer-related mutations.
Authors: Millholland John M. , Campo Maria F. , Fernandez Cecilia A. , Shuber Anthony P.
Published: February 2017

304

Background: We have recently described an ultra-deep amplicon sequencing method for FGFR3 in urine that closely replicates the sensitivity found in tissue. While FGFR3 mutations are present in a large fraction of non-invasive tumors, these mutations are rarely detected in invasive bladder tumors. To complement our existing FGFR3 deep sequencing assay, we have developed a sequencing assay for TP53. Mutations in TP53 are commonly found in advanced bladder cancer, and show little overlap with FGFR3 mutations. This proof of concept study demonstrates detection of FGFR3 and TP53 in bladder cancer tissue. Methods: The FGFR3 sequencing assay was performed as described previously, permitting the detection of 9 mutations associated with bladder cancer. Similarly, amplicons were designed against TP53 exons 5-8 using, permitting the detection of 133 unique TP53 mutations previously detected in bladder cancer. Primary amplification was performed on DNA isolated from 3 10µ tissue sections. The resulting PCR products were used as template for emulsion PCR and sequenced using the Ion Torrent PGM. Samples were analyzed for total DNA reads and number of mutant sequencing reads to determine percent mutation. Results: Previously we analyzed 151 non-invasive bladder tumor samples for the presence of FGFR3 mutations. Of these samples, 93 out of 151 (61.5%) were positive for FGFR3 mutations. An additional set of 10 high stage bladder tumor samples were analyzed for mutations in TP53. Of these samples, 5 out of 10 (50.0%) were positive for TP53 mutations, while a separate sample was found to be positive for FGFR3 only. Importantly, a TP53 mutation was detected in a Tis carcinoma in situ sample. These studies will be expanded to a larger set of bladder cancer tissues and urine samples to more accurately assess clinical performance of this FGFR3/TP53 deep sequencing assay. Conclusions: We have developed a multiplexed FGFR3 and TP53 sequencing assay that can detect mutations in a broad range of bladder cancer stages. The complementarity of mutations found in these two genes may allow for the detection of a larger fraction of patients with undiagnosed bladder cancer.
DNA repair capacity and tumor recurrence in patients with non-muscle-invasive bladder cancer (NMIBC).
Authors: Donahue Timothy F. , Donat S. Machele , Patel Himali , Chou Joanne F. , Bayuga Sharon , Olson Sara H. , Zerillo Jessica Ann , Dominguez Gemma , Leoce Nicole M. , Herr Harry W. , Orlow Irene
Published: February 2017

305

Background: NMIBC requires lifelong surveillance to monitor for recurrence. Identifying patients at greatest risk and altering surveillance accordingly could impact health care cost. Inadequate DNA repair may increase the risk for developing subsequent tumors. This prospective study evaluated the association between DNA damage/repair capacity and tumor recurrence with the goal of finding new prognostic markers. Methods: Patients newly diagnosed with NMIBC (n=100) who received standard care provided blood samples and completed risk surveys and were followed for a median of 78 mos. DNA damage in peripheral blood lymphocytes measured with the Comet Assay revealed constitutive damage, sensitivity to carcinogens after exposing cells to the tobacco-derived carcinogen BPDE, and repair capacity after allowing cells to repair post BPDE induced damage. DNA damage was expressed as log-transformed Tail Intensity. Median time to recurrence and cumulative incidence of recurrence at 4 mos were estimated by Kaplan-Meier methods and compared by log-rank test. Hazard ratios for recurrence in association with patient characteristics and DNA damage/repair variables were estimated with Cox proportional hazard models. Associations of DNA damage/repair variables between patients’ characteristics were tested with Wilcoxon Rank-Sum. Results: This NMIBC cohort included patients with mean age 64 yrs and 71% males. Tumors were high grade in 74% and multifocal in 34%. Median time to recurrence was 6 months and 42/69 recurrences occurred <4 mos. Patients with higher grade/stage, multifocality, and intravesical therapy had higher cumulative incidence of recurrence at 4 mos (p<0.01). Those with higher stage/grade compared to low stage/grade tumors showed significant reduction in DNA repair capacity after exposure to BPDE (p<0.03). Conclusions: In univariate analysis, DNA damage is associated with higher stage and higher grade tumors; however host DNA damage/repair capacity does not predict recurrence in NMIBC. Traditional disease characteristics including multifocality, high-grade, increasing stage, and intravesical therapy remained predictors of recurrence.
A multi-analyte assay for the noninvasive detection of bladder cancer.
Authors: Miyake Makito , Goodison Steve , Chang Myron , Dai Yunfeng , Urquidi Virginia , Rosser Charles Joel
Published: February 2017

306

Background: Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa. Herein, we report the diagnostic utility of various multivariate combinations of these biomarkers. Methods: We performed a case-controlled validation study in which voided urines from 550 patients (220 tumor bearing subjects) were analyzed. The urinary concentrations of 14 biomarkers (IL-8, MMP-9,MMP-10, SDC1,CCL18, PAI-1, CD44, VEGF, ANG, CA9,A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. Results: An 3-biomarker model (CA9, PAI-1 and IL-8) achieved the most accurate BCa diagnosis (sensitivity 90%, specificity 88%). These data show that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection. Conclusions: Further validation studies are under way to investigate the clinical utility of this panel of biomarkers for BCa diagnosis and disease monitoring.
Phase I trial of zirconium 89 (Zr89) radiolabeled J591 in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Morris Michael J. , Pandit-Taskar Neeta , Carrasquillo Jorge A. , O' Donoghue Joseph A. , Humm John , Lyashchenko Serge K. , Haupt Eric C. , Bander Neil Harrison , Tagawa Scott T. , Holland Jason P. , Smith-Jones Peter M. , Lewis Jason Stuart , Solomon Stephen Barnett , Scher Howard I. , Larson Steven M.
Published: February 2017

31

Background: Presently, there are no means of accurately and reproducibly imaging bone metastases for patients with mCRPC. We are investigating a prostate-specific imaging method that can directly visualize metastases using PSMA as a target and Zr89 radiolabeled anti-PSMA antibody J591 as a tracer. Following the FDA roadmap for biomarker development, we report the first human data on the tracer and its preliminary analytic validation. Methods: 5 mCi of Zr89-J591 was administered intravenously and 4 serial PET/CT scans were obtained within the following time intervals post-injection: 2-4 hours, 18-30 hours, 2-5 days, and 6-7 days. Pharmacokinetic (PK) sampling occurred at 5, 30, and 60 minutes post-injection, and at each PET scan. Patients underwent standard cross-sectional imaging, bone scintigraphy, and FDG PET scanning. Metastatic sites were biopsied in order of preference: Zr89-J591 and FDG positivity, then Zr89-J591 and FDG mismatch, and lastly standard imaging and any PET mismatch. Results: Ten patients were scanned, 132 Zr89-J591 positive sites were detected, and 12 lesions (5 bone, 6 node, 1 lung) in 8 patients were biopsied. Tissue correlation: 12/12 biopsies were positive for cancer. 11/12 biopsied lesions (5 bone, 5 node, 1 lung) were positive on Zr89-J591 imaging. 10/12 were positive by standard scans or FDG. 1 lesion was negative by Zr89-J591 PET, but positive by other modalities. Immunokinetics: Blood clearance T1/2α: 7 +/- 4.5 h (1.1-14 h); T1/2β: 62 +/- 13 h (51-89 h); Whole body clearance T1/2: 219 +/- 48 h (153-317 h). Dosimetry: Maximum retention in liver 8 +/- 1.5 SUV; Kidney 4.1 +/- 0.8 SUV; Tumor 8.2 +/- 6.5 SUV (mean SUV in bone 11.13 +/- 7.57 vs. soft tissue 4.31 +/- 2.59). Optimal time for patient imaging after injection, in terms of tumor to background ratios was 7 +/- 1 days. Conclusions: Zr89-J591 imaging demonstrates excellent tumor localization, pathology correlation, and can demonstrate the presence of tumor even when lesions are negative by standard imaging or FDG PET imaging. PK properties of the tracer have been defined. Use of Zr89-J591 to direct biopsies of metastases provides excellent yield. Further studies to examine reproducibility and post-treatment effects are planned. Clinical trial information: NCT01543659.
Selective organ preservation with neoadjuvant chemotherapy in the treatment of muscle invasive transitional cell carcinoma (TCC) of the bladder.
Authors: Hafeez Shaista , Huddart Robert Anthony
Published: February 2017

310

Background: Radiotherapy has been previously associated with high treatment failure for those with muscle invasive bladder cancer. Evidence suggests modern organ sparing approaches may have favourable outcome in appropriately selected patients. We investigate whether response to neo-adjuvant chemotherapy can guide selection for bladder preservation and identify those patients likely to have greater success with radical radiotherapy treatment. Methods: Retrospective analysis of 94 patients with T2-T4aN0M0 bladder TCC treated between January 2000 and June 2011. Patients received platinum based chemotherapy following transuretheral resection of bladder tumour, with repeat cystoscopy (+biopsy) performed to guide subsequent management. Poor responders were advised to proceed with surgery. We report on the outcome of 79 individuals who received radiotherapy. Results: 56 (60%) patients achieved complete response following chemotherapy (72% with stage T2). 15 (16%) patients achieved partial pathological response. 12 patients had radiological assessment of partial response made. 11 patients had poor response. All patients achieving complete response, 22 with partial response and 1 with poor response proceeded to radical radiotherapy. Median time to disease progression following radiotherapy was 17months (range 8-91). 5 patients developed invasive recurrence, 17 developed superficial recurrence, 4 developed local nodal disease and 7 developed metastasises. After median follow-up of 36 months (range 6-114), 50 patients were alive with no disease, 24 had died (14 from metastatic bladder cancer and 10 from other causes). 5 patients were alive with active disease (4 with localized and 1 with metastatic disease). 13 required cystectomy (9 for superficial disease, 3 for invasive recurrence, and 1 for treatment related toxicity). Of those alive and disease free 84% had an intact bladder. 82% had an intact bladder at last follow-up or death. Conclusions: Neoadjuvant chemotherapy followed by radical radiotherapy allows bladder preservation in over 80% of selected patients with survival rates comparable to contemporary surgical series.
Cost analysis of adjuvant management strategies in early-stage testicular seminoma.
Authors: Cox John A. , Gajjar Shefali R. , Lanni Thomas B. , Swanson Todd A.
Published: February 2017

320

Background: Acceptable post-orchiectomy management strategies for stage I seminoma include surveillance (SV), para-aortic (PA-RT) radiation therapy, dog-leg (DL-RT) or a single cycle of carboplatin (Carbo). The follow-up recommendations for each option were recently amended by the National Comprehensive Cancer Network (NCCN) in 2012. As such, surveillance imaging after treatment, a contributor to costs, was significantly scaled back. This was driven, in part, by the maturation of data from the MRC TE 19/EORTC 30982 study along with an effort to decrease exposure to frequent CT scans. Methods: NCCN guidelines were used to design treatment plans for each of the acceptable adjuvant treatments strategies: SV, Carbo (AUC=7), PA-RT (20 Gy), DL-RT (20 Gy) and salvage chemotherapy (bleomycin, etoposide, and cisplatin x 3 cycles). NCCN guidelines for growth factor support and anti-emetic use were incorporated into the treatments. Follow-up charges, including weighted costs for salvage for each modality, were generated for 10 years based on both the 2012 and the 2011 NCCN guidelines. According to published literature, the anticipated failure rate for SV, either DL-RT or PA-RT, or Carbo was 18%, 4%, and 5% respectively. 2012 Medicare reimbursement rates (both facility and professional charges) were used to determine the actual reimbursement for each treatment course over a 10-year period. Results: Under the current 2012 NCCN recommendations, the total Medicare reimbursement for SV, PA- RT, DL-RT, and Carbo, when factoring in the cost of salvage, were $10,643, $11,678, $9,662, and $7,870 respectively. This is compared to the reimbursement under the 2011 NCCN guidelines for SV, PA- RT, DL-RT, and Carbo of $20,986, $11,517, $9,394, and $20,365. Conclusions: Reduced imaging during SV or after adjuvant therapy has significantly narrowed the difference in reimbursement between adjuvant management options. This is driven primarily by the integration of results from the MRCTE19/EORTC 30982 outcomes and patterns of failures. We are currently in the process of using Treeage models to fine-tune treatment costs and patient variables to better assess cost-effectiveness between adjuvant treatment modalities.
Preoperative intensity modulated radiation therapy for retroperitoneal sarcoma.
Authors: El Bared Nancy , Taussky Daniel , Mehiri Selma , Patocskai Erika , Donath David
Published: February 2017

322

Background: The use of intensity modulated radiation therapy (IMRT) has allowed for the administration high doses to retroperitoneal sarcomas (RSTS) while limiting toxicity to adjacent organs. The purpose of our study is to assess the outcome and toxicities of patients with RSTS treated with neoadjuvant external beam radiation (EBRT) therapy using IMRT. Methods: This is a retrospective study of 21patients treated with preoperative IMRT for primary or recurrent RSTS between 2005 and 2011. Overall survival (OS) and local recurrence free survival (LRFS) were computed using the Kaplan-Meier method (log-rank test). Acute and chronic toxicities were assessed according to the CTCAE v. 3 criteria. Results: The actuarial 3 and 5-year OS and LRFS was 66% and 51%, 57% and 41% respectively. Factors predictive for LRFS were microscopically negative margins (p=0.022), a median tumor diameter < 15 cm (p=0.007) and a pathology of liposarcoma (p=0.021); however, patients treated for recurrent disease fared worse (p=0.04). As for OS, grade 1 histology was a predictive factor for better outcome (p=0.05). EBRT was generally well tolerated. Acute gastrointestinal grade 1 or 2 toxicity occurred in 33% of patients and one patient had unexplained post-radiation grade 2 fever that resolved after tumor resection. As for chronic toxicities 24% of our patients presented grade 1 gastrointestinal toxicity and one patient presented grade 3 small bowel stenosis not clearly due to radiation toxicity. Conclusions: Despite the location and volume of the tumors treated, preoperative IMRT was very well tolerated in our patients with retroperitoneal sarcoma. Unfortunately local recurrences remain common and dose escalation is to be considered.
Is there an intermediate risk group of nonseminoma?
Authors: Hajek Jaroslav , Cvek Jakub , Jackaninova Jana , Skacelikova Eva , Krhut Jan , Havranek Ondrej , Feltl David
Published: February 2017

323

Background: To evaluate predictive factors of testicular nonseminoma cancer. Methods: Between 2000 and 2012, 189 patients with testicular nonseminoma cancer were evaluated. Stages according to TNM classification were I, II, and III for 84 patients (60%), 49 (26%), and 56 (30%). The median age of the patients was 31 years (range 18-77 years). Treatment was based on orchiectomy plus chemotherapy (bleomycine/etoposide/cisplatin and vinblastine/ifosfamide/cisplatin) and retroperitoneal lymphadenectomy in residual disease. Treatment protocol was updated regularly according to international standards. Overall survival (OS) was evaluated according to the stage, Karnofsky index (KI), and dose intensity of chemotherapy with the Kaplan-Meier method at 5% significance level. Results: There was a significant difference between OS in patient with the different stages (log-rank test, p=0.000), however, detailed analysis revealed that there is significantly worse survival in stage IIIC only (10-years OS for IIIC vs. IIIA+B, 35% vs. 88%, p=0.001) while the difference among IIIB and lower stages was not significant (p=0.383) and 10-years OS was 94%. Dose intensity of chemotherapy proved to be a significant predictive factor for OS in stage IIIA+B patients. Patients with no dose reduction had a significantly higher OS than those with any kind of dose reduction (10-years OS 96% vs. 0%, log-rank test, p=0,000). In stage IIIC, however, the dose intensity had no influence on OS (log-rank test, p=0.167). Unlike dose intensity, in stage III disease KI had no prognostic significance for OS (KI<80 versus KI≥80, Log-rank test, p=0,627) and this is true both for stages IIIA+B and for stage IIIC. Conclusions: Standard of care in testicular nonseminoma cancer offers excellent prognosis with no significant differences in OS for good and intermediate risk groups. On the other hand, outcomes for stage IIIC are poor and further intensification of treatment is warranted. We have found no impact of performance status on OS neither for stage IIIA+IIIB nor stage IIIC. Reduction of chemotherapy dose has a negative impact on OS in patients with stage IIIA+IIIB and should be avoided if possible.
A meta-analysis of patient outcomes with subcentimeter disease after chemotherapy for metastatic nonseminomatous germ cell tumor (NSGCT).
Authors: O'Donnell Elizabeth , Gray Kathryn P. , Ravi Praful , Sweeney Christopher
Published: February 2017

324

Background: Around a quarter of men with metastatic nonseminatous germ cell tumor (NSGCT) have a residual mass, typically in the retroperitoneum, after chemotherapy. While post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is accepted to be the best way to manage large retroperitoneal masses, the treatment of small residual masses (≤1cm) is controversial. Both PC-RPLND and surveillance produce good outcomes for men in this situation, and we sought to review our experience of surveillance and synthesize the cumulative findings in the form of a meta-analysis. Methods: We searched PubMed and abstracts from ASCO and AUA to identify relevant, English language studies. Inclusion criteria was the presence of a subcentimeter post-chemotherapy retroperitoneal mass. The Dana-Farber Cancer Institute cohort was constructed from a database of men undergoing cisplatin-based chemotherapy for metastatic NSGCT. The outcomes of interest were the proportion with necrosis, teratoma or active cancer on histology at PC-RPLND, and the total number of relapses, retroperitoneal (RP)-only relapses and overall survival in men undergoing surveillance. Results: A total of 47 men formed our surveillance cohort and three relapsed with a median follow-up of 5.4 years and median time to relapse of 12.7 months. All three were alive at a median of 4.2 years after relapse with salvage therapy. On meta-analysis, the pooled estimates of necrosis, teratoma and active cancer in the 588 men who underwent PC-RPLND were 71%, 24% and 4% respectively. Of the combined 455 men who underwent surveillance, the pooled estimate of relapse rate was 5%, with an RP-only relapse rate of 3%. Overall, of the 15 men who suffered an RP-only relapse on surveillance, two died of disease. Conclusions: Surveillance is an alternative strategy for managing men with minimal residual RP disease after chemotherapy and avoids an RPLND in about 95% of men who are cured with chemotherapy alone.