bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor-directed PET imaging of bone metastases in metastatic castration-resistant prostate cancer (mCRPC) using Zr-89 labeled anti-prostate specific membrane antigen (PSMA) antibody J591.
Authors: Morris Michael J. , Pandit-Taskar Neeta , Tagawa Scott T. , Nanus David M. , Solomon Stephen Barnett , Carrasquillo Jorge A. , Reuter Victor E. , Lewis Jason Stuart , Beylergil Volkan , O' Donoghue Joseph A. , Lyashchenko Serge K. , Martinez Danny F. , Curtis Kristen Rebecca , Durack Jeremy C. , Cheal Sarah M. , Bander Neil Harrison , Scher Howard I. , Larson Steven M.
Published: February 2017

25

Background: There is no standard imaging modality that specifically and accurately images prostate cancer metastases, hampering assessments of tumor distribution, prognostication, and response. J591 is a humanized antibody that targets the external domain of PSMA, which is copiously expressed in metastatic disease and upregulated in mCRPC. We have previously reported on the feasibility, and PK and biodistribution properties of Zr-89-J591 in 10 patients (Morris et al, GU ASCO 2013). We now report on the targeting/accuracy in 49 patients with mCRPC. Methods: Following standard CT/MRI, bone scintigraphy, and FDG PET imaging, 5 mCi of Zr-89-J591 was administered intravenously. Zr-89-J591 was imaged 6-8 days after injection. Positive scan findings were confirmed, where possible, with biopsies in the following preference: Zr-89-J591 and FDG positivity, then Zr-89-J591 and FDG mismatch, and lastly standard imaging and any PET mismatch. Results: A total of 535 unique bone lesions in 49 patients were identified using all imaging modalities. 339 (63%) of these were evident on bone scans, 302 (56%) on CT, 202 (38%) on FDG PET, and 490 (92%) on Zr-89-J591 PET. The concordance between bone scans and Zr-89-J591 was 303/490 (62%). 102 sites were seen only on Zr-89-J591 and not on any other imaging modality. 44 biopsies were performed from 33 patients; 21 of those biopsies were bone. The histopathologic correlation for bone is provided in the table below. All positive biopsies were J591 positive (16/16); sensitivity of J591 was =100%, and positive predictive value (16/18) was 89%. Conclusions: Imaging using J591 PET/CT detects bone disease at greater rates than any other imaging modality tested. Biopsy data of J591 positive lesions suggest that most J591 positive lesions represent biopsy confirmed prostate metastasis. We are now testing minibodies based on J591 that may target faster, offering a more favorable imaging schedule. Clinical trial information: NCT01543659. [Table: see text]
Interstitial fibrosis in radical prostatectomy specimen treated with neoadjuvant therapy and its relationship to biochemical outcome and castration-resistant status in high-risk prostate cancer.
Authors: Hashimoto Yasuhiro , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Yoneyama Takahiro , Koie Takuya , Ohyama Chikara
Published: February 2017

251

Background: Interstitial fibrosis (IF) have been known to occur in radical prostatectomy specimens treated with hormonal therapy. We previously reported that neoadjuvant therapy for high-risk prostate cancer (Pca) with luteinizing hormone-releasing hormone (LHRH) agonist and low-dose estramustine phosphate (EMP) (LHRH + EMP) significantly improved biochemical recurrence (BCR) free survival. In this study, we quantified IF in radical prostatectomy specimens treated with neoadjuvant LHRH + EMP, and we examined whether degree of IF has impact on BCR free survival or subsequent castration-resistant status. Methods: High-risk Pca was defined by the D’Amico stratification system. A total of 103 patients with high-risk Pca were enrolled in this study from July 2005 to August 2010. The LHRH + EMP therapy included the administration of the LHRH agonist and 280 mg/day of EMP for six months before the radical prostatectomy. BCR was defined as the prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after the prostatectomy. Castration-resistant prostate cancer (CRPC) is defined by PSA or radiographic progression in the castrate levels of testosterone (< 50 ng/dL). A quantitative analysis of IF was performed using computer-assisted imaging. Results: The average patient age was 67.2 (49 to 78), and the median initial PSA level was 18.8 ng/mL (4.2–95.6). All patients completed six months of LHRH + EMP neoadjuvant therapy with no delays in the radical prostatectomy. At a median follow-up period of 64.0 months, BCR occurred in 41 patients (39.8%) and CRPC occurred in nine patients (8.7%). The average IF rate was 0.43 (0.33–0.55). The five year BCR-free survival rates for the groups with IF rates less than 0.42 and greater than 0.42 were 74.7% and 50.0%, respectively. The log-rank test was significantly different between the two groups (p = 0.010). We could not identify CRPC in the patients with IF rates less than 0.42. Conclusions: Although the present study was small and preliminary, the IF rate may have a predictive potential for biochemical outcome and the occurrence of CRPC after neoadjuvant therapy for high-risk Pca. Further study is warranted to elucidate its clinical significance.
Prospective evaluation of prescribing preferences (PPref) by U.S.-based oncologists in the postdocetaxel mCRPC patient.
Authors: Ryan Charles J. , Green Mark R. , Britton Susan L. , Buettner Arden , Lankford Maria , Neely Douglas
Published: February 2017

258

Background: In May 2013 we studied the PPref of 90 U.S.-based medical oncologists (MOs) in the setting of various progression patterns during/after docetaxel-prednisone (DP) therapy for mCRPC using a validated, proprietary, live, case-based market research tool. A core case scenario with 4 DP therapy outcomes was constructed. Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case - 59 y.o. with radical prostatectomy followed by PSA failure at 15 months (MOS) followed by salvage RT. 16 MOS post RT followed by rise in PSA and 3.5 cm pelvic node followed by over 42 MOS he responds to multiple systemic therapies (ST) including CAB, anti-androgen withdrawal, sipuleucel-T (Provenge) therapy, abiraterone-prednisone (AP). Now again has PSA progression, increasing bone disease and bone related symptoms followed by initiation of DPCT. PPref for 4 outcomes of DP were probed: (1.) 6 cycles (cy) of DP 75 mg/m2 Q 3 wk followed by pain elimination and PSA response followed by stop of DP due to cumulative myelosuppression and progressive fatigue. The pt. is more active off CT and he is PS1. 3 MOS later followed by asymptomatic 30% rise in PSA. (2.) 4 cy of DP followed by decrease in PSA, bone pain, and node size. Prior to cy 6, he has asymptomatic PSA progression. (3.) 4 cy of DP → decrease in PSA, node size, and bone pain. Prior to cy 6, he has PSA and pain progression. (4.) 2nd cy of DP followed by progression as best response, with increased bone pain, PSA, and pelvic nodal disease. Results: See Table. Conclusions: Second-line PPrefs following DPCT were scenario dependent. ENZ-based therapy is most common, even in this AP refractory patient population. Chemotherapy selection is more likely in the presence of more rapid and symptomatic disease progression. Despite the availability of active therapies, surveillance is still chosen by many in asymptomatic patients. [Table: see text]
Using NBN to predict biochemical relapse following image-guided radiotherapy (IGRT) for intermediate-risk prostate cancer (IR-PCa).
Authors: Berlin Alejandro , Lalonde Emilie , Zafarana Gaetano , Sykes Jenna , Ramnarine Varune Rohan , Lam Wan , Meng Alice , Milosevic Michael , van der Kwast Theodorus , Boutros Paul C , Bristow Robert Glen
Published: February 2017

26

Background: Despite the use of clinical prognostic factors, 20 to 40% of patients with intermediate-risk prostate cancer (IR-PCa) fail local treatment for unexplained reasons. Given that an accurate DNA damage response (DDR) may be associated with genetic instability and radioresponse, we investigated whether copy number alterations (CNAs) in DDR genes are predictive or prognostic following local treatment. Methods: Using array comparative genomic hybridization (aCGH), we characterized CNAs in biopsies derived from 126 IR-PCa pts. who underwent image-guided radiotherapy (IGRT). We studied the DDR-sensing genes: MRE11A, RAD50, NBN, ATM, and ATR. The IGRT cohort (median dose: 76.4Gy; median follow-up: 7.8yrs) was compared to a radical prostatectomy (RP) cohort (154 pts. from Memorial Sloan-Kettering Cancer Center database; median follow-up: 4.8yrs). CNAs were then tested for their independent prognostic capability using Kaplan-Meir method and Cox proportional hazard models. Results: In our IGRT cohort, m,ost frequent DDR gene CNAs were: NBN 20 of 126 (15.9%), ATR 11of 126 (8.7%), and ATM 7 of 126 (5.5%). NBN CNAs were mainly gains (19/20) and strongly correlated with increased NBN-mRNA abundance compared to NBN-neutral cases (p=0.016). CNAs in DDR genes were not associated with GS, prostate-specific antigen, or T-stage. Importantly, NBN gain ranked among the top 3.3% of all genes in terms of its strength of association with the percent of the genome altered (PGA). After adjusting for clinical factors in a multivariate model, NBN gain was a significant independent predictor of 5 years-biochemical relapse-free rate (bRFR) following IGRT (48.6% versus 78.8%; HR = 3.14, 95% CI: 1.42-6.94, p=0.004). No DDR CNA was prognostic in the RP cohort. Increased NBN mRNA expression correlated to radioresistance in vitro (i.e. clonogenic surviving fraction after 3Gy) in five prostate cancer cell lines (R2= 0.665). This relationship was not observed for any of the other DDR genes. Conclusions: NBN copy number gain or increased expression correlates with tumor genomic instability, decreased bRFR (IGRT- but not surgery-treated pts.) and intrinsic prostate cancer cell radioresistance. If validated in independent IGRT cohorts, NBN gain could be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches.
Exosomal microRNA as prognostic biomarkers in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Huang Xiaoyi , Yuan Tiezheng , Sun Zhifu , Costello Brian Addis , Quevedo Fernando , Tan Winston , Nandy Debashis , Longenbach Sherri , Wang Liang
Published: February 2017

260

Background: The purpose of this study was to evaluate cell free nucleic acid based biomarkers for prognosis in mCRPC stage. Methods: Uniformly collected blood from mCRPC patients was processed for plasma which was used for exosomal RNA extraction. RNA sequencing was applied to examine microRNA (miRNA) profiles initially in a discovery cohort of 23 mCRPC patients. The sequences from fastq files were mapped to human miRBase (release 19) for known miRNA read counts. A software package (miRDeep2) was used for novel miRNA prediction. Cox regression was used for association of candidate miRNAs with overall survival (OS), defined as time from development of mCRPC to death or last follow up after adjusting for Gleason Score (GS) and time on androgen deprivation (AD) for hormone sensitive disease. miRNAs significantly associated with OS (FDR<0.05) were then validated in an independent cohort of 100 mCRPC subjects using univariate Cox regression. Results: RNA sequencing generated >10 million mappable reads per specimen in the discovery cohort. Among these reads ~50% were known miRNAs which included 1237 unique RNA sequences. Due to low abundance of most RNA transcripts, only miRNAs (n=250) with >/= 32 reads (on average) were analyzed. Four mRNAs (miR-1290, -1246, -375 and a predicted miRNA on chr. 12) were associated with OS(FDR<0.05). These were evaluated as prognotic markers in the independent cohort (N=100) using real time RT-PCR. Median time on AD for this cohort prior to progression to mCRPC was 35.7 (range: 3.5-136) months; median GS was 7; median follow up after mCRPC development was 12.5 (1-41) months at which time 28 patients had died. Elevated expression for miR-1290 and -375 were associated with shorter OS after adjusting for GS and AD time with a Hazard Ratio (HR) for miR-375 of 1.19 (CI: 1.006-1.18); (p=0.04) and a HR for miR1290 of 1.58 (CI:1.01-2.4); (p=0.04). A stronger association with shorter OS was observed for elevated expression of both miRs-HR of 2.02 (CI: 1.1-3.6) (p=0.01). Conclusions: Blood-based nucleic acid assays are easily accessible for biomarker development in mCRPC. Results from this study suggest specific exosomal miRs are of prognostic value in mCRPC and should be validated in larger cohorts.
Presence of intraductal carcinoma of the prostate on needle biopsy as a prognostic factor for prostate cancer in radical prostatectomy patients.
Authors: Kato Masashi
Published: February 2017

268

Background: Intraductal carcinoma of the prostate (IDCP) is seen with widely invasive, biologically aggressive prostate cancer. A recent study has shown this morphologic pattern is useful for prognostication of biochemical recurrence after radical prostatectomy, whereas there is no paper to report biopsy finding of IDCP to be a positive predictor of progression-free survival (PFS) and cancer-specific survival (CSS). Methods: This retrospective study included men with high-risk prostate cancer treated with radical prostatectomy between 1991 and 2005, and we reviewed slides of biopsy samples. Presence of IDCP was defined using previously published diagnostic criteria by a single genitourinary pathologist. Analyzed factors included age, prostate-specific antigen (PSA), clinical T stage, higher biopsy Gleason score (bGS), presence of Gleason pattern five, and IDCP on biopsy samples. Finally, a total of 205 patients with high-risk prostate cancer were entered in our retrospective clinicopathological analysis. Results: Patient mean age was 68. Baseline characteristics included a PSA greater than 20 ng/ml at diagnosis in 122 cases (60%), clinical stage greater than T2 (cT) in 86 (42%), and bGS ³a8 in 150 (73%) in all patients. Follow-up period was 86 months on average. The presence of IDCP on needle biopsy was in 75 (37%). Forty-four patients showed clinical failure, and 20 patients died of the disease. Patients with IDCP showed a higher increased PSA level, higher increased bGS, and more advanced cT than those without IDCP (p < 0.0001). In univariate analysis, IDCP (p < 0.0001), cT (p < 0.0001), bGS (p = 0.0002), and presence of Gleason pattern five (p=0.004) were significantly associated with PFS; IDCP (p < 0.001) and cT (p = 0.02) were significantly associated with CSS. In multivariate analysis, IDCP (p< 0.0001; hazard ratio (HR), 3.574) and cT (p= 0.004; HR, 3.087) were significantly associated with PFS; IDCP (p = 0.001; HR, 8.405) and PSA level (p = 0.0044; HR, 2.920) were significantly associated with CSS. Conclusions: Presence of IDCP on needle biopsy can be a significant predictor of PFS and CSS when analyzing factors of biopsy samples in high risk prostate cancer.
Cytoreductive radical prostatectomy (CRP) in patients with prostate cancer (PCA) and low-volume osseous metastases.
Authors: Heidenreich Axel , Thissen Andrea K. , Piper Charlotte , Pfister David J. K. P. , Porres Daniel
Published: February 2017

272

Background: Androgen deprivation (ADT) represents the standard treatment in men with prostate cancer (PCA) and osseous metastases. Unlike therapeutic approaches in other solid tumors, RP is usually ignored due to the common view that the biology of the disease is attributed to preexisting metastases. Recently, it has been shown that potentially lethal cancers persist even after neoadjuvant ADT and chemotherapy. We explored the outcome of patients with PCA and low volume skeletal metastases who were subjected to ADT and cytoreductive radical prostatectomy (CRP). Methods: Eighteen patients with biopsy proven, completely resectable PCA, minimal osseous metastases (equal to or less than three hot spots on bone scan), absence of visceral or extensive lymph node metastases were included in the pilot study. All patients (pts) underwent neoadjuvant ADT with luteinizing hormone-releasing hormone (LHRH) analogues for 6 months. If the PSA serum level decreased to less than 0.4 ng/ml and osseous lesions disappeared on control scan, pts were considered suitable for extended RP followed by 2 years adjuvant ADT. Results: Mean age was 61 (42 to 69), the mean PSA was 96.3 (72 to 139) ng/ml and 0.29 (0 to 0.39) ng/ml at recruitment and at 6 months, respectively. Mean number of bone lesions was 1.9 (1 to 3) and all lesions disappeared after 6 months of ADT. Pathohistology revealed pT2c in 4 (22.2%), pT3a and pT3b in 3 (16.7%) and 11 (61.11%) pts, respectively. Seven (38.9%) pts and three (16.7%) pts had lymph node metastases or positive surgical margins (PSM). PSM were treated with adjuvant radiation therapy ad 66.6Gy. No Clavien grade 3 to 5 complications occurred. The mean follow-up is 29 (3 to 52) months, three (16.7%) pts relapsed. The remainder is without evidence of disease. Conclusions: CRP is feasible in well selected men with low volume osseous metastases who respond well to neoadjuvant ADT. These men have a life expectancy of around 7 years and CRP reduces the risk of locally recurrent PCA and local complications. CRP might be a new treatment option in the multimodality management of PCA and minimal metastatic disease.
Meta-analysis of randomized trials to study the impact of prednisone on toxicities and survival in metastatic castration-resistant prostate cancer.
Authors: Naik Gurudatta , Morgan Charity , Galsky Matt D. , Oh William K. , Sonpavde Guru
Published: February 2017

28

Background: The impact of daily oral prednisone (P) on toxicities and outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) is unclear. We conducted a meta-analysis of randomized trials comparing regimens that included P in only one arm. Methods: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2013. Eligible studies were selected in an unbiased manner and limited to randomized trials enrolling patients with mCRPC and comparing regimens administering P in only one arm. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Arms containing P were compared with arms without P for severe toxicities grade 3 or higher and overall survival (OS). Results: Five randomized trials were published or presented with P in only one arm: by Scher and colleagues comparing docetaxel (D) plus P versus D plus DN101 (n=953), by Higano and colleagues comparing DP versus GVAX (n=621), by Small and colleagues comparing DP versus GVAX plus D (n=394), by Fossa and colleagues comparing P versus flutamide (n=201) and by Petrylak and colleagues comparing mitoxantrone plus P versus D plus estramustine phosphate (n=770). The total number of patients was 2,939, of whom 1,471 received therapy not containing P and 1,468 received therapy containing P. All five trials were eligible for analysis of toxicities, but the Fossa trial was excluded for the OS analysis due to lack of required parameters. There was no difference between the non-P and P groups for severe toxicities (incidence rate ratio [IRR] = 0.82, p = 0.712, I2 = 97.9%). When examining toxicities as a reason for discontinuing therapy, the non-P groups were not different from the P groups (relative risk [RR] = 1.24, p = 0.413, I2 = 86.8%). The non-P groups demonstrated no difference in OS compared to the P groups (HR = 1.09, p = 0.531, I2= 79.7%). The meta-analysis is limited by the trial level design and small number of patients and does not exclude a favorable palliative impact of P. Conclusions: This meta-analysis of randomized trials in mCRPC suggests no significant impact on severe toxicities and OS with the use of daily oral prednisone.
In vitro efficacy of MAGMAS inhibition in prostate cancer.
Authors: Powers Benjamin C. , Das Bhaskar , Bouzahzah Boumediene , Van Veldhuizen Peter J. , Borrego-Diaz Reyes Emma
Published: February 2017

281

Background: Prostate cancer is the second most common cancer worldwide in males. The initial treatment in advanced cases is medical or surgical castration. The outlook declines when prostate cancer advances independently, despite the aforementioned castration. Within the last ten years, a handful of new agents have proven effective in this castration-resistant phase, but finding more effective, novel ways of treating advanced prostate cancer is warranted. MAGMAS (mitochondria-associated, granulocyte-macrophage colony stimulating factor (GM-CSF) signaling molecule) is a protein ubiquitously expressed in eukaryotic cells that plays a key role in embryonal development in a variety of species. Overexpression of MAGMAS has anti-apoptotic effects, as GM-CSF is a growth factor essential for survival, proliferation and differentiation of cells. MAGMAS and GM-CSF receptor levels have been shown to be overexpressed in prostate cancer, but do not correlate with pathological grade or clinical stage. The purpose of our study was to evaluate the efficacy of a MAGMAS inhibitor, synthesized by Dr Bhaskar Das, in androgen-dependent and androgen-independent prostate cancer cell lines, as well as in a normal prostate cell line as another control. Methods: The different cell lines were treated with MAGMAS inhibitor at various concentrations in vitro. For analysis, we used MTT Cell Proliferation assay at 24 and 48 hours, per manufacturer’s protocol. We tested MAGMAS inhibitor effect on apoptosis/necrosis, cell migration and microtubule destabilization as well. Results: After prostate cancer cell lines were treated with MAGMAS inhibitor in vitro, cell proliferation and migration decreased, apoptosis and necrosis were induced, and microtubules were destabilized, all showing more impressive results in the androgen-independent cells. MAGMAS inhibition did not affect cell proliferation in the normal prostate cells. Conclusions: In vitro studies show MAGMAS inhibition proves efficacious in both androgen-dependent and androgen-independent prostate cancer cell lines. This will be evaluated further in a xenograft mouse model.
Prevalence and adverse impact of extended antibiotic prophylaxis in urologic oncology surgery.
Authors: Mossanen Matthew , Calvert Josh , Holt Sarah , James Andrew Callaway , Wright Jonathan L. , Porter Michael P. , Gore John L.
Published: February 2017

294

Background: Providers exhibit variation in the selection of the class, dose, and duration of prescribed antibiotic prophylaxis (ABP) to prevent postsurgical infections. We sought to evaluate ABP practice patterns for common inpatient urologic oncology surgeries and ascertain the association between extended ABP and hospital-acquired Clostridium difficile (C. diff) infections. Methods: From the PREMIER database for 2007–2012, we identified patients who underwent radical prostatectomy (RP), radical or partial nephrectomy (Nephx), or radical cystectomy (RC). We defined extended ABP from charges for antibiotics ≥ 2 days after surgery; exclusive of patients with a switch in antibiotic class within 2 postoperative days for presumption of infection. We identified postoperative C. diff infections using ICD-9 diagnosis codes. Hierarchical linear regression models were constructed by procedure to identify patient and provider factors associated with extended ABP. Logistic regression models evaluated the association between extended ABP and postoperative C. diff infection, adjusting for patient and provider characteristics. Results: We identified 59,184 RP patients, 27,921 Nephx patients, and 5,425 RC patients. RC patients were more likely to receive extended ABP (56%) than RP (18%) or Nephx (29%) patients (p<0.001). Other factors associated with extended ABP included prolonged postoperative length of stay (OR ≥ 1.69, p<0.001 for all procedures), and surgical volume (p<0.001 for highest vs. lowest volume quartiles). Hospital identity explained 35% of the variability in ABP after RP, 23% after Nephx, and 20% after RC. Among Nephx and RC patients, extended ABP was associated with significantly higher odds of postoperative C. diff infection (OR 3.79, 95% CI 2.46–5.84, and OR 1.64, 95% CI 1.12–2.39, respectively). Conclusions: We identified marked hospital-level variability in extended ABP following RP, Nephx, and RC, which was associated with significantly increased odds of hospital-acquired C. diff infections. Efforts to increase provider compliance with national ABP guidelines may decrease preventable hospital-acquired infections after urologic cancer surgery.
NeuACT, a phase II, randomized, open-label trial of DN24-02: Updated analysis of HER2 expression, immune responses, product parameters, and safety in patients with surgically resected HER2+ urothelial cancer.
Authors: Bajorin Dean F. , Sharma Padmanee , Gomella Leonard G. , Plimack Elizabeth R. , O'Donnell Peter H. , Hoffman-Censits Jean H. , Flaig Thomas W. , Quinn David I. , Sims Robert Brownell , Locker Michael , Sheikh Nadeem A. , DeVries Todd , Lerner Seth P.
Published: February 2017

296^

Background: DN24-02 is an investigational autologous cellular immunotherapy (ACI) consisting of antigen presenting cells (APCs) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to granulocyte-macrophage colony-stimulating factor. In the ongoing NeuACT (N10-1; NCT01353222) trial, patients (pts) with high-risk, HER2+ urothelial cancer (UC) are randomized 1:1 to either adjuvant DN24-02 or surveillance. Updated analyses are presented. Methods: Eligibility criteria include radical surgical resection of primary ≥pT2 or pN+ UC (bladder or upper tract) with HER2 expression ≥1+ by immunohistochemistry. Pts randomized to DN24-02 undergo 3 cycles of leukapheresis and infusion at 2-week intervals. Product potency is assessed at each infusion. Immune responses and adverse events (AEs) are measured at multiple time points. Results: By July 2013, tumor specimens from 226 pts had been screened. Of these, 75% (95% CI 69–81%) had HER2 expression of ≥1+ in the primary tumor, 32% had ≥2+ and 8% had 3+. In pts with available lymph node samples (n=83), 84% (95% CI 75–91%) had a HER2 score of ≥1+ in the lymph nodes; 49% and 14% had ≥2+ and 3+, respectively. Pts with 1+ HER2 expression had similar immune responses to BA7072 as those with higher HER2 levels. APC activation (CD54 upregulation) was observed at each infusion in the first 30 pts who had completed the 3 infusions, but was typically greater at infusions 2 (median 15.56; range: 6.42–23.97) and 3 (14.69; 8.24–30.86) than infusion 1 (7.35; 4.04–14.34). In the 5 pts with available data, BA7072 and HER500 specific antibody responses increased from baseline for at least 12 months. Most (92.3%) AEs were grade 1–2 in severity, including all AEs that occurred ≤1 day after infusion. Conclusions: The high frequencies (≥75%) of ≥1+ HER2 scores in primary tumor and lymph node samples confirm that HER2 expression is common in muscle-invasive and node+ UC. DN24-02 product potency data suggest an immunologic prime-boost effect. The observed humoral responses are the first data suggesting prolonged immune responses with an ACI in UC. Most AEs were grade 1–2 in severity. Clinical trial information: NCT01353222.
Geographic and racial disparities in the utilization of low-volume cystectomy hospitals for bladder cancer.
Authors: Casey Martin Francis , Gross Tal , Stensland Kristian D. , Oh William K. , Galsky Matt D.
Published: February 2017

302

Background: Extensive research has demonstrated volume-outcome benefits for select cancer surgeries, such as cystectomy. However, barriers to the use of high volume cystectomy hospitals have not been comprehensively explored. Methods: The New York Statewide Planning and Research Cooperative System was utilized to obtain data on all inpatients who underwent cystectomy for bladder cancer from 1997-2011. Volume status was defined by dividing patients into quintiles based on the number of cystectomies performed by each hospital in 1997-2001. Multiple logistic regression was used to assess the impact of distance and race on use of low volume hospitals. Driving distances were calculated using a geographic information system. Race was stratified by the racial profile of a subject’s community to explore the underlying causes of racial disparities. Results: A cohort of 8,712 cystectomy patients was identified. The number of available high volume hospitals increased over time, consistent with regionalization of surgeries. Minimum travel distance to high volume hospitals decreased over time for the general population, but living >21 miles still increased risk for low volume hospital utilization (see Table). Racial disparities were most prominent among blacks living in black communities, despite generally living closer to high volume hospitals (median travel distance of 5.3 miles versus 16.6 miles for whites living in white communities). Conclusions: Regionalization of cystectomies has occurred in New York State, as has been observed in multiple other regions of the United States. However, geographic and racial disparities exist in the use of high volume cystectomy hospitals. [Table: see text]
EAU and NCCN surveillance guidelines for bladder cancer: Do they effectively capture recurrences following cystectomy?
Authors: Stewart Suzanne B. , Boorjian Stephen A. , Psutka Sarah P. , Cheville John C. , Thapa Prabin , Tarrell Robert F. , Tollefson Matthew K. , Thompson Robert Houston , Frank Igor
Published: February 2017

310

Background: The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) provide general guidelines for bladder cancer (BC) surveillance following radical cystectomy (RC). However, it is unclear how well these guidelines capture recurrences after surgery. Herein, we assess the ability of current guidelines to effectively capture BC recurrence following RC and propose a risk stratified and recurrence site-specific surveillance strategy. Methods: We reviewed our institutional database of 1,800 patients who underwent primary RC between 1980-2007. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods: EAU—5yrs; NCCN—2yrs. Patients were then stratified according to stage: < = pT1Nx-0, > = pT2Nx-0, pN+, and recurrence site: urothelium, abdomen, chest, other. Recurrence free survival estimates for stage groups and recurrence site were assessed with Kaplan Meier models. Results: Of the 1,800 patients, 634 (35.2%) were classified as > pT2Nx-0 and 234 (13%) as pN+ and overall 228 (12.7%) received perioperative chemotherapy. Median postoperative follow-up was 10.6yrs (IQR 6.8-15.2), during which 716 (39.8%) patients developed recurrence. Of these recurrences, 492 (68.7%) would have been detected using the NCCN guidelines and 644 (89.8%) by EAU recommendations. However, ending oncologic surveillance at 5 years would only capture 81.7% of all recurrences for < = pT1Nx-0 patients and 83% of urothelial specific recurrences across all stage groups. Capture of 90% of recurrences, by stage group, in the urothelium, abdomen and chest would require surveillance for 8yrs, 8yrs and 4yrs, respectively in < = pT1Nx-0, 6yrs, 4yrs and 3yrs in > = pT2Nx-0 and 3yrs, 3yrs and 2yrs for pN+ patients. Conclusions: Duration of surveillance recommended for BC following RC by the EAU and NCCN do not comprehensively capture recurrences seen, specifically, in low risk patients and in cases of urothelial recurrence. Guidelines using risk stratification and site-specific recurrence patterns to assign length of surveillance may allow providers to better individualize surveillance regimens.
Multi-institutional evaluation of the prognostic significance of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper-tract urothelial carcinoma (UTUC).
Authors: Bagrodia Aditya , Krabbe Laura-Maria , Gayed Bishoy A. , Kapur Payal , Darwish Oussama M. , Bernstein Ira , Xie Xian-Jin , Wood Christopher G. , Zigeuner Richard , Weizer Alon Z. , Raman Jay D. , Remzi Mesut , Langner Cord , Roscigno Marco , Bolenz Christian , Bensalah Karim , Sagalowsky Arthur I. , Shariat Shahrokh F. , Lotan Yair , Margulis Vitaly
Published: February 2017

323

Background: Alterations in the MTOR and HIF pathways may have prognostic significance in bladder carcinoma. We evaluated the predictive value of altered MTOR-pathway biomarkers in upper tract urothelial carcinoma (UTUC). Methods: Multi-institutional review of clinicopathological data on patients receiving extirpative surgery for UTUC from 1990-2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, p4E-BP, phosphorylated-AKT, PTEN, HIF-1a, Raptor and Cyclin D was performed on tissue microarrays from radical nephroureterectomy specimens. Predictive markers were identified by regression analyses. Significance of altered markers was assessed with Kaplan-Meier and Cox regression analysis. Results: 620 patients with a mean age of 69 years were included. 37% of patients had non-organ confined (T3/T4 and/or N+) disease. 74% of patients had high-grade disease and 22% had LVI on final pathology. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariable analysis, PI3K (OR 1.28, p=0.001) and Cyclin D (OR 3.45, p=0.05) were significant predictors of clinical outcomes. Cumulative marker-score was defined as low-risk (zero/one altered marker) or high-risk (Cyclin D AND PI3K altered). Patients with high-risk marker-score had a significantly higher proportion of high-grade disease (91% vs. 71%, p<0.001), non-organ confined disease (61% vs. 33%, p<0.001), LVI (35% vs. 20%, p=0.001), and lymph node metastases (22% vs. 6%, p<0.001). Kaplan-Meier analysis demonstrated a significant difference in CSM based on risk groups. On multivariable analysis for CSM incorporating non-organ confined disease, grade, LVI, tumor architecture, and marker-score, high-risk biomarker-score was an independent predictor of CSM (HR 1.5, 95%CI 1.04-2.3, p=0.03). Conclusions: Alterations in MTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of MTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens.
Clinical T1 urothelial bladder cancer: USC experience.
Authors: Alemozaffar Mehrdad , Djaladat Hooman , Cai Jie , Miranda Gus , Schuckman Anne , Daneshmand Siamak
Published: February 2017

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Background: Patients with clinical T1 (cT1) urothelial bladder cancer (UBC) present a dilemma regarding the decision to proceed with radical cystectomy (RC) or conservative therapy. We review outcomes of patients with cT1 UBC who underwent RC. Methods: Retrospective review of 1,964 patients undergoing RC for UBC at our institution from 1971-2008 revealed 442 patients with cT1 disease on last TURBT (excluding patients with any TURBT with >cT1 or receiving neoadjuvant therapy) of whom 97 had muscle present on last TURBT. Results: Of 442 patients with cT1 UBC, 260 (58.8%) remained pT2, and 58 (13.1%) had positive lymph node (LN+) at RC; therefore, 182 (41.2%) had more extensive disease pathologically than clinically. LN+ patients were more likely than pT2 to have LVI on TURBT (24.1% vs 11.5% vs 11.3%, p=0.029) and RC (67.2% vs 5.8% vs 36.3%, p<0.001). No clinical variables were associated with upstaging to >pT1 or LN+ disease on multivariate analysis (MVA). 5-yr recurrence-free survival (RFS) was 75.4% with MVA associating worse RFS with >pT2 (HR=1.819, p=0.02), LN+ (HR=8.202, p<0.001), pathologic LVI (HR=2.022, p=0.002), multifocal disease (HR=1.306, p<0.001), and increasing TURBTs (HR=1.306, p<0.001). 5-yr overall survival (OS) was 68.4% with MVA associating worse OS with increasing age (HR=2.234, p<0.001), >pT2 (HR=1.557, p=0.0055), LN+ (HR=4.391, p<0.001), pathologic LVI (HR=1.641, p=0.002), and increasing TURBTs (HR=1.116, p=0.005). When limited to patients with muscle present on last TURBT (N=97), following RC there were 65 (67%) remaining pT2, and 9 (9.3%) were LN+; therefore, 31 (33%) had more extensive pathologic disease than thought clinically. Their 5-yr RFS was 81.4% with MVA associating worse RFS with LN+ (HR=9.111, p=0.007) and increasing TURBTs (HR=1.408, p=0.028). Their 5-yr OS was 73.5% with MVA associating worse OS with LN+ (HR=7.976, p=0.004). Conclusions: Patients with cT1 UBC have a significant rate of upstaging to >pT1 or LN+ disease at cystectomy, even with muscle present at last TURBT. Although LVI may be associated with more extensive disease favoring cystectomy over conservative management, there are no reliable clinical predictors to determine upstaging.
Assessment of bone metastases in patients (pts) with urothelial carcinoma using 18F-sodium fluoride PET/CT (18F-NaF) versus 18F-fluorodeoxyglucose PET/CT (18F-FDG).
Authors: Weinberg Benjamin Adam , Lindenberg Maria Liza , Kurdziel Karen A. , Steinberg Seth M. , Liewehr David J. , Khadar Kattie , McKinney Yolanda , Choyke Peter L. , Apolo Andrea Borghese
Published: February 2017

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Background: 18F-NaF has shown improved sensitivity for bone imaging when compared to conventional planar imaging or SPECT/CT using 99mTc-MDP. We compared the number of bone lesions detected on 18F-NaF versus 18F-FDG in urothelial cancer pts with known bone metastases undergoing treatment. Methods: Pts enrolled in a prospective single-arm phase II study of cabozantinib underwent 18F-NaF and 18F-FDG scans at baseline and at 8 weeks of therapy. In a lesion-based analysis independently confirmed by a nuclear medicine physician, abnormal foci of radiotracer uptake were categorized by location (skull, spine, pelvis, thorax, or long bones) and by disease state (benign, malignant, or indeterminate). A patient-based analysis was performed to determine if findings indicated disease progression, stable disease, or improvement of disease, based on the number of lesions and standardized uptake values (SUVs). Results: 294 total bone lesions were identified at baseline in 10 pts (8 male and 2 female, ages 44-73). 18F-NaF identified more lesions than 18F-FDG at baseline, 294 vs. 119. In a paired analysis, the median difference was 11.5 more lesions detected per patient on 18F-NaF vs. 18F-FDG (by Wilcoxon signed-rank test, p = 0.023). More total thoracic bone lesions at baseline, 100 vs. 23, were also detected on 18F-NaF vs. 18F-FDG, median 6.5 vs. 1.0 with a median difference of 6 more lesions per patient on 18F-NaF (p = 0.016). 18F-NaF also detected more skull lesions at baseline, 19 vs. 1, which was clinically but not statistically significant (p = 0.250). There was general concordance in the patient-based analysis; only 1 18F-NaF scan demonstrated progressive disease while its corresponding 18F-FDG scan showed stable disease. Conclusions:18F-NaF identified more lesions than 18F-FDG at baseline, making it a good staging exam. However, there was agreement between 18F-NaF and 18F-FDG in terms of tumor response in almost all the follow-up scans. Therefore, although a greater number of bone lesions are seen in 18F-NaF compared with 18F-FDG, the clinical significance in assessing treatment response remains to be determined. Clinical trial information: NCT01688999.
Venothromboembolism and radical cystectomy: Prevalence of risk factors and comparison of anticoagulation use.
Authors: Sun Andrew , Djaladat Hooman , Schuckman Anne , Miranda Gus , Daneshmand Siamak
Published: February 2017

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Background: Radical cystectomy is a major pelvic surgery associated with relatively high rates of venothromboembolism (VTE). This study focuses on prevalence of known risk factors in patients undergoing radical cystectomy who suffered a symptomatic VTE and compared use of warfarin and heparin in prophylaxis. Methods: We conducted a retrospective review of 2,730 patients who underwent open cystectomy at USC between 1971-2012 using the IRB approved bladder cancer database. Patients who suffered VTE during the peri-operative period were identified. Preoperative, operative, and postoperative risk factors for VTE were analyzed. Data on use of anticoagulation was obtained and used to compare a historical cohort of warfarin use as prophylaxis (1971-2007) to the modern cohort of subcutaneous heparin use (2009-2012). A Chi-squared test was used to determine significance of any differences in prophylaxis use. Results: A total of 129 patients (4.7%) with symptomatic VTE were identified. 112/129 (86.8%) fit intent to cure inclusion criteria and were further evaluated for demographic information (85% male, median age 69.9, median BMI 27.9, and smoking history in 61.6%) and risk factors. Of pre-operative VTE risk factors, previous chemotherapy (9.8%) and other active medical illness (17.4%, e.g. atrial fibrillation, hypothyroidism, congestive heart failure) were most common. Median operative time was 363 minutes; median EBL was 800 ml with median transfusion of 2.0 units of PRBCs. The median day of first ambulation was POD 3, median LOS was 11 days, and a median interval between surgery and VTE diagnosis was 20.5 days. 15.1% of VTE patients also had a post-op infection. Of the 129 VTE cases, the overall rate from 1971-2007 (treated with warfarin) was 4.1%, while the rate from 2009-2012 (treated with heparin) was 6.3% (p=0.054). Percent of patients with a VTE occurring after discharge from 1971-2007 and 2009-2012 were 2.3% and 4.1%, respectively (p=0.052). Conclusions: Most VTEs occur after discharge, indicating a possible need for VTE prophylaxis beyond the immediate post-op period. There was a trend toward reduced risk of VTE with post-operative use of warfarin compared to heparin.
Assessment of bowel disorders following radial cystectomy and urinary diversion for muscle-invasive transitional cell carcinoma of the bladder.
Authors: Kramer Mario W. , Kabbani Mohammad , Kabbani Abdul-Rahman , von Klot Christoph A. J. , Tezval Hossein , Peters Inga , Herrmann Thomas R. W. , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

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Background: Articles reporting and specifying bowel disorders after radical cystectomy as long-term complications are sparse. However, numerous patients report on bowel function alteration and/or defecation disorders or even stool incontinence. For better qualification and quantification we present our data of a large cohort of patients evaluated with a newly developed questionnaire. Methods: For this purpose a novel non validated questionnaire was developed. The questionnaire was sent to 253 patients who had been treated with radical cystectomy between 2006 and 2012 to assess possible changes in bowel function and its impact on health related quality of life. Of those, 89 patients reported on their current status. Questions were related to their overall satisfaction as well as to their quality and severity of bowel disorders following pelvic surgery for bladder cancer. Results: In total 40 (44.9%) patients reported of a persistent change in bowel function after surgery. Most frequent were constipation (28.9%), diarrhea (18.4%) or both (21.1%) followed by flatulence (31.6%). Patients who experienced bowel function alteration but who are still satisfied reported predominantly of constipation (35.3%) and flatulence (41.2%) but not diarrhea. Twenty-three (25.8%) patients are currently not satisfied with their bowel function. Of those, 82.6% complaint about frequent flatulence, 75% report on softer stools, 65.2% have irritable bowel symptoms, 26.1% experience faecal incontinence and 73.9% are affected by serious life restrictions due to bowel disorder. Defecation frequency increased significantly (p<0.001). There is a significant reduction in life quality (p=0.004), medical condition (p=0.008) and energy level (p=0.035). A significant correlation could be found for higher T-stage (p<0.05) and positive lymph nodes (p<0.03). No differences could be observed between patients who received ileal-conduit vs. orthotopic neobladder or MAINZ I pouch urinary diversion. Conclusions: Long-term bowel disorders after cystectomy are an underestimated issue. A better understanding might lead to modifications of surgical procedures.
Validation of a whole-blood RNA prognostic signature in metastatic castration-resistant prostate cancer (mCRPC) patients.
Authors: Oh William K. , Chippada Venkata Uma , Wang Li , Reese Emma , Yee Tiffany , Kochukoshy Teena , Tsao Che-Kai , Galsky Matt D. , Zhu Jun , Gong Yixuan
Published: February 2017

36

Background: We developed a whole-blood RNA transcript-based six gene signature (ABL2, SEMA4D, ITGAL, C1QA, TIMP1, CDKN1A), which separates patients with metastatic castration-resistant prostate cancer (mCRPC) into high- and low-risk survival groups (Ross et al. Lancet Oncology, 2012). In this study, the prognostic utility of the signature is validated on two independent platforms: an updated qPCR platform and an RNA-sequence platform in a new cohort of patients. The dynamic changes in the gene expression are examined during disease progression in serial samples from individual patients. Methods: Whole blood RNA was extracted from PAXgene tubes drawn from 63 patients with prostate cancer representing a range of clinical disease states. Serial samples were collected from a subset of patients (n=34). Survival prediction scores were derived independently based on the RNA-transcript levels of the six genes as quantified by a new ViiA 7 qPCR platform and by Illumina RNA-sequence. Results: The six gene signature scores generated on both qPCR and RNA-sequence platforms remain highly prognostic, separating mCRPC patients into high- and low-risk survival groups (logrank test; p-value for qPCR <0.001; p-value for RNA-seq <0.001). In contrast, prostate-specific antigen (PSA) fails to predict survival in the same cohort. There is a weak correlation between PSA and the six gene score (p-value of spearman correlation=0.14), indicating that the six gene score provides unique information regarding disease status. Patients with serial blood draws demonstrated no relationship with PSA changes. Patients with localized and hormone sensitive prostate cancer had significantly lower six gene scores (p-value=0.036). Individual gene analysis revealed that two genes, ABL2 and ITGAL, as the major contributors to the prognostic score. Conclusions: Our results further validate the prognostic significance of a six gene whole blood RNA signature, using an independent cohort and independent platforms.