bluuebunny/crossref_metadata_2025_split huggingface dataset:
68Ga-DOTA-Bombesin (68Ga-RM2 or 68Ga-Bombesin) PET versus 68Ga-PSMA PET: A pilot prospective evaluation in patients with biochemical recurrence of prostate cancer.
Authors: Iagaru Andrei , Minamimoto Ryogo , Hancock Steven Lee , Mittra Erik , Loening Andreas , Vasanawala Shreyas 
Published: February 2017

331 Background: Detection of prostate cancer (PC) after biochemical recurrence (BCR) remains a great challenge. RM2 is a synthetic bombesin receptor antagonist, which targets gastrin-releasing peptide receptors (GRPr). PSMA is a membrane antigen expressed on prostate cancer cells. Here we present a comparison of 2 novel PET tracers, 68Ga-RM2 and 68Ga-PSMA, in patients with BCR with prior non-contributory conventional imaging. Methods: Ten men (67-83 year-old; mean ± SD: 74.3 ± 5.9) with BCR PC were imaged with 68Ga-RM2 and 7 of them also had 68Ga-PSMA PET. The SUVmax and SUVmean measurements were recorded in normal tissues and areas of uptake outside the expected physiologic biodistribution. Results: All 7 patients who had both scans had rising PSA (range: 3.5-36.5 ng/mL; mean±SD: 13.5 ± 11.5) and non-contributory conventional imaging (CT, MRI, 18F FDG PET/CT, 18F NaF PET/CT, 99mTc MDP bone scan). 68Ga-PSMA had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, while 68Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake values uptake outside the expected physiologic biodistribution were not statistically different between 68Ga-PSMA and 68Ga-RM2. 68Ga-PSMA localized in a lymph node and seminal vesicle in one patient with no abnormal 68Ga-RM2 uptake. In 2 patients abdominal peri-aortic lymph nodes were more easily visualized by 68Ga-RM2 due to lack of interference by radioactivity accumulation in the small intestine. Conclusions: 68Ga-PSMA and 68Ga-RM2 have distinct biodistribution in this small cohort of patients with BCR PC. High uptake in multiple areas outside the expected physiologic biodistribution suggests that both 68Ga-PSMA and 68Ga-RM2 are promising PET radiopharmaceuticals for localization of disease in patients with BCR PC and non-contributory conventional imaging. The differences in target density, biodistribution and clearance pathways may result in the superiority of one of the two tracers in different patients. 68Ga-RM2 shows similar sensitivity to 68Ga-PSMA and has the potential for being FDA-approved in the future. Clinical trial information: NCT02440308.
Correlation of galeterone-induced degradation of the androgen receptor with inhibition of a deubiquitinating enzyme.
Authors: Dransfield Daniel T. , Namdev Nivedita , Jacoby Douglas B , Ferrante Karen 
Published: February 2017

345 Background: Galeterone is a highly selective oral small molecule drug candidate that disrupts androgen receptor (AR) signaling. It degrades the AR (IC50 ~1µM), is a potent CYP17 lyase inhibitor ( < 50nM), and possesses AR antagonist activity (~600nM). Galeterone-induced AR degradation was observed in models having either full-length AR or known constitutively active truncated forms of the AR receptor that lack the ligand binding domain (LBD), AR-V7 and AR567es. The LBD of the AR is not required for galeterone-dependent AR degradation. Galeterone-induced degradation activity is blocked by co-administration of the proteasome inhibitor MG132. Furthermore, galeterone-induced degradation of AR can be blocked by selective knock-down of the E3 ligases, Mdm2 and CHIP. Methods: We utilized a series of biochemical and cell-based in vitro studies to further elucidate and characterize additional signaling molecules in the proteasomal dependent mechanism of galeterone-induced AR degradation. Results: We screened a panel of 22 deubiquitinating enzymes (DUBs) in vitro and demonstrated that galeterone inhibited enzymatic activity of the DUB, USP12 with IC50 in the single digit micromolar range. In addition, we used surface plasmon resonance to demonstrate that dose-dependent inhibition of USP12 activity involves direct binding of galeterone to USP12 and USP12/UAF1 complexes with a KD of ≤ 10µM. Conclusions: Interestingly, USP12 is a co-activator of AR and selective knock-down of this DUB has been shown to increase AR degradation. USP12 has been linked to regulation of the phosphatases PHLPPs through ubiquitination. PHLPPs dephosphorylate AKT, providing an important regulatory mechanism for controlling the PI3K/AKT pathway. Since it is known that galeterone induces an increase in pAKT and pMdm2, the latter being a substrate of activated AKT, this suggests that inhibition of USP12 regulates pAKT levels through enhanced degradation of PHLPPs via increased ubiquitination. These data suggest that a differentiating mechanism of galeterone from other AR targeting agents is through inhibition of USP12, leading to enhanced AR degradation.
Implementing a CTC-based clinical trial assay for selecting AR-V7+ patients for enrollment in a pivotal phase 3 study (ARMOR3-SV).
Authors: Dransfield Daniel T. , Ball Glyn 
Published: February 2017

348 Background: ARMOR3-SV is a randomized phase 3, multi-center study comparing galeterone to enzalutamide in men with metastatic (M1) castrate resistant prostate cancer (CRPC) expressing androgen receptor splice variant-7 mRNA (AR-V7) who have not yet received chemotherapy, or other second generation androgen signaling inhibitors. AR-V7 is a truncated, constitutively active splice variant of the androgen receptor (AR) that lacks the ligand binding domain (LBD) and has been implicated in prostate cancer progression. Recently, the presence of AR-V7 in circulating tumor cells (CTCs) has been associated with a lack of responsiveness to both abiraterone and enzalutamide, whereas galeterone, a selective small molecule that potently degrades the androgen receptor, has demonstrated activity in preclinical model systems expressing AR-V7 and clinically in patients with C-terminal loss, of which AR-V7 is the most common form. Methods: Utilizing the lab test developed at JHU as a model system, we sought to develop a clinical trial assay utilizing immunomagnetic bead isolation of CTCs followed by mRNA isolation and cDNA generation. We then developed a duplexed PCR assay using Taqman chemistry to detect the full-length AR (AR-FL) and AR-V7. Negative patient samples were used to establish the limit of blank and assay cut-off and synthetic oligonucleotides to establish the limit of detection. Results: The AR-FL and AR-V7 assay shows linear response to template dilution to the assay cut-off Ct. Blood spiked with LNCaP and LNCaP95 cells were used to demonstrate assay suitability and sensitivity. We have successfully detected AR-FL and AR-V7 in select CRPC patient samples. We have also demonstrated assay reproducibility and have shown that the assay remains consistent in the presence of select interfering substances. Conclusions: For the ARMOR3-SV trial, this clinical trial assay is being utilized globally at central laboratories to screen patient blood samples for AR-V7 expression in evaluable CTCs as the first criterion for inclusion in this study. Clinical trial information: NCT02438007.
Biopsychosocial distress screening using the National Comprehensive Cancer Network (NCCN) distress thermometer (DT) and patient reported outcome measurement information system (PROMIS) in an academic genitourinary (GU) medical oncology practice.
Authors: Guancial Elizabeth A. , DaSilva Christopher , Baran Andrea , Sabatka Sandra , Baumhauer Judith , Duberstein Paul 
Published: February 2017

350 Background: The NCCN defines “distress” as a “multifactorial…emotional experience…that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment.” NCCN DT scores ≥ 4 on a scale of 1-10 are associated with increased biopsychosocial distress among oncology patients. We piloted the use of an electronic tool for distress screening in an academic GU medical oncology practice to determine feasibility and impact on workflow. Methods: At each clinic visit, patients completed a modified NCCN DT with distress score only and pain interference, depression, and anxiety PROMIS domains on an iPad before meeting the clinician. Results were immediately available in the electronic medical record. Results: Between July 1, and August 31, 2015, 108 assessments were completed by 73 patients; 12% were new patients and 88% were follow-ups. Patients ranged from 30 to 93 years of age. Mean DT score was 3.67 [standard deviation (SD) 2.79]. DT scores of ≥ 4 were reported in 41% of assessments. Mean distress scores based on cancer stage were: stages 1-3, 4.04 (SD 2.96; N = 23); and stage 4, 3.56 (SD 2.75; N = 85). Mean distress scores based on cancer diagnosis were: prostate, 3.20 (SD 2.38; N = 46); urothelial, 3.97 (SD 3.35; N = 33); kidney, 3.92 (SD 2.55; N = 24); and testicular, 4.80 (SD 3.42; N = 5). Mean T scores for each of the PROMIS domains were: pain interference, 54.16 (SD 10.28; N = 103); depression, 49.54 (SD 8.95; N = 101), and anxiety, 50.79 (SD 9.37; N = 101). Median time to assessment completion was 3.77 minutes (mean 6.15 minutes). Mean times by age groups were: 50-59, 7.65 minutes (N = 21); 60-69, 5.57 (N = 48); 70-79, 11.61 (N = 16); and ≥ 80, 10.21 (N = 12). Conclusions: Electronic biopsychosocial distress screening at each clinic visit is feasible and has minimal impact on workflow. Pain interference but neither anxiety nor depression scores were increased in this population. Future research is needed on the influence of cancer stage and type on distress and on the associations between NCCN DT and PROMIS scores.
Effect of asymptomatic recurrence detection after nephroureterectomy on prognosis in patients with upper urinary tract urothelial carcinoma.
Authors: Hatakeyama Shingo , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

364 Background: It is unknown whether routine follow up with body computed tomography (CT) to detect asymptomatic visceral recurrence after nephroureterectomy improves patient survival. We accessed the impact of follow up with body CT on patient survival after nephroureterectomy. Methods: A total 212 nephroureterectomy for upper urinary tract urothelial carcinoma were performed at our hospital between Feb 1995 and Oct 2015. All patients had regular follow up with chest x-ray, urine cytology and cystoscopy every 3 to 6 months, blood biochemical test, and CT of the chest and abdomen every 6 to 12 months. Additional examinations were required for symptomatic recurrence. We investigated the first site and date of tumor recurrence. Overall survival in patients with recurrence stratified by the mode of diagnosis (asymptomatic vs. symptomatic) was estimated using the Kaplan-Meier methods and compared with the log rank test. Cox proportional hazard regression models were used to evaluate the impact of the mode of diagnosing recurrence on survival. Results: A total 43 patients (20%) experienced recurrence after surgery, of whom 31 (72%) were asymptomatic and 12 (28%) were symptomatic. The most common symptoms at recurrence were pain in 7, hematuria in 2 , appetite loss in 1 , edema in 1 , palpable mass in 1, general malaise in 1 patients. Overall survival was not significantly different between in patients with asymptomatic vs. symptomatic recurrence; however, survival after tumor recurrence were better in patients with asymptomatic recurrence (P = 0.033). Moreover, multivariate analysis showed symptomatic recurrence was selected as a risk factor for overall survival after recurrence. Conclusions: Routine oncological follow up after nephroureterectomy for early detection of asymptomatic visceral recurrence was associated with patient survival. Further study is necessary to establish the optimal follow up regimen balancing the benefit of asymptomatic detection with the increased cost of routine surveillance.
Comprehensive genomic profiling of urothelial carcinoma of the kidney and ureter: Comparison with urothelial carcinoma of the bladder and impact on potential for targeted therapy selection.
Authors: Pal Sumanta K. , Elvin Julia Andrea , Ali Siraj Mahamed , Hoffman-Censits Jean H. , Vergilio Jo-Anne , Suh James , Mian Badar , Fisher Hugh A.G. , Nazeer Tipu , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S. 
Published: February 2017

371 Background: Urothelial carcinoma of the upper tract (UTUC) has distinct clinical and pathologic features from UC of the bladder (UCB). We compared the comprehensive genomic profile (CGP) of UTUC with UCB. Methods: DNA was extracted from 40 microns of FFPE sections from 195 consecutive cases of relapsed/metastatic UTUC and 295 cases of UCB. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 627X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), insertions/deletions (INDELs), copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the UTUC patients was 65.7 years (range, 35-86); 74 (38%) were female and 121 (62%) were male. There were 174 (89%) kidney and 21 (11%) ureteral UTUCs assessed. In total, 51 (26%) and 138 (71%) were stage III and IV, respectively, at the time of CGP. Samples for sequencing were obtained from primary tumor in 157 (81%) cases and from metastatic sites in 38 (19%) cases. There were 1,243 total GA (6.4 GA/sample) involving 203 individual genes and 384 CRGA (1.97 CRGA/sample) involving 51 genes. The most frequent GA were non-CRGA mutations in TP53 (46%), CDKN2A (43%) and CDKN2B (36%). The most frequent CRGA were in FGFR3 (28%), PIK3CA (15%) and CCND1 (12%). In comparison with UCB, statistically equivalent CRGA in FGFR3 (28% vs 21%), PIK3CA (15% vs 20%) and total ERBB2 (11% vs 16%) were identified. Of the 14 UTUC with ERBB2 non-amplification alterations, 6 (43%) featured a micropapillary growth pattern virtually identical to the frequency in UCB (40%). Conclusions: CGP of UTUC uncovers a wide variety of CRGA that can respond to targeted therapy including frequent CRGA in FGFR3, PIK3CA and ERBB2. CRGA in UTUC are generally similar to those found in UCB. Further study of targeted therapy for genomically characterized cases in a clinical trial setting for UTUC appears warranted.
Comprehensive characterization of 412 muscle invasive urothelial carcinomas: Final analysis of The Cancer Genome Atlas (TCGA) project.
Authors: Lerner Seth P. , Kim Jaegil , Kwiatkowski David J. , Getz Gad , Weinstein John N. , Cherniack Andrew , Guo Guangwu , Akbani Rehan , Hoadley Katherine A. , Kim William Y. , Robertson Gordon , Mungall Andrew J. , Hinoue Toshinori , Laird Peter W. , Al-Ahmadie Hikmat , Rosenberg Jonathan E. , Bellmunt Joaquim , Bajorin Dean F. , Hansel Donna E. , Creighton Chad J. ,   TCGA Bladder Cancer Working Group
Published: February 2017

405 Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve muscle invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, microRNA and (phospho-) protein expression, transcript splicing, gene fusions, viral integration, pathway perturbation, clinical correlates, and histopathology Results: There was a high overall somatic mutation rate (8.0/Mb), as previously reported, with a median of 245 and mean of 348 coding region mutations per sample. There were 54 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. TP53 remained the most commonly mutated gene, and chromatin-modifying genes (MLL2, ARID1A, KDM6A) were also frequently mutated. KRAS, ERBB2, RB1, and ELF3 showed significant increased frequencies of mutation. High mutation burden was associated with improved outcome (p = 0.0004). APOBEC mutagenesis explained 70% of the mutation burden and also was associated with survival. 167 genes were silenced by promoter DNA hypermethylation in at least 5% of tumors. Several SMGs were also epigenetically silenced at various frequencies (ZNF773, CDKN2A, FAT1, CASP8). The previously identified four mRNA subtypes were predicted on the larger set identifying a similar proportion of samples in each subtype. We identified 5 expression subtypes based on reverse-phase protein arrays(344 tumors). Five miR expression subtypes were strongly associated with 4 mRNA-based subtypes (P = 3.8E-37) and associated with overall survival (P = 0.05). Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide a robust basis for functional studies to further our understanding of the biology of bladder cancer, and aid in the development of more precisely targeted therapies.
Impact of relapse site on oncological outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma.
Authors: Yamashita Shinichi , Ito Akihiro , Mitsuzuka Koji , Kawasaki Yoshihide , Shintaku Ichiro , Tochigi Tatsuo , Soma Fumihiko , Namima Takashige , Katoh Shinnosuke , Ota Shozo , Kyan Atsushi , Orikasa Kazuhiko , Takeda Atsushi , Numahata Kenji , Aizawa Masataka , Ioritani Naomasa , Adachi Hisanobu , Kawamorita Naoki , Kaiho Yasuhiro , Arai Yoichi ,   Tohoku Urological Evidence-Based Medicine Study Group
Published: February 2017

426 Background: Most upper urinary tract urothelial carcinomas (UTUC) are invasive and advanced with a poor prognosis. Patients often relapse after treatment with radical nephroureterectomy (RNU). However, little is known about an association between sites of recurrence after RNU and oncological outcomes. The present study retrospectively evaluated the impact of a first recurrence site on survival. Methods: A total of 650 patients with UTUC treated by RNU at 12 institutions that participated in the Tohoku Urological Evidence-Based Medicine Study Group between 2000 and 2011 were initially enrolled. Patients who experienced relapse other than intravesical recurrence after RNU were included in this study. Those who had metastasis at the time of UTUC diagnosis or missing data regarding the time and location of relapse were excluded. Finally, 173 patients were eligible to participate in this study. Survival rates were analyzed using Kaplan-Meier curves and the log-rank test, and factors predicting survival were assessed using multivariate analyses. Results: The median follow-up after relapse was nine months. The cancer-specific survival rates at one and two years after relapse were 49% and 22%, respectively. Cancer in 59 (34%), 32 (18%), 23 (13%), and 94 (53%) patients recurred in the lung, liver, bone and lymph nodes, and 23 (13%) had local recurrence. The one-year cancer-specific survival rates were 44%, 27%, 22% and 52% among patients with metastasis of the lungs, liver, bone and lymph nodes respectively, and 41% among those with local recurrence. The survival rate was worse among 48 patients with metastasis at multiple sites, than in those with metastasis at a single site. Fourteen (8%) patients with a single lymph, lung or local recurrence survived for over three years after a first relapse. Multivariate analyses selected the liver, bone and local recurrence as critical factors for cancer-specific survival. Conclusions: Liver or bone metastasis was a negative prognostic factor for UTUC with relapse after RNU. Information about recurrence sites might be helpful for patient counseling.
The impact of androgen deprivation and pelvic radiation on the development of bladder cancer.
Authors: Hafez Navid , Wang Rong , Hurwitz Michael E. , Ma Xiaomei , Petrylak Daniel Peter 
Published: February 2017

439 Background: The male predilection of urothelial bladder cancer (UBC) as well as the expression of the androgen receptor in bladder tissue point to the role for androgens in UBC tumorigenesis. Animal studies demonstrate a potential role for androgen deprivation in diminishing UBC. More recently, two separate groups demonstrated decreased rates of both primary and recurrent UBC in prostate cancer patients previously receiving androgen deprivation therapy (ADT). Given the common use of radiation therapy (RT) in the treatment of localized prostate cancer, and previous data supporting the increased frequency of UBC in prostate cancer patients treated with RT, the interaction between ADT and RT in UBC remains an important consideration. Methods: Using the linked SEER-Medicare database, we investigated the interactions among ADT, RT and UBC by performing a retrospective cohort study of elderly (age 66-99) prostate cancer patients diagnosed between 1999-2011. Kaplan-Meier analysis and Cox proportional modeling were used to determine the risk of developing secondary bladder cancer after prostate cancer treatment (based on exposure to ADT, RT, both, or neither). All analyses were two-sided. Results: Of 121,927 patients with primary prostate cancer, 1,466 (1.20%) developed subsequent UBC with a median follow up of 5.08 years (range 0.003-12.00). Compared with patients never receiving ADT or RT (n = 43,809), the hazard ratios for the development of secondary bladder cancer in patients ever receiving ADT but no RT (n = 14,009), RT but no ADT (n = 16,672), or both ADT and RT (n = 17,465) were 0.76 (95% confidence interval [CI]: 0.63-0.91 ), 0.73 (95% CI: 0.64-0.83), and 0.69 (95% CI: 0.61-0.79), respectively. Conclusions: Both ADT and RT are independently associated with a reduced risk of secondary bladder cancers in prostate cancer patients. The finding of decreased UBC incidence in patients receiving RT was surprising, and in direct contradiction to previous studies of similar patient populations. Possible explanations include differences in cohort selection, changes in RT delivery, and differences in control groups.