bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physician and patient factors influencing management recommendations in stage I testicular seminoma: A survey among radiation oncologists in the United States.
Authors: Arvold N. D. , Catalano P. J. , Sweeney C. , Hoffman K. E. , Nguyen P. L. , Balboni T. A. , Fossa S. D. , Travis L. B. , Beard C. 
Published: February 2017

225 Background: Post-orchiectomy adjuvant radiotherapy (RT) for stage I seminoma is associated with long-term toxicity, and management strategies with a lower treatment burden achieve the same excellent cure rate. Because studies suggest that radiation oncologists in the United States (U.S.) continue to recommend RT for these patients, we sought to identify factors associated with management recommendations. Methods: We conducted a one-time internet-based survey among 578 randomly selected U.S. radiation oncologists specialized in genitourinary oncology. Results: Response rate was 45% (n = 261). Forty-nine percent of respondents worked in university-affiliated practices. Sixty-two percent of respondents always/usually recommended adjuvant RT for stage I seminoma patients, whereas 21% always/usually recommended surveillance and 3% always/usually recommended chemotherapy. One-third (33%) expressed concerns that patients who relapsed during surveillance could not be salvaged, and 97% recommended against surveillance if they felt a patient was unreliable for regular follow-up. Although 88% of physicians were aware of a risk of second malignant neoplasms (SMN) after adjuvant RT, 85% underestimated the magnitude of this risk. Only 20% of physicians were aware of a possible association between sub-diaphragmatic RT and an increased risk of cardiovascular disease. Compared to physicians not typically recommending RT, physicians who always/usually recommended RT were more likely to believe that patients may not be salvaged at relapse during surveillance (p = 0.008) and were less aware of the association between RT and SMN (p = 0.04). Conclusions: Respondents who always/usually recommend post-orchiectomy RT for stage I seminoma patients are more likely to underestimate late RT morbidity and to believe surveillance is associated with increased mortality. Given the equivalent efficacy and reduced morbidity of surveillance compared to RT, our findings underscore the need for ongoing physician education to increase appropriate clinical implementation of surveillance strategies. No significant financial relationships to disclose.
Antitumor effects of AR-42, a novel histone deacetylase inhibitor, in embryonal carcinoma.
Authors: Bhinder A. S. , Varma V. , Abbaoui B. , Thomas-Ahner J. M. , Kulp S. K. , Chen C. , Clinton S. K. , Mortazavi A. 
Published: February 2017

232 Background: Histone deacetylase inhibitors (HDACIs) modulate gene expression and induce cellular differentiation, growth inhibition and apoptotic cell death by chromatin hyperacetylation. Developmental arrest of germ cell differentiation earlier in the life is responsible for the pathogenesis of germ cell tumors (GCT). With current treatment nearly 95% of patients with GCT can be cured. Yet, effective agents with less toxicity are desired. In addition, those with relapsed/refractory disease have a dismal prognosis, indicating a clear need for new, more effective agents. Here we assess the antitumor effects of AR-42, a novel HDACI in in vitro and in vivo models of embryonal carcinoma. Methods: In vitro effects of AR-42 and suberoylanilide hydroxamic acid (SAHA) were evaluated in NTERA-2, an embryonal carcinoma (EC) cell line derived from a human testicular cancer. Cell viability (MTS assay), apoptosis (caspase 3/7 activity and PARP cleavage), cell cycle analysis (flow cytometry) and HDAC inhibition (immunoblotting) were assessed. The in vivo efficacy of AR-42 was assessed in a NTERA-2 xenograft tumor model in male athymic nude mice. Mice were fed control diet and diet containing AR-42 at an average dose of 25 mg/kg/day. Tumor volumes and weights were used as in vivo endpoints. Results: Treatment of NTERA-2 cells with both agents at 0.1-10 μM concentrations showed a time- and dose-dependent reduction in cell viability. Both agents significantly induced apoptosis, cell cycle inhibition and hyperacetylation of histones H-3 and H-4 in a dose-dependent manner. In vitro studies showed that AR-42 was more potent than SAHA. In our rodent model, AR-42-containing diet resulted in a significant reduction in tumor volumes and weights (50% and 56%, respectively). The results for intratumoral changes of proliferation and apoptosis are pending. There were no significant toxicities associated with AR-42, except for testicular atrophy, known to be reversible. Conclusions: AR-42 appears to be a potent inhibitor of EC through different mechanisms, orally bioavailable and well tolerated in our rodent model. Our data indicates that AR- 42 may have clinical value in the treatment of GCT and requires further investigation in clinical trials. No significant financial relationships to disclose.
Use of metabolomic profiling to identify potential markers and mechanism for bladder cancer progression.
Authors: Putluri N. , Vasu V. T. , Shojaie A. , Thangjam G. S. , Vareed S. , Tallman C. T. , Putluri V. , Butler C. , Giri J. G. , Sana T. R. 
Published: February 2017

250 Background: Bladder cancer (BCa) is the second most prevalent urological malignancy and the fourth highest cause of cancer-related death in the United States that is known to be caused by defects in xenobiotic metabolism, which is not well understood. Using unbiased mass spectrometry we report the metabolomic profiles in BCa tissues and demonstrate its biomarker potential as well reveal a possible mechanism regulating altered xenobiotic metabolism in these tumors. Methods: Total metabolome from clinically annotated bladder-derived tissues were examined using mass spectrometry coupled to reverse and aqueous normal phase separation of compounds. Class- specific metabolites were examined in urine specimens for their biomarker potential as well as analyzed using Oncomine Concept Map for alterations in bioprocesses. The latter was validated using a collection of molecular techniques like Q-PCR, immunoblot analysis, methylation assays and use of methyl transferase inhibitor, on bladder-derived cell lines and patients specimens. Results: A total of 2,019 compounds were detected across the 58 bladder-derived specimens, of which 50 named compounds were differential between BCa and its adjacent benign tissue. These included aromatic compounds like aniline, catechols as well as polyamines and S-adenosyl methionine (SAM). A subset of these compounds, were detected in urine and could distinguish BCa from benign, non-muscle-invasive from muscle invasive tumors and delineate patients responding to chemotherapy and TURBT. Bioprocess mapping of BCa-specific metabolome revealed co-enriched concepts describing methylation and cytochrome P450 (CYP) driven xenobiotic metabolism in bladder tumors. The role of methylation in regulation of CYP activity in BCa was confirmed using a combination of Aza-treatment, methylation-specific PCR and bisulphite sequencing on bladder-derived cell lines and tissues. Conclusions: Unbiased metabolomic profiling reveals potential non-invasive metabolic markers for early detection, prognosis and therapeutic response of BCa as well as describes a role for methylation induced silencing of CYP1A1 and 1B1resulting in deficient xenobiotic metabolism in BCa. No significant financial relationships to disclose.
MC0553: A phase II safety and efficacy study with the VEGF receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer.
Authors: Pili R. , Qin R. , Flynn P. J. , Picus J. , Millward M. , Ho W. M. , Pitot H. C. , Tan W. , Erlichman C. , Vaishampayan U. N. 
Published: February 2017

259 Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma. Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle. Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending. Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. [Table: see text]
A phase 0 microdosing trial to identify chemoresistance in bladder cancer.
Authors: Pan C. , Wang S. , He M. , de Vere White R. , Lara P. , Gandara D. R. , Mack P. C. , Turteltaub K. , Henderson P. T. 
Published: February 2017

264 Background: DNA damage is the critical step in cancer cell response to platinum (Pt) chemotherapy. We hypothesize that low levels of Pt-induced DNA damage are predictive of chemoresistance. Accelerator mass spectrometry (AMS) is an ultrasensitive method for measuring radiocarbon. By measuring 14C bound to DNA, AMS can detect carboplatin-induced DNA damage after patients receive one subtoxic microdose of 14C-labeled carboplatin. Methods: Cancer cells and mice bearing tumor xenografts were treated with one microdose (1/100th of the therapeutic dose) or one therapeutic dose of [14C]carboplatin. Carboplatin-DNA adducts and other relevant parameters such as drug influx/efflux, intracellular drug inactivation, and repair of DNA damage, were measured and correlated with response to chemotherapy. Results: AMS detected Pt-DNA damage when cancer cells and mice with tumor xenografts were exposed to one microdose of [14C]carboplatin. The levels of microdose-induced DNA damage were linearly proportional to the DNA damage caused by the therapeutic drug dose (R2=0.92, p<0.001); and these levels of DNA damage correlated with chemoresistance. Low DNA damage predicts chemoresistance. Measuring drug uptake/efflux, intracellular inactivation and DNA repair allowed insight into some resistance mechanisms. We have opened a phase 0 microdosing trial to study patients with bladder cancer who are scheduled to receive Pt-based chemotherapy. One subtoxic microdose of 14C-carboplatin will be administered to these patients before biopsy. Pt-induced DNA damage and repair in left-over tumor biopsy specimens and other relevant parameters will be measured and correlated with the response and toxicity of chemotherapy. Molecular analysis of genes such as ERCC1 and RRM1 will be analyzed and compared with this phase 0 results. We have opened a similar phase 0 trial in dog patients with bladder cancer. Conclusions: The levels of DNA damage induced by nontoxic microdosing carboplatin can potentially predict chemoresistance in cancer cell lines. The clinical data of the phase 0 trial will be presented. No significant financial relationships to disclose.
Exclusive chemoradiotherapy without TURBT for frail and elderly patients with an invasive bladder cancer: Which platin fits better?
Authors: Khoury C. , Martin E. , Gauthier M. , Crehange G. , Ladoire S. , Cormier L. , Bonnetain F. , Miny J. , Bosset J. , Maingon P. 
Published: February 2017

279 Background: Frail and elderly patients (pts) with invasive bladder carcinoma (BC) are often unfit for surgery. Whether exclusive concomitant chemoradiotherapy (cCRT) without TURBT could be performed in a curative-intent remains uncertain. Methods: From 1996 to 2007, 68 pts were treated with exclusive cCRT. Median age was 77.5 years (70-91). WHO performance status (PS) at baseline were: PS 0: 27 pts; PS 1: 36 pts; PS 2; 4 pts; PS 3: 1 pt. 31 pts (45.5%) had a Charlson's score ≥ 5. Tumors were staged T1 (5 pts), T2 (44 pts), T3 (13 pts) and T4 (6 pts). 87.5% of the pts were clinically staged N0. Transuretral resection bladder tumor (TURBT) was incomplete and thus done for a diagnostic purpose only. 58 pts had an urothelial tumor (85.29%). External radiotherapy (ERT) was delivered with 1.8-2.0 daily fractions: median total dose of 63Gy [18Gy-69.4Gy] to the bladder and 92% of the pts had a whole pelvic ERT: median dose: 37.2Gy [18Gy-46Gy]. Drug was either cisplatin (CDDP) for 40 pts or carboplatin (CBDCA) for 28 pts. Overall survival (OS) and progression-free survival (PFS) rates were evaluated. Results: The rate of compliant pts with the full course of cCRT was 77.9% (53 pts). 5 pts stopped cCRT for acute urinary adverse events (AE) whereas 8 pts stopped chemotherapy only for hematological or renal biochemical AE. For late toxicity, 5 pts had a G3/4 toxicity (1 rectal bleeding, 1 urinary bleeding, 1 recto-urinary fistula, 1 urinary incontinence and 1 urinary retention). Median follow-up was 4.6 years [CI95%: 3.43-5.93]. Of the 68 pts, 14 are alive (13 recurrence-free) amongst the 61 evaluable pts and 47 have died (24 recurrence-free). OS rates at 2 and 5 years were 50% (CI95%: [37.45%-61.44%]) and 31% (CI95%: [13.67%-38.43%]). PFS rates at 2 and 5 years were 37.4% [CI95%: 25.89%-48.82%] and 22% [CI95%: 12.25%- 33.61%], respectively. OS and PFS rates were worse for pts treated with CBDCA in comparison with those treated with CDDP (p= 0.01 for OS and p= 0.03 for PFS). Combined 5-FU did not impact either OS or PFS. Conclusions: cCRT for elderly pts with a BC was feasible. For selected pts with a good PS, the adequate drug that should be combined with a conventional full course of ERT remains CDDP. No significant financial relationships to disclose.
Efficacy of immediate post-TUR mitomycin-C (MMC) instillation in high-risk non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG).
Authors: Park J. , Song K. , Jo M. 
Published: February 2017

281 Background: To evaluate the efficacy of immediate post-TUR MMC instillation in high risk non-muscle-invasive bladder cancer treated with BCG. Methods: From January 2000 to December 2007, 162 high-risk non-muscle-invasive bladder cancer patients underwent TUR and BCG instillation at our institution. Among them 76 patients received additional immediate post-TUR MMC instillation (Group A), and remaining 86 patients underwent TUR and BCG instillation only (Group B). 60mg of MMC was mixed with 50ml of normal saline and was instilled in bladder within 2 hours after TUR. Tice strain BCG 12.5mg was used with 6-week induction course followed by 3-week maintenance every 3 months. The recurrence rate, time to recurrence, and stage and grade at recurrence were investigated. The mean follow-up was 33.4 months. Results: There were no significant differences in the characteristics of both groups, including age, sex, stage, and grade. Group A showed significantly lower recurrence rate than Group B (26.3% vs 48.8%, p=0.003). Group A showed somewhat longer time to recurrence but it was not statistically different (24.9 months vs 21.8 months, p=0.293). The change in stage and grade at recurrence were not different between 2 groups ( Table ). The 5-year recurrence free survival rate was significantly higher in Group A (72% vs 42%, p=0.003). Conclusions: The immediate post-TUR MMC instillation significantly reduced recurrence in high risk non-muscle-invasive bladder cancer patients treated by BCG. But it did not influenced the stage and grade at recurrence. [Table: see text] No significant financial relationships to disclose.
Utility of quantitative fluorescent in situ hybridization (FISH) to predict non-muscle-invasive bladder cancer (NMIBC) recurrence.
Authors: Rosevear H. M. , Lightfoot A. J. , O'Donnell M. A. 
Published: February 2017

286 Background: Urovysion's (Abbot Laboratories, Downers Grove, IL) FISH analysis is used to monitor bladder cancer recurrence in patients with a history of NMIBC and is often reported as a binary variable (normal/abnormal). We investigated whether the percentage of abnormal cells as determined by FISH analysis in patients with a history of NMIBC correlated with risk of recurrence. Methods: At our institution, barbotage FISH analysis is routinely done along with cystoscopy and cytology on both high risk (Ta/T1 high grade or CIS) and low or intermediate risk patients (all others) at every 3-month follow-up for the first year post-resection. We retrospectively reviewed 241 consecutive NMIBC patients and identified 399 FISH analyses for which we had one year follow-up. Normal FISH analyses were defined as 2 or fewer abnormal cells per sample. We calculated the percentage of abnormal cells and correlated that to the number of patients who had a recurrence of NMIBC as defined by positive high grade cytology or tumor on cystoscopy during the first year of follow-up. Results: The sensitivity, specificity, and positive and negative predictive values of FISH analysis if reported as a binary variable was 55, 43, 16 and 89%, respectively. Considering only those patients with abnormal FISH, the average percentage of abnormal cells for patients who were found to have NMIBC recurrence at 1 year was 38% (range 6–100) compared to 21% (range 6–100) for patients who were recurrence-free at 1 year (p<0.0001). High risk patients who recurred within 1 year had a statistically higher percentage of abnormal cells as compared to those who did not recur within 1 year (50% [range 6–100] vs. 25% [range 6– 100], respectively p=0.001). There was no difference in the percentage of abnormal cells for those patients with low or intermediate risk disease based on recurrence within 1 year (22% [range 6–100] vs. 20% [range 6–100], respectively p=0.25). Conclusions: The percentage of abnormal cells in FISH analysis correlates with risk of recurrence for patients with high risk disease and can be used to guide surveillance interval decisions in patients with no other evidence of recurrence. [Table: see text]
Could a salvage surgery after chemotherapy have clinical impact on cancer survival in patients with metastatic urothelial carcinoma?
Authors: Bekku K. , Saika T. , Kobayashi Y. , Kishimoto R. , Edamura K. , Abarzua F. , Nasu Y. , Kumon H. 
Published: February 2017

287 Background: A clinical impact of salvage surgery after chemotherapy in patients with metastatic urothelial carcinoma on cancer survival is controversial. We verified a clinical role of salvage surgery with analyzing long-term outcome after salvage surgery in patients with metastatic urothelial carcinoma treated with cisplatin/gemcitabine/paclitaxel-based chemotherapy at a single institution. Methods: From 2003 to 2010, 31 of 47 patients (66%) with metastatic urothelial carcinoma showed objective responses (CR in 4, PR in 27) after multiple courses of the chemotherapy. Twelve of 27 patients with PR underwent salvage surgeries after the chemotherapy (10 male and 2 female, median 61.0 years old). All of the patients underwent metastatectomy of residual lesions (10 of retroperitoneal lymphnodes, 2 of lung). Seven of the patients underwent radical surgeries for primary lesions as well. Progression-free survival and overall survival of the patients were analyzed retrospectively in comparison with those of patients without salvage surgery. Results: All 12 patients could achieve surgical CR. Pathologic findings showed pathological CR in 2 patients. In median follow-up 32.5 months (range: 4.5-65.4), progression-free survival and overall survival in patients with salvage surgery were better than those in 16 PR patients without the surgery (72.9% vs 0%, and 91.7% vs 10.6% at 2 years, p=0.0005 and 0.0003; log-rank test). Conclusions: Although there were several biases in patients backgrounds (e.g., metastatic lesion, number, age), salvage surgery in patients with residual tumor after GCP chemotherapy could have strong impact on cancer survival. Surgical CR should be achieved in an affordable patient who is responder of GCP therapy. No significant financial relationships to disclose.
Robotic radical cystectomy: Medium-term oncologic follow-up.
Authors: Mmeje C. , Nunez-Nateras R. , Pruthi R. , Nielsen M. E. , Wallen E. , Humphreys M. , Castle E. P. 
Published: February 2017

288 Background: We report our experience with robot assisted radical cystectomy (RARC) with regard to medium-term (at least 2 year) oncologic outcomes. Methods: A total of 275 patients have undergone RARC and urinary diversion at two institutions for invasive bladder cancer between 2005-present. We performed a retrospective analysis of the 139 patients who underwent RARC with a minimum of 2 years follow-up. Medium term oncologic outcomes including recurrence rates, time to recurrence, recurrence free survival (RFS), disease specific survival (DSS) were analyzed. Follow-up was measured from time of surgery to time of most recent clinical follow-up. Results: This cohort of patients consisted of 108 men (78%) and 31 women (22%) at a mean age of 67.3 years (range 45-86 years). Sixty-one (44%) patients had ≤ pT2 disease, 38 (27%) pT3/T4 disease, and 40 (29%) N+ disease. The mean number of lymph nodes removed was 18 (range 3-41). The average clinical follow up in this case series was nearly 3 years with a mean of 35.9 months (range 24-64 months). At this follow-up, 39 patients have recurred, 27 patients died of disease, and 5 patients died of other causes giving an overall RFS, DSS, and OS rates of 80%, 71%, and 68%, respectively. The mean (median) time to recurrence was 12.3 months (10 months). These findings are consistent with prior reports of the oncologic outcomes for open radical cystectomy. Conclusions: The oncologic follow-up of patients undergoing RARC appears to be favorable with acceptable outcomes in the medium-term (mean – 3 years). As our follow-up increases, we should expect to truly define the long-term clinical appropriateness and oncologic success of this procedure. No significant financial relationships to disclose.