bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world (RW) evidence of vinflunine in metastatic urothelial cancer (mUC): A systematic review of seven European studies.
Authors: Passalacqua Rodolfo , Medioni Jacques , Castellano Daniel E. , Ullén Anders , Bamias Aristotelis , Hussain Syed , Hegele Axel
Published: February 2018

463

Background: Vinflunine is the only chemotherapy agent for which there is a marketing authorisation in Europe for platinum-pretreated patients (pts) with mUC, based on a randomized phase III clinical trial. However, RW data regarding long-term efficacy and safety of vinflunine in unselected populations is needed. We conducted a systematic review gathering RW data from published observational European studies. Methods: Controlled studies and case series were excluded. We systematically explored the following endpoints: Overall Response Rate (ORR), Progression-Free Survival (PFS), Overall Survival (OS) and toxicity. Results: From 2014 to 2017, seven post-marketing studies including 750 pts were published: one was prospective and six were retrospective. Median ORR and median OS ranged from 13% to 29% and 6.3 to 11.9 months (mo) respectively (see Table below). In long-term survivors, OS reached 20.5 mo. Initial doses ranged from 250 to 320 mg/m2 adapted to patient’s conditions. In multivariate analysis, OS was found to be associated with the following risk-factors at baseline: ECOG PS >0, hemoglobin <10 g/dl, and presence of liver metastasis. The favorable safety profile demonstrated in randomized trials was confirmed. Main toxicity was hematological: neutropenia (G 3/4 in 1% to 23%) and anemia (G 3/4 in 4% to 33%). Constipation seemed to be less frequent than previously reported (G 3/4 in 5% to 22%). Conclusions: This is the largest experience of vinflunine use in platinum-pretreated pts with mUC. In our RW evidence, vinflunine shows both efficacy and a safe profile in an unselected patient population with similar criteria as in the pivotal trial. These findings reinforce the role of vinflunine in mUC, particularly if compared to evidence with taxanes or the increasing costs of immunotherapy.[Table: see text]
Real-world survival and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma treated with second-line therapy after platinum-based chemotherapy.
Authors: Simeone Jason C , Nordstrom Beth L , Patel Ketan , Klein Alyssa B , Horne Laura
Published: February 2018

466

Background: Median overall survival for patients with locally advanced/metastatic urothelial carcinoma (UC) who fail standard platinum-containing chemotherapy is 5–7 months, and there is no current standard of care for these patients. As immuno-oncology (IO) therapies are being developed for the treatment of UC, including some recent approvals, a better understanding of the current real-world treatment patterns and effectiveness of treatments is needed. Methods: Patients with locally advanced/metastatic UC receiving second-line therapy after platinum-based chemotherapy were identified from the Flatiron Oncology electronic medical record database from 2011–2016. Treatment patterns, including the most common regimens and total number of systemic therapy treatment lines, were characterized. Median overall survival (OS) and associated 95% confidence intervals (CI) were calculated from the start of second-line therapy using Kaplan-Meier curves. Results: A total of 476 patients met all study criteria; mean age was 70.1 ± 9.2 years and 74.2% were male; <3% were tested for PD-L1 during follow-up. Platinum-based chemotherapies were most commonly prescribed (Table 1), 4.4% received IO during second-line. Median OS from start of second-line therapy was 8.3 months (95% CI: 7.2–8.9). Conclusions: Real-world OS among locally advanced/metastatic UC patients who received second-line therapy after platinum-based chemotherapy was less than one year, similar to prior estimates. It remains to be seen how the introduction and increasing uptake of IO may affect OS. [Table: see text]
The Bristol Bladder trial: A single-arm phase II trial of cisplatin and cabazitaxel for muscle invasive transitional cell carcinoma of the urinary bladder prior to radical cystectomy.
Authors: Bahl Amit , Masson Susan , Challapalli Amarnath , Bravo Alicia , Pearson Sylvia , Hilman Serena , Persad Raj , Koupparis Anthony , Rowe Edward , Foulstone Emily , Evans Heidi , Oxley Jon , Greenwood Rosemary , Kirk Hannah , Huckett Rebecca , Kabala Julian , Ash-Miles Janice , Dailami Narges , Perks Claire , Holly Jeff
Published: February 2018

468

Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle invasive transitional cell carcinoma (MI-TCC). However response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel (CBZ) with cisplatin (CIS) in this setting. Methods: A single arm phase 2 study was designed with 80% power to detect an objective response rate (ORR) of >35%. Patients with MI-TCC were included if fit to receive neoadjuvant chemotherapy and to undergo radical cystectomy. Treatment was with CIS 70mg/m2 and CBZ 15mg/m2 on day 1 of a 21 day cycle, for 4 cycles prior to surgery. Primary prophylaxis was with pegylated GCSF. Toxicity was recorded using CTCAE v.4.03. Objective response was defined as a reduction in Tumour (T) stage from T2 or greater at diagnosis, to T1 or less at radical cystectomy. QoL data was assessed during and after chemotherapy using EQ-5D and EORTC-BLM30 questionnaires. Results: 28 patients were enrolled with median age 68.6 years (range 47-79). Response outcome (first 23 cases) and toxicity data (first 24 cases) are in this abstract; the remaining cases, currently scheduled for surgery, will be added to the final presentation. Pathological complete response (pCR) was observed in 7/23 patients (30.4%) and ORR was 56.5% (13/23). 18/24 (75%) completed 4 cycles; reasons for stopping were disease progression (2/24, 8.3%), adverse events (2/24, 8.3%) and patient choice (2/24, 8.3%). 7/24 patients (29%) experienced treatment related grade 3 and 4 adverse events. Conclusions: These results demonstrate that CIS and CBZ chemotherapy has an acceptable safety profile and is well tolerated in this setting. This combination shows promising efficacy (pCR 30.4%, ORR 56.5%) prior to definitive treatment for MI-TCC. Response outcomes for all patients and QoL data will be reported in the final presentation. Grade 3/4 adverse events. Clinical trial information: NCT01616875. [Table: see text]
Next generation sequencing of urothelial bladder cancer: Memorial Sloan Kettering Cancer Center experience in 454 patients.
Authors: Isharwal Sumit , Audenet Francois , Drill Esther N. , Ostrovnaya Irina , Pietzak Eugene J. , Al-Ahmadie Hikmat , Cha Eugene K. , Donahue Timothy F. , Teo Min Yuen , Funt Samuel , Arcila Maria E. , Berger Michael F. , Rosenberg Jonathan E. , Bajorin Dean F. , Coleman Jonathan , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Iyer Gopa
Published: February 2018

469

Background: Genomic characterization of urothelial bladder cancer (UBC) may help to identify alterations associated with tumor stage, novel therapeutic targets and biomarkers to predict outcomes. Methods: 454 UBC patients were sequenced using next generation sequencing assay (MSK−IMPACT). 264 patients (123 NMIBC, 112 MIBC and 29 metastatic) were chemotherapy naïve primary tumors. Results: Patients whose primary tumors harbored TP53, RB1, TP53/MDM2, and cell cycle pathway alterations more frequently presented with advanced disease whereas those with tumors containing FGFR3, and RTK/RAS/RAF pathway alterations generally presented with NMIBC (all FDR < 0.001). TP53, RB1, TP53/MDM2, and cell cycle pathway alterations were associated with worse overall and metastasis free survival whereas FGFR3 alterations were associated with more favorable overall and metastasis free survival (all FDR < 0.05). RTK/RAS/RAF pathway alterations were associated with more favorable metastasis free survival (FDR = 0.01). MIBC with no DDR alterations, DDR alterations of unknown significance and DDR deleterious alterations had pathologic downstaging rates of 37%, 48% and 81% with platinum-based neoadjuvant chemotherapy (p = 0.013). Patients with ERCC2 mutations had significantly higher pathologic downstaging with platinum-based neoadjuvant chemotherapy compared to patients without ERCC2 mutations (p = 0.025). MIBC with DDR alterations had better overall survival with neoadjuvant chemotherapy compared to MIBC without DDR alterations (p = 0.04). Of note, MIBC cases with and without DDR alterations have similar overall survival in the absence of neoadjuvant chemotherapy (p = 0.78). Conclusions: TP53, RB1 and FGFR3 alterations as well as TP53/MDM2, cell cycle and RTK/RAS/RAF pathway alterations showed an association with tumor stage and patient outcomes. MIBC with DDR alterations had higher pathological downstaging as well as better overall survival compared to MIBC without DDR alterations with platinum−based neoadjuvant chemotherapy. In absence of neoadjuvant chemotherapy, MIBC with and without DDR alterations have similar patient outcomes.
Utility of lymph node dissection for clinical node negative upper tract urothelial cell carcinoma: A multicenter study.
Authors: Hamilton Zachary , Haifler Miki , Krabbe Laura-Maria , Clinton Timothy N , Han Daniel , Ryan Stephen , Reddy Madhumitha , Field Charles , Bloch Aaron , Wan Fang , Uzzo Robert , Margulis Vitaly , Derweesh Ithaar
Published: February 2018

474

Background: Upper tract urothelial cell carcinoma (UTUC) is an uncommon malignancy with disparate outcomes. Although use of lymph node dissection (LND) for urothelial cell carcinoma of the bladder has survival benefit even in setting of negative nodal status, therapeutic benefit of LND in the setting of clinical node negative disease for UTUC is unclear. We evaluated survival outcomes for UTUC after LND. Methods: Multicenter retrospective analysis of UTUC patients undergoing nephroureterectomy (NU) for clinical node negative, non-metastatic disease from 2001-2016 (cTis/1-T3N0M0). The cohort was divided based on pathologic lymph node status (pNx, pN0, and pN+). Primary outcome was overall survival (OS). Secondary outcome was recurrence free survival (RFS). Cox regression (CR), logistic regression (LR) and Kaplan−Meier (KMA) analyses were utilized. Results: 191 patients were analyzed (mean age 71.1 years, mean follow up 30.4 months, 27% ureteral location). LND was performed in 40.8% (78) and pN+ was noted in 11.0% (21). Mean number of nodes removed for pN0 = 6.6 and pN+ = 3.9 (p = 0.22). On CR for worsened all-cause mortality, significance was noted for ≥pT2 (OR 1.9, p = 0.031), recurrence (OR 2.3, p = 0.003), and pN+ (OR 2.8, p = 0.004). On KMA, 5 year OS stratified by pathologic node status and nuclear grade (grade 1-2 = LG; grade 3-4 = HG) noted negative survival effect associated with pN+ and HG disease (pN0 LG 85.7%, pN0 HG 41.2%, pNx LG 58.1%, pNx HG 51.1%, pN+ HG 10.7%, log-rank p < 0.001). No patient with pN+ had LG disease. On LR HG disease was predicted only by increasing clinical tumor size (OR 1.3, p = 0.032). No significant difference in complications was noted between the groups (p = 0.1). Conclusions: In clinical node negative disease, LND for UTUC did not have survival benefit; however, LND for UTUC provided prognostic information without significantly increasing risk of complications. Finding of pN+ disease was associated with worsened prognosis. LND may be omitted in LG disease yet should be considered in patients with HG disease and increasing tumor size. Further investigation is requisite.
Bladder cancer rapid autopsy: A mechanism for collecting metastatic tumor tissue and establishing xenograft models of metastatic disease.
Authors: Lam Hung-Ming , Vakar-Lopez Funda , Hsieh Andrew Caleb , Corey Eva , Montgomery Robert B. , Wright Jonathan L.
Published: February 2018

478

Background: Patients with metastatic bladder cancer have a poor prognosis with a median survival of only 9-15 months. Understanding the biology of metastatic bladder cancer has been historically difficult due to a paucity of specimens and models that recapitulate human disease. We established a bladder cancer rapid autopsy program to systemically acquire metastases, and build patient-derived xenograft (PDX) and organoid models for biological studies. Methods: Patients with metastatic bladder cancer were consented and a rapid autopsy was performed 2-6 hours after death to allow acquisition of normal and metastasis specimens. Frozen and formalin-fixed and paraffin embedded specimens were collected and pathological evaluation was performed on each specimen. Additionally, tumors were implanted subcutaneously into SCID mice to establish PDXs. Once PDXs were developed, PDXs were dissociated for companion organoid culture. Clinical history and treatment information was documented for each patient. Results: We have performed 10 bladder cancer rapid autopsies to date, and have acquired 105 metastatic and 45 normal specimens. The pathological subtypes of patients include urothelial cell carcinoma (5/10), squamous cell carcinoma (3/10), and plasmacytoid variant of urothelial carcinoma (2/10). The cohort has been treated BCG only (1/10), chemotherapy (3/10), and chemotherapy and immune checkpoint inhibitors (6/10). The leading site of metastasis was the liver (7/10) and lung (7/10), followed by lymph node (5/10), bone (5/10), intestine (4/10), and omentum (2/10). Half (5/10) of the patients had extensive liver metastases that allow acquisition of multiple tumor foci. For the first time, PDX and organoids from two independent metastases (omentum – CoCaB 14.1 and liver –CoCaB 14.2) from the same patient were successfully developed. Conclusions: This bladder cancer rapid autopsy program provides an important volume of metastatic tumor specimens for study. Importantly, the first bladder cancer PDX derived from metastasis has been developed. The availability of metastatic bladder cancer specimens, PDXs, and organoids will allow biological studies of advanced disease.
Plasmacytoid urothelial carcinoma: A clinicopathological study.
Authors: Hashemi-Sadraei Neda , Perrino Carmen M , Monn M. Francesca , Bandali Elhaam , Cheng Liang , Idrees Muhammad , Bihrle Richard , Koch Michael O. , Eble John , Kao Chia-Sui , Albany Costantine , Pili Roberto , Grignon David A. , Kaimakliotis Hristos Z.
Published: February 2018

482

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare variant histology with poor prognosis. We report clinical outcomes on patients with PUC. Methods: We retrospectively reviewed treatments and outcomes in patients with PUC seen at our institution from 1996 through 2016. The Kaplan-Meier method was used to calculate overall survival. Results: A total of 69 patients with a median age of 68 years were identified. Five patients presented with metastatic disease, whereas 64 were diagnosed with clinically localized PUC. Fifty-seven patients underwent radical cystectomy and the remainder elected for bladder preservation approaches. At time of cystectomy, 6 patients were found to have pathologically organ-confined disease (≤pT2 N0), and 51 had non-organ-confined disease (pT3,T4 or N+), 2 of which were noted to have diffuse peritoneal carcinomatosis. Twenty-eight patients had positive surgical margins, most of which had extensive infiltrative disease not amenable to complete excision. Of the 14 patients who received neoadjuvant cisplatin-based chemotherapy, 10 (71.4%) patients had lymph node involvement and 12 (85.7%) had pT3/4 disease at cystectomy. Only one patient had a pathologic complete response with pT0N0. Thirteen patients received adjuvant chemotherapy, 2 of which received neoadjuvant chemotherapy as well. Two patients received immunotherapy, with only a short-lived response. Median survival for all patients with PUC from time of initial diagnosis was 17.7 months (mo), and 14.0 mo from time of cystectomy for patients undergoing radical cystectomy. Patients with desmoplastic morphology tended to have the worst clinical outcomes (median survival 10.1 mo), whereas classic and pleomorphic subtypes had better survival (median survival 18.6 and 30.4 mo, respectively) (p = 0.083). Conclusions: PUC is an aggressive variant with overall poor outcomes. There appeared to be three morphologic subtypes of plasmacytoid disease; classic, desmoplastic and pleomorphic, with potentially distinct survival outcomes. Chemotherapy, whether in the neoadjuvant or adjuvant setting, or immunotherapy, appeared to have little effect on this cohort. Molecular markers/genomic analysis may provide insight to novel therapeutic approaches.
Significance of serum buttyrylcholinesterase level before chemotherapy as an independent predictor of overall survival in patients with metastatic upper-tract urothelial cancer.
Authors: Yoneyama Takahiro , Kodama Hirotake , Hosogoe Shogo , Kusaka Ayumu , Tokui Noriko , Yoneyama Tohru , Imai Atsushi , Yamamoto Hayato , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2018

486

Background: Systemic inflammation is a common host reaction to cancer progression. Serum level of buttyrylcholinesterase (BChE) have been reported to reflect the presence of inflammation and other clinical conditions. BChE is an alphaglycoprotein found in the nervous system and liver. Its serum level is reduced in many clinical conditions, such as liver damage, injury, infection, and malignant disease. We retrospectively evaluated the potential prognostic significance of buttyrylcholinesterase before chemotherapy as an independent predictor of overall survival in patients with advanced upper-tract urothelial cancer. Methods: We treated seventy-four patients (52 men and 22 women) with advanced upper-tract urothelial cancer (UTUC) at our clinic between August 2004 and September 2017. The average age was 69.3 (43–89), and average eGFR was 50.5 (11.6–99.3) ml/minute/1.73m2. Mean observation period was 28.7 (3–111) months. Levels of serum BChE (normal range 168-470 U/L) were measured 1 week before chemotherapy. The average serum level of BChE were 240.6 U/L (53-509). The patients received 2 courses of GCarbo consisted of 800mg/m2 gemcitabine on days 1, 8, and 15 and carboplatin (AUC 4) on day 2. If this regimen was effective, another 2 courses of GCcarbo was performed. If this regimen did not induce any tumor size reduction, we switched to 2 courses of GCarboD (D; 70mg/m2) treatment as second-line treatment. Results: GCarbo regimen yielded 5 cases (6.8%) of CR, 32 (43.2%) of PR, and the average duration of response of 11.4 (2–29) months. GCarboD treatment was administered in 21 cases, and yielded 2 (9.5%) PR and a duration of response was 31.5(7-50) months. The median over-all survival period was 14.3 months. When analyzed by serum BChE level, the ovearall survival were 22.0 months in the BChE > 168 U/L group and 11.0 months in the BChE < 168 group (p = 0.0035). The level of serum BChE showed no association with treatment effect. Conclusions: Serum BChE level before chemotherapy may have the potential to predict overall survival in patients with advanced upper-tract urothelial cancer.
Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression.
Authors: Joerger Markus , Cassier Philippe , Penel Nicolas , Cathomas Richard , Richly Heike , Schostak Martin , Janitzky Andreas , Wermke Martin , Nogova Lucia , Tai David Wai-Meng , Sayehli Cyrus , Grüllich Carsten , Grande Enrique , Navarro Alejandra , Park Se Hoon , Gillessen Silke , Nogai Hendrik , Bender Sebastian , Ellinghaus Peter , Schuler Martin H.
Published: February 2018

494

Background: Activation of FGFR signaling is involved in a variety of malignancies including advanced urothelial cancer (UC). Rogaratinib is an oral pan-FGFR kinase inhibitor. We report here the results from a phase I expansion cohort in UC patients prescreened for FGFR1-3 mRNA expression levels and activating mutations. (NCT01976741) Methods: Patients with advanced urothelial carcinomas were selected based on high FGFR1-3 mRNA expression in biopsy specimens. Selected patients were treated with rogaratinib 800mg twice daily until tumour progression, untolerable toxicity, or withdrawal. Tumor response was assessed by RECIST, v1.1. Adverse events were reported using CTCAE v4.03 criteria. Results: A total of 219 UC patients were prescreened for FGFR1-3 mRNA expression levels and FGFR3 activating mutations, with 99 samples (45%) found to be FGFR-positive. Of those, 87% of samples were positive for FGFR3 mRNA, 5% for FGFR1 mRNA and 8% were double FGFR mRNA-positive (FGFR1/2, 1/3 or 2/3). Frequency of FGFR3 activating mutations in UC samples was 7%, all of which also had high FGFR3 mRNA. Fifty two patients (median prior line of treatment 2) started treatment and 51 were evaluable for response. Rogaratinib was generally well tolerated and AEs manageable with dose modification. The most common AEs were diarrhea (49%) and hyperphosphatemia (49%). Objective response rate (ORR) was 24% (12/51; all PRs) and disease control rate (DCR) was 73% (37/51). Eleven of 12 pts with a PR were positive for FGFR3 mRNA, 5 of whom also had FGFR3 mutations, and one patient was positive for FGFR1 mRNA. Ten FGFR-positive UC patients had prior immuno-oncology (I/O) treatment, 9 of whom had progressive disease as best response. For these 10 patients the ORR was 30% and the DCR 80%. Conclusions: Selection of pts for treatment with rogaratinib based on FGFR mRNA expression levels was feasible and identified drug-sensitive patients with and without underlying DNA alterations. Rogaratinib had a favorable safety profile and showed promising anti-tumor activity in UC patients. Responses and disease stabilization were observed with rogoratinib in UC pts refractory to prior I/O treatment. Clinical trial information: NCT01976741.
Prognostic impact of percentage of squamous differentiation in patients with nonbilharzial squamous cell carcinoma and transitional cell carcinoma treated with radical cystectomy.
Authors: Slim Marine , Comperat Eva , Roupret Morgan , Parra Jerome , Simon Jean-Marc , Khayat David , Bitker Marc-Olivier , Spano Jean-Philippe , Malouf Gabriel G.
Published: February 2018

498

Background: Squamous differentiation has been reported to occur in 10-22 % of transitional cell carcinoma. The prognostic impact of squamous differentiation is controversial. In addition, it remains unclear whether the percentage of squamous differentiation impact outcome of patients with nonbilharzial squamous cell carcinoma and transitional cell carcinoma treated with radical cystectomy Methods: We performed a retrospective study of patients with non-bilharzial squamous variants or squamous bladder carcinoma treated in two French institutions. The percentage of squamous differentiation was determined by an expert GU pathologist on radical cystectomy specimens. Progression-free survival (PFS) and cancer-specific survival (CSS) were analyzed according to the percent of squamous differentiation. Survivals were estimated using the Kaplan-Meier method and compared using multivariate Cox proportional hazard regression analysis. Results: Forty patients were identified including 28 and 12 patients which tumors were classified as transitional cell carcinomas cases with squamous cell differentiation and pure non-bilharzial squamous bladder carcinoma, respectively. Patients with tumors harboring more than 50% of squamous differentiation had a PFS of 6.3 months as compared to 60.2 months for those with squamous differentiation present in less than 50% (p = 0.014). In multivariate analysis, the percentage of squamous differentiation was the only independent prognostic factor for PFS (HR = 2.63 (IC 95%: 1.22-5.67). First site of recurrence of patients with squamous differentiation ≥50% were more frequently the pelvis (72% versus 17 %; p = 0.049). No difference in CSS were observed between patients with tumors < 50% or ≥50% squamous differentiation (16.3 months versus 62 months) (p = 0.2). Conclusions: Extensive squamous differentiation in bladder cancer is associated with poor PFS and pelvic progression, suggesting that those patients might benefit from adjuvant pelvic radiotherapy. Larger studies are needed to validate these findings.
Hypoxia related mRNA biomarker to predict biochemical failure and metastasis for prostate cancer.
Authors: Choudhury Ananya , Yang Lingjian , Roberts Darren , Takhar Mandeep , Vinayak Bhandari , Bibby Becky , Cheng Wei-chen , Haider Syed , Thiruthaneeswaran Niluja , Hoskin Peter , McArt Darragh , Jain Suneil , Buffa Francesca Meteora , Erho Nicholas , Bristow Robert G. , Boutros Paul Christopher , Davicioni Elai , West Catharine
Published: February 2018

5

Background: Hypoxia is an important regulatory factor in tumorigenesis and is associated with a poor prognosis. Patients with high risk locally advanced disease account for 13-21% of prostate cancer cases and the ten year cancer specific survival rate for these patients is 62%. Patients with hypoxic tumours could benefit from hypoxia modifying therapeutics in addition to radiotherapy. Clinical companion biomarkers are needed to stratify patients who would benefit from hypoxia modifying therapy in addition to radiotherapy. Methods: RNA-seq analysis was performed on prostate cell lines (PNT2-C2, PC-3, LNCaP and DU145) exposed to 1% hypoxia for 24 hrs. A prostate cancer hypoxia gene signature was derived in silico using publicly available prostate gene expression data sets and the RNA-seq data. The biomarker was then independently validated in multiple cohorts of prostate cancer patients with localized diseases receiving prostatectomy alone, prostatectomy plus adjuvant radiotherapy, prostatectomy plus salvage radiotherapy, or definitive radiotherapy alone. Results: In vitro the hypoxia inducible expression of the hypoxia gene signature was tested at 1% and 0.1% oxygen of which 21 of the 28 genes were regulated by hypoxia. Patients stratified as high hypoxia were associated with significantly poorer 5-year biochemical recurrence free survival in patients undergoing prostatectomy alone, prostatectomy plus adjuvant radiotherapy and definitive radiotherapy alone. In multivariable analysis, the biomarker retained significance after correcting for confounding factors including Gleason group, PSA, a molecular classifier, etc. In another cohort of prostatectomy and salvage radiotherapy treated patients, the mRNA signature predicts metastasis free survival in both univariable and multivariable analyses. Conclusions: We derived a de novo mRNA signature based on hypoxia-regulated genes. The biomarker consistently predicts biochemical failure and metastasis for prostate cancer patients with localized disease.
Managing low risk prostate cancer: A cost analysis.
Authors: Gaylis Franklin , McGill Kevin , Levy Susan S , Ball Catherine E , Prime Hillary , Dato Paul , Cohen Edward ,   ASCO Authors' Group
Published: February 2018

50

Background: Healthcare costs in the US continue to rise at an unsustainable rate. Prostate cancer (PCa) accounts for 21% of all new cancer cases in men and is predicted to incur a cost of $18.53 billion in the next few years. In this study we examined the costs associated with managing low-risk PCa with traditional treatment options compared to Active Surveillance. Methods: One hundred ninety-five patients were identified as NCCN defined low-risk PCa (Gleason score ≤ 6, PSA < 10, clinical stage T1c to T2a) between January 1, 2012 to June 30, 2013 at Genesis Healthcare Partners (GHP). Ninety three (48.7%) patients had at least 3 years of follow-up care and formed the cohort for analysis. Treatment paths analyzed included active surveillance (AS), radical prostatectomy (RP), stereotactic body radiation therapy (SBRT) and intensity-modulated radiation therapy/image-guided radiation therapy (IMRT/IGRT). Patients’ charts were examined for all episodes of care during the three-year period subsequent to their first positive biopsy and cost attribution to each episode was based on a cost-to-Medicare perspective using the Medicare Physician Fee Schedule (MPFS) for GHP. Total and annual costs of care were compared for patients followed for a 3-year period using one-way analysis of covariance (ANCOVA), covarying for patient age and Charlson Comorbidity Index (CCI). Results: Active surveillance ($4,072 ± $1354) compared to RP ($9,972 ± $1571), SBRT ($26,294 ± $2049), and IMRT/IGRT ($40,438 ± $2091) had significantly lower total 3-year costs ( p < .001, ɳ² = .44) compared to those in the other treatments group. Specific characteristics of the AS cohort’s treatment path included an average number of biopsies of 2.0 ± 0.8 and only six (21%) patients had at least one MRI performed during their treatment path. Active surveillance with a more costly genomic study (n = 4) incurred a cost of $9,475 ± $1456 over three years. Conclusions: Active surveillance may be considered a beneficial management strategy for low-risk PCa from a cost perspective. The cost effective benefit as well as the avoidance of treatment (surgery, radiation therapy) related side effects, support its consideration as a value-based care model, the primary goal of the Medicare Access and Chip Reauthorization Act.
Role of mTORC2 and nitric oxide in bladder cancer invasion.
Authors: Sahu Divya , Hansel Donna E. , Klemke Richard , Boss Gerry
Published: February 2018

504

Background: In the United States, bladder cancer is the fourth most common cancer, with an estimated 79,000 new diagnoses and 17,000 deaths in 2017, and the eleventh most common cancer worldwide. The key driver of bladder cancer stage progression is tumor cell invasion which has limited response to current chemotherapy options and hence, newer therapies directed against invasion are key to improving the treatment of bladder cancer. Our laboratory has identified mammalian target of rapamycin complex 2 (mTORC2) as a driver of bladder cancer cell invasion. We have also recently shown that arginine, the nitric oxide (NO) precursor, is implicated in bladder cancer progression. We evaluated the interaction between these two pathways to promote invasion. Methods: Expression of inducible and endothelial nitric oxide synthases (iNOS and eNOS) in FFPE tissue sections of progressive disease was assessed by IHC and correlated with histopathology, progression and stage based on moderate to strong expression (2+, 3+) compared to absent to weak expression (0, 1+).We utilized gene silencing methods and NOS inhibitors and NO scavenger for effects on bladder cancer invasion and migration. We assessed mTORC2 pathway activity and NOS levels in invasive cell tip protrusions called “invadopodia” and evaluated if mTORC2 regulates NOS localization and/or activity. We used a novel zebrafish model to characterize the effects of mTORC2 and NO on bladder cancer metastases. Results: We found that eNOS and iNOS are elevated in invasive human bladder tumors and cell lines and their ablation reduces bladder cancer cell migration and invasion. mTORC2 silencing can affect levels of iNOS and eNOS in bladder cancer cell lines. Silencing of mTORC2, eNOS or iNOS reduced metastases of bladder cancer cells within zebrafish. Conclusions: mTORC2 pathway is a key driver of bladder cancer invasion and metastases by regulating the NO pathway and both mTORC2 and NO can be targets for bladder cancer therapy, which would benefit patient outcomes.
Molecular characterization of brain metastases in patients with metastatic urothelial cancer.
Authors: Nizam Amanda , Trump Donald L. , Aragon-Ching Jeanny B.
Published: February 2018

509

Background: Urothelial cancers are the 6th most common cause of all new cancer cases in 2017. Metastatic disease to the brain is rare but has a poor prognosis. There is little information regarding the phenotypic and molecular characteristics of urothelial cancers involving the brain. We sought to evaluate the clinical and tumor molecular characteristics in patients with metastatic urothelial cancer to the brain. Methods: In a single institution retrospective chart review, 48 patients were found to have metastatic bladder cancer from 2006 to 2015, 4 had brain metastases. The demographics, stage, phenotypic characteristics and molecular characteristics using Oncomine, a cancer microarray platform targeting 143 cancer genes, was determined. Results: Of the 4 patients identified with metastatic brain urothelial cancer, 3 were men. 2 had both upper tract and bladder urothelial cancers and 2 had bladder cancer alone. 3 had prior nephroureterectomy and/or radical cystectomy initially and had subsequent development of initial distant metastases at a median of 7.9 months, and time between the first to brain metastases at a median onset of 11.8 months. Median overall survival (OS) was short upon diagnosis of brain metastasis with a median OS of 119 days (range: 96 – 391 days) from the time of brain metastasis diagnosis. All received surgical resection followed by radiation for brain metastases. Three patients had brain tumor examined for comprehensive somatic tumor profiling using the Oncomine panel. Results showed APC mutation in patient 1, loss of TP53, BRCA-2 loss of function mutation with MSH2 deletion in patient 2, as well as FGFR3 gene mutation and TP53 mutation in patient 3. All patients received prior platinum-based systemic therapy with additional FGFR3-therapy for patient 3 and atezolizumab for patient 4. Conclusions: Metastatic brain urothelial cancers are rare events with a uniformly poor prognosis. The role for targeted therapy and immunotherapy is still evolving.
CT-based texture characterization of lymphadenopathy in urothelial carcinoma: Prediction of treatment response.
Authors: Tejura Tapas K , Quinn David , Varghese Bino , Cen Steven Yong , Hwang Darryl , Chen Frank K , Desai Bhushan , Fan Ting-Wei , Duddalwar Vinay
Published: February 2018

514

Background: Promising treatments are emerging for urothelial carcinoma, although there is no reliable method for predicting treatment response on an individual basis. Extraction of quantitative tumor-texture features from clinical radiologic images may distinguish between cancers which may be more responsive to treatment. Our purpose is to analyze CT-based textural features of urothelial cancer lymph node metastases prior to treatment and classify them to categories for response. Methods: In this IRB approved retrospective study, 36 patients with a proven diagnosis of urothelial cancer who were scheduled to have chemotherapy (Eribulin) and had pre- and post-treatment imaging were included. A total of 66 abnormally enlarged lymph nodes (> 1.5 cm short-axis) were identified. Using RECIST 1.1 as treatment standard, lymph nodes were categorized into 3 categories: Complete or partial response (CR, PR), Stable disease (SD), and Progressive disease (PD). Texture analysis was performed using six different textural methods ranging from 1st order statistical methods such as histogram analysis to higher-order methods such as image-frequency analysis. Depending on data normality, ANOVA or Kruskal Wallis test were used to assess signal difference across CR/PR, SD, and PD categories univariately. Classification Tree (CART) was used to explore potential multivariate prediction model. Results: 34 lymph nodes were categorized as CR/PR, 19 categorized as SD, and 13 categorized as PD. Univarate data analysis showed that of the various textural, histogram-based metrics: Correlation, Variance, Standard deviation, Sum/difference of averages, Homogeneity/Dissimilarity have statistically significantly difference across response categories (p<0.05). CART analysis show preliminary evidence of predicting PD with 85% sensitivity but 54% false positive. Conclusions: CT-based textural features can differentiate between urothelial cancers which are more likely to respond to treatment. Validation with larger sample size and inclusion of data from other sites of metastases will aid in the identification of reliable imaging-texture based biomarkers for treatment stratification.
Survival after surgical or radiotherapeutic treatment for high-risk localized prostate cancer: A National Cancer Database analysis with comprehensive treatment group imbalances adjustments.
Authors: Ennis Ronald D. , Hu Liangyuan , Ryemon Shannon Nicole , Lin Joyce , Mazumdar Madhu
Published: February 2018

55

Background: There are no randomized trials to guide a high-risk localized prostate cancer patient’s treatment decision between radiotherapeutic and surgical options. Comparative studies have been limited by their ability to match patients based on pre-treatment prognostic variables and to adjust for the cancer–related, medical and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods: We analyzed the outcome of all patients in the National Cancer Database with high-risk clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD) or EBRT+brachytherapy (brachy)±AD. Inverse probability of treatment weighting (IPTW) was used to adjust for covariate imbalance between treatment groups. Time-dependent Cox proportional hazards (TDCPH) model was then used to evaluate differences between treatment groups. Because of imbalances in the frequency of pathologic lymph node sampling between the treatment groups, a predictive model of pathologic nodal (pLN) status was built using PSA, Gleason score and clinical T stage and predicted pLN status was used to repeat the IPTW and TDCPH model. Results: 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT+brachy±AD (HR 1.17 (0.88, 1.55)). However, EBRT+AD was associated with higher mortality than RP (HR 1.53 (1.22, 1.92)). Adjustment for predicted pLN status did not change the results. Subset analysis of EBRT+AD patients who received ≥7920 cGy narrowed the difference but remained significant (HR 1.32 (1.02, 1.66)). Conclusions: After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions and socioeconomic factors, this analysis showed no difference in survival between patients treated with RP vs. EBRT+brachy±AD. EBRT+AD was associated with lower survival. Randomized trials comparing these three methods of treatment are urgently needed.
Impact of Medicaid expansion on diagnosis and management of patients with testicular cancer.
Authors: Shen Xinglei , TenNapel Mindi
Published: February 2018

551

Background: One crucial aspect of the Affordable Care Act is the optional Medicaid expansion, which started in 2014. Patients with testicular cancer may derive particular benefit from Medicaid expansion due to demographics overlap. We hypothesize that Medicaid expansion would improve outcome in these patients. Methods: We reviewed the Surveillance Epidemiology and End Results (SEER) database for testicular cancer diagnosed from 2010 to 2014. Among the SEER regions, we separated in to states that did (CA, CT, HI, IA, KY, MI, NJ, NM, WA) or did not (AK, GA, LA, UT) undertake expansion. Medicaid data from CMMS were used to measure the degree of Medicaid expansion (EXP). Data from 2010-2013 was used as baseline, and 2014 as the effect of EXP. Chi-square test was used to compare between groups. Results: We identified 12731 cases of testicular cancer from 2010 to 2014. Within SEER regions, overall Medicaid enrollment increased by 30.4% from 2013 to 2014 in the EXP states, and by 8.4% in non-EXP states. Expansion did not affect incidence of testicular cancer. In the EXP states, Medicaid coverage for testicular cancer increased from 14.8% to 19.4% in 2014 (p < 0.001) and uninsured decreased from 8.7% to 4.3% (p < 0.001). In non-EXP states, coverage with Medicaid (9.7% to 8.8%, p = 0.60) and uninsured (13.6% to 12.9%, p = 0.68) did not change. Within individual states, we noted a linear correlation between % increase in Medicaid enrollment and % decrease in uninsured cases (R = 0.58). Among Medicaid patients in EXP states, stage I cases increased (52% to 60%), stage III cases decreased (27% to 20%). There was no change among insured patients (70.6% to 73.3% for stage I, and 10.9% to 9.1% for stage III). In contrast, in non-EXP states, Medicaid patients had decrease in stage I and increase in stage III cases. Medicaid patients had higher rates of no treatment and lower rates of lymph node assessment for stage II NSGCT compared to insured patients, but this did not vary with EXP. Conclusions: Medicaid expansion reduced rate of uninsured for patients with new diagnosis of testicular cancer. There was a shift to earlier stage of diagnosis in Medicaid patients, but no apparent effect yet on management. Future studies will focus on change over time and effect on survival.
Diagnostic radiation and testicular germ cell tumor risk.
Authors: Nead Kevin Thomas , Mitra Nandita , Weathers Benita , Pyle Louisa T , Nathanson Katherine L. , Kanetsky Peter A
Published: February 2018

556

Background: Both incidence of testicular germ cell tumor (TGCT) and use of diagnostic radiation have increased in recent decades. In a quarter of diagnostic scans in children, direct and indirect radiation dose to the testes exceeds 20 mSv, which surpasses thresholds associated with malignancy risk (~5 mSv). Here, we examine the association between exposure to diagnostic radiation and TGCT risk in a case-control study. Methods: Cases were enrolled in a hybrid hospital- and population-based setting and controls were recruited from the community. Participants reported on exposures to x-ray/CT below the waist and lower GI series, and we derived a combined variable for any exposure. After imputation to infer missing data, we compared baseline characteristics and used multivariable logistic regression adjusting for age and race to determine the risk of developing TGCT according to number of exposures and age at first exposure. Results: As expected, cases (n = 1088) were more likely than controls (n = 1458) to be white, have a family history of TGCT, and have a history of cryptorchidism (p < 0.05). There was an increased risk of TGCT with a greater number of exposures for both x-ray/CT (ptrend= 0.002) and the combined diagnostic radiation variable (ptrend< 0.001). Compared to those without any exposure, risk was greatest among those reporting ≥6 exposures for x-ray or CT (OR, 9.6; 95% CI, 4.6-19.9; p < 0.001) and the combined variable (OR, 5.8; 95% CI, 3.2-10.4; p < 0.001), after adjusting for age at first exposure. Early first exposure before eleven years of age increased risk of TGCT for x-ray/CT (OR, 2.36; 95% CI, 1.17-4.77) and combined radiation exposure (OR, 1.96; 95% CI, 1.05-3.67) compared to later first exposure after seventeen years of age, adjusting for total exposures. Analyses limited to observed data only yielded similar results. Conclusions: Exposure to diagnostic radiation below the waist, particularly among younger individuals, may increase TGCT risk. These results should be validated. As the testes are present outside the body and rarely examined using diagnostic radiation, a unique opportunity for shielding exists. Efforts to reduce testicular dose and optimize shielding practices should be prioritized.
Glypican 3 (GPC3) expression in a lethal subgroup of refractory cisplatin-resistant testicular germ cell tumor (TGCT).
Authors: Chahoud Jad , Zhang Miao , Lin Song-Chang , Lin Sue-Hwa , Tu Shi-Ming
Published: February 2018

559

Background: The oncofetal protein GPC3 has been tested as a therapy target. Early phase clinical trials established the safety and efficacy of anti-GPC3 chimeric antigen receptor modified T cells in patients with refractory or relapsed GPC3+ hepatocellular carcinoma. In TGCT, GPC3 is preferentially expressed at presentation in certain germ cell histological phenotypes (yolk sac tumor [YST], choriocarcinoma), but not in others (embryonal carcinoma, teratoma, seminoma). The aim of this study is to evaluate GPC3 expression in a lethal subgroup of refractory cisplatin-resistant TGCT. Methods: We retrospectively evaluated 615 patients diagnosed with TGCT from January 2000 to December 2010. We identified patients who died from their TGCT. The histologic makeup of primary tumors, next-generation sequencing data and the clinical course of disease were determined for each patient. We prospectively evaluated GPC3 expression by immunohistochemistry (IHC) using a mouse monoclonal antibody (YP7), on tumor tissue from these patients with lethal, heavily pretreated, cisplatin-resistant TGCT. Results: We identified seven patients with fatal and cisplatin-resistant TGCT, with a median age of 30 (28-50) years and a median number of prior therapies of 5 (2-8), including 3 patients who received high-dose chemotherapy with autologous stem-cell transplant. The prospectively collected samples were from different sites of metastasis: lymph nodes (n = 4), peritoneal carcinomatosis (n = 2), and lung (n = 1). The tissue histology comprised YST (n = 2), YST + choriocarcinoma (n = 1), YST + teratoma (n = 1), teratoma (n = 1), and somatic transformation (n = 2). No consistent genetic aberration was detected. The viable germ cell tumor components comprising YST and choriocarcinoma (n = 4) stained strongly positive in a membranous distribution for GPC3. While samples with teratoma and somatic transformation histology (n = 3) did not stain for GPC3. Conclusions: Potentially lethal, heavily pretreated, cisplatin-resistant viable germ cell tumors have enhanced expression of GPC3. Targeted therapy directed against GPC3 could benefit patients harboring such tumors and further investigation is of value.
Is surveillance without immediate treatment an option for newly diagnosed testicular germ-cell cancer patients with borderline size retroperitoneal lymph nodes on computed tomography scan?
Authors: Milk Nadav , Leibovitch Ilan , Keizman Daniel , Dresler Hadas , Sternberg Itay
Published: February 2018

560

Background: The AJCC TNM Staging System for Testicular Cancer (TC) does not set a minimal diameter to define positive lymph nodes (LN) on computed tomography scan. It is common to refer to LN ≥ 1 cm in diameter as positive, even though benign LN in the borderline size of 1-1.5cm are common. Our goal is to describe the outcome of TC patients with borderline size retroperitoneal LN of undetermined significance managed initially with surveillance. Methods: We retrospectively reviewed the medical records of all TC patients treated at our institution during 2006-2016. Demographic, clinical, laboratory, imaging, pathological, treatment and surveillance data were obtained. Results: Of a total of 109 TC patients, 25 patients (22.7%) with borderline size LN were assigned to an active surveillance protocol by our tumor board. Median age at the time of orchiectomy was 37.2 years (IQR, 23.9-40.3). With a median follow-up of 3.9 years (IQR 1.7-6.5), overall survival rate in the group was 100%. Nine of 25 patients (36%) relapsed and were treated within a median of 4.9 months (IQR 2.2-5.5). Median follow-up for 16 patients who did not relapse was 3.4 years (IQR 1.5-5.4). Relapse-free survival was 71% (95% CI 48-85), and 61% (95% CI 38-77) at one and two years, respectively. Orchiectomy pathology included pure seminoma in 18/25 (72%), and a nonseminomatous tumor in 7/25 (28%). Tumor type was not associated with likelihood of relapse (p = 0.66). The median LN diameter at the time of diagnosis was 11 mm (IQR 9-12, mean 10.4). LN diameter was not associated with likelihood of relapse (p = 0.34). Patients who relapsed during follow-up were significantly younger at the time of TC diagnosis than patients who did not relapse (Median age 23.9 years [IQR 19.6-35.2] and 39.2 years [IQR 34.3-47.9] respectively, p = 0.0056). Conclusions: Surveillance alone for TC patients with borderline size LN of undetermined significance at diagnosis is a possible option and may help avoid overtreatment in 60% of these patients.