bluuebunny/crossref_metadata_2025_split huggingface dataset:
A retrospective analysis of patients with intermediate-risk germ cell tumor (IRGCT) treated at Indiana University from 2000 to 2010.
Authors: Albany Costantine , Satpute Shailesh R. , Brames Mary J. , Suleiman Yaman , Al Nasrallah Nawar , Perkins Susan M. , Hanna Nasser H. , Einhorn Lawrence H. 
Published: March 2020

4534 Background: Based on the International Germ Cell Cancer Collaborative Group (IGCCCG), IRGCT represents 26% of non-seminomas and 10% of seminomas with 2 year PFS of 74% (63-85%). Most patients are treated with 4 cycles of Bleomycin, Etoposide and Cisplatin (BEP). However, the optimal therapy for this heterogeneous group is not well defined. Our hypothesis was that many patients with IRGCT may not require BEPx4 as they are clinically closer to good risk rather than to poor risk disease. Methods: We conducted a retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) between 2000- 2010. We identified 170 pts with IRGCT of whom 84 consecutive pts received their therapy at IU. 2 chemotherapy categories were identified: BEP (or equivalent) x4 or BEPx3 (+/-EPx1). Results: 45 pts received either BEPx4 (41), VIPx4 (2) or BEPx2 followed by HDCTx2 (2). 39 pts received BEPx3 (9) or BEPx3+EPx1 (30). Treatment decisions were based on clinical characteristics and markers amplitude. There were 78 (93%) non-seminoma, 6 (7%) seminoma. 27 (32%) stage II and 57 (68%) stage III. Mean AFP 3899 (range 1000-9550; n=50), mean hCG 16354 (range 5000-49000; n=34). The overall 1 and 2 year Kaplan-Meier estimates were 93% and 87% for PFS and 98% and 92% for OS. Results are depicted below. Conclusions: Our results for patients with IRGCT treated from 2000-2010 are superior to the IGCCCG pts treated from 1975-1990. Routine administration of BEPx4 probably represents overtreatment in a substantial percent of IRGCT. [Table: see text]
Large retroperitoneal lymph nodes (RPLN) as a novel risk factor for venous thromboembolism (VTE) in germ cell tumor (GCT) patients (pts) receiving first-line chemotherapy (chemo).
Authors: Tran Ben , Beausoleil Michel S , Amir Eitan , Jewett Michael A , Sturgeon Jeremy F. G. , Anson-Cartwright Lynn , Chung Peter W. M. , Warde Padraig Richard , Winquist Eric , Moore Malcolm J. , Bedard Philippe 
Published: March 2020

4535 Background: VTE causes substantial morbidity and mortality in GCT pts. The Khorana model is a validated predictive model that stratifies VTE risk in cancer pts receiving chemo; Khorana score ≥3 (K3) identifies pts at high risk. Many GCT pts have bulky RPLN that can cause venous stasis in the lower limbs. This study examines the incidence of VTE in GCT pts and assesses large RPLN as a novel predictor of VTE risk. Methods: Retrospective data from the Princess Margaret Hospital GCT database was complemented by review of medical records. GCT pts receiving 1st line chemo between 2000-2010 were included. Pts diagnosed with VTE prior to chemo and pts receiving thromboprophylaxis (TP) were excluded. Pts diagnosed with VTE during or within 3 months of completing chemo were identified. Large RPLN were defined as having maximal diameter ≥5cm. Odds ratios for VTE risk with large RPLN and K3 were calculated. Discriminatory accuracy (DA) of each predictor was calculated using area under the receiver operating characteristic curves (AUROC). An external cohort from London Regional Cancer Program, with similarly collected data, was used to validate results. Results: In the test cohort 21 (10%) of 216 pts developed VTE. Both large RPLN (OR 6.2, p<0.001) and K3 (OR 11.8, p<0.001) were significantly associated with VTE. Positive predictive value (PPV) was lower for large RPLN compared to K3 (21% v 44%, p<0.014) but sensitivity was greater (71% v 40%, p=0.001), while DA showed no difference (AUROC 0.73 v 0.67, p=0.46). In the validation cohort 10 (9%) of 111 pts developed VTE. There was a non significant trend for associations between VTE and both large RPLN (OR 2.54, p=0.16) and K3 (OR 4.5, p=0.13). When compared to K3, sensitivity was greater for large RPLN (60% v 20%, p=0.003), but there was no difference in PPV (14% v 29%, p=0.25) or DA (AUROC 0.61 v 0.57, p=0.72). Conclusions: VTE occurs in 1 in 10 GCT pts receiving curative chemotherapy. Large RPLN is a novel and clinically applicable predictor of VTE risk, although prospective validation would be beneficial. Randomized controlled trials of TP in GCT pts should be considered in pts at high risk of VTE, identified by large RPLN or K3.
Association of inherited genetic variation with clinical outcome in patients with advanced renal cell carcinoma treated with mTOR inhibition.
Authors: Pomerantz Mark M , Gray Kathryn P. , Schutz Fabio Augusto Barros , Percy Andrew , Lampron Megan , Signoretti Sabina , Hirsch Michelle S. , Rosenberg Jonathan E. , Lee Gwo-Shu Mary , McDermott David F. , Atkins Michael B. , Kantoff Philip W. , Freedman Matthew L , Choueiri Toni K. 
Published: March 2020

4543 Background: Mammalian target of rapamycin (mTOR)-targeted therapy is standard in patients with metastatic renal cell carcinoma (mRCC). Predictive biomarkers for response are lacking. We sought to characterize outcome after mTOR inhibition based on germline variation in 2 critical genes in the mTOR pathway: phosphoinositide-3-kinase catalytic alpha (PIK3CA) and mTOR. Methods: 76 Americans of European ancestry treated with temsirolimus or everolimus for mRCC were included. Germline DNA was genotyped for all common genetic variation (minor allele frequency [MAF] >0.05) across PIK3CA and mTOR, tagging with single nucleotide polymorphisms (SNPs) at r2>0.8. Associations between genotype and progression-free survival (PFS) and overall survival (OS) from the start of mTOR-targeted therapy were measured using univariate Cox model. Results: Among 76 patients, 66% were poor or intermediate risk and 89% received prior systemic therapies. Median follow up was 23.7 months. Median PFS and OS were 4.3 and 12.7 months, respectively. Two intronic PI3KCA SNPs were significantly associated with PFS and OS, and a SNP in the 5’ UTR of mTOR was associated with OS. Associations were maintained when adjusted for age, gender and MSKCC RCC risk categories using Cox PH model (Table). The PI3KCA SNPs are in modest linkage disequilibrium (r2 ~0.36). Conclusions: We suggest that inherited variation at PIK3CA is associated with PFS and OS after mTOR inhibition. If results are validated, prospective studies could explore the role of genotyping in treatment selection for mRCC. Further work will be needed to identify causal alleles and define the mechanism underlying the associations. [Table: see text]
Safety and activity of the investigational agent orteronel (ortl) without prednisone in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rising prostate-specific antigen (PSA): Updated results of a phase II study.
Authors: George Daniel J. , Corn Paul G. , Michaelson M. Dror , Hammers Hans J. , Alumkal Joshi J. , Ryan Charles J. , Bruce Justine Yang , Moran Susan , Lee Shih-Yuan , Mortimer Peter , Hussain Maha 
Published: March 2020

4549 Background: Ortl is an investigational, oral, non-steroidal selective 17,20-lyase inhibitor that suppresses androgen production. Ortl affects cortisol synthesis less than similar agents due to limited inhibition of 17α-hydroxylase, and may permit steroid-free dosing. Ortl 300 mg BID was examined in patients (pts) with nmCRPC and rising PSA. Methods: Eligible pts had nmCRPC with PSA ≥2 ng/mL (PSA ≥8 ng/mL if doubling time >8 mo), and surgical/medical castration, with testosterone (T) <50 ng/dL. Prior chemotherapy, ketoconazole, or concomitant corticosteroids were excluded. Starting dose of ortl was 300 mg BID and continued until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was the percentage of pts with PSA ≤0.2 ng/mL after 3 mo. Secondary endpoints included safety, PSA kinetics, time to metastases, changes in endocrine markers and circulating tumor cells (CTCs). Results: 39 pts were enrolled with baseline demographics including median age 71 y, ECOG PS ≤1, median PSA 12.1 ng/mL (range 2.6-67.8), T 7.9 ng/dL (1.4–17.3), and ACTH 19 ng/L (n=33; 0-47); 3 pts had dose reduction due to adverse events (AEs). Gr ≥3 AEs occurred in 16 pts (drug-related in 14); Gr ≥3 AEs ≥5% were dyspnea (8%), hypertension (13%), fatigue, hypokalemia, pneumonitis (5% ea). 7 pts (18%) had serious AEs; most common was pneumonitis (2=Gr 3, 1=Gr 2). 8 pts discontinued due to AEs; 2 pts required corticosteroids. At 3 mo, 6 pts (16%) achieved PSA ≤0.2 ng/mL; PSA50 and PSA90 rates were 76% and 32%, respectively; median PSA declined by 83% (n=34); median T declined by 89% to 0.78 ng/dL (n=31), and median ACTH increased by 171% to 43 ng/L; median cortisol declined by 21%. At 6 mo, PSA50 and PSA90 rates were 45% and 21%, respectively. Median time to PSA progression was 14.8 mo. 17 pts (44%) were on treatment >6 mo. Of 37 pts with baseline CTC/7.5 mL assessed, only 1 had CTC ≥5 and converted to <5; 6 had 1–4 CTCs at baseline, none converted to ≥5 during treatment. Conclusions: Ortl without steroids produces marked and durable declines in T and PSA, has manageable toxicities, and is feasible in men with nmCRPC.
Time to testosterone (T) and PSA rises during first “off treatment” interval (1OFF-2ON) of intermittent androgen deprivation (IAD) as prognostic for time to castration resistance (CRPC) and prostate cancer mortality (PCM) in men with biochemical relapse (BR).
Authors: Yu Evan Y. , Kuo Kevin F , Hunter-Merrill Rachel , Gulati Roman , Hall Suzanne P , Gambol Teresa E , Etzioni Ruth D , Higano Celestia S. 
Published: March 2020

4557 Background: A recent phase III trial of intermittent vs. continuous AD supports IAD as standard of care for men treated with AD for BR. To identify potential prognostic factors during 1OFF, times to T and PSA rises from our prospective trial of IAD in men with BR were analyzed in relation to times to CRPC and PCM. Methods: 72 men with BR after definitive local therapy were treated with IAD, each cycle consisting of 9 months of leuprolide and flutamide followed by a variable “off treatment” interval. T and PSA were followed monthly; AD was resumed when PSA reached a pre-specified value. Cycles repeated until CRPC, defined as ≥2 PSA rises with T≤50 ng/dL. Markers of interest from 1OFF-2ON were time to first T>50, time from first T>50 to first PSA rise ≥0.1 ng/mL, time to first PSA rise ≥0.1, and PSA doubling time (PSAdt), calculated using the first 3 PSA measurements starting from first PSA ≥0.1. The associations of these markers with CRPC and PCM were evaluated using Cox proportional hazards models (or logistic regression if the Cox proportional hazards assumption was not met), controlling for age at study entry and Gleason score categorized to ≤7 or >7. Results: A 30-day increase in time to first T>50 was significantly associated with a 75% increase in the risk of PCM. A 30-day increase in time to PSA rise from 1OFF or after T>50 was significantly associated with a 23% or 72% reduction in the risk of CRPC, respectively. While neither of the associations of PSAdt with CRPC or PCM were significant, they were of moderate size: PSAdt displayed a moderate reduction in risk of CRPC by 35% and PCM by 38%. Conclusions: During the first “off treatment” interval of IAD, the time to first T>50 is prognostic for PCM. Time to first PSA rise after 1OFF and after first T>50 are both prognostic for CRPC. [Table: see text]
Predictive biomarkers in circulating tumor cells (CTC) from patients with castration-resistant prostate cancer (CRPC) through genomic analysis.
Authors: Danila Daniel Costin , Anand Aseem , Yao Jianchao , Gierszewska Magdalena , Kramer Melissa , Muller Stephanie , Fleisher Martin , McCombie William R. , Scher Howard I. 
Published: March 2020

4562 Background: Mutations in the ligand binding domain of androgen receptor (AR) in prostate cancer cells may alter their sensitivity to treatment with specific antiandrogens. To predict for tumor sensitivity to treatment with novel AR targeted therapies, we explored the frequency of mutation detection and copy number alteration in CTC isolated from patients with CRPC enrolled on trials with these targeted therapies. Methods: We used fluorescence-activated cell sorting (FACS) methodology to enrich EpCAM+, CD45-, DAPI- cells. For mutation detection and genomic copy number alteration in CTC in low number of cancer cells found in clinical samples, we optimized next-gen deep sequencing by Illumina. Results: In patients with progressive CRPC , >10 or >50 EpCAM+ events (EPE) were isolated by FACS in 88% or 58% of patients, in whom 32% and 10% had unfavorable (>5 cells/7.5 ml) CTC counts using CellSearch. EPE, expressing prostate-specific mRNAs, provide sufficient high quality DNA for genomic sequencing and copy number analysis. Adequate coverage was obtained from as few 50 EPE, with a recovery rate of 89% from FACS sorted samples. The detection threshold of a mutation was established at 1:4 alleles. To further expand genomic profiling in CTC, we optimized Nimblegen exome mutation detection by deep sequencing on HiSeq PE101. Our initial analysis established the polymorphism frequency detection thresholds in heterogeneous cell populations, and confirmed the sequencing coverage. Somatic missense mutations in AR, APC and TP53 found in CTC but not in paired WBC were confirmed by Sanger sequencing. In parallel, copy number alterations in CTC are studied. Conclusions: Somatic mutations detected in CTC isolated from patients with CRPC can serve as predictive markers of tumor sensitivity to targeted therapies. We established standard operating procedures for specimen processing, and confirmed the sequencing coverage and polymorphism detection thresholds in heterogeneous cell population. Currently we are proceeding to clinical samples to study the associations between specific molecular alterations in CTC as predictive markers of sensitivity and clinical outcomes.
The impact of preoperative ASA score and serum albumin on early complication and survival rate of patients undergoing radical cystectomy for bladder cancer.
Authors: Djaladat Hooman , Fairey Adrian Stuart , Cai Jie , Miranda Gus , Skinner Eila C. , Daneshmand Siamak 
Published: March 2020

4576 Background: American Society of Anesthesiologist Score (ASA-S) is used to evaluate patient physical status before surgery. Serum albumin (Alb) is also a marker of nutritional status. We evaluated the impact of preoperative ASA-S and Alb on early complication rate and survival of patients who underwent radical cystectomy for bladder cancer. Methods: 1964 patients with primary bladder cancer underwent radical cystectomy between 1971 and 2008 at USC. Preoperative serum Alb and ASA-S were available in 1471 and 1140 patients respectively. Post cystectomy early complication was defined as any surgery related/unrelated event leading to lengthening hospital stay or re-admission within 90 days of surgery. Recurrence free survival (RFS) and overall survival (OS) for these cohorts were reviewed using a Kaplan-Meier and Cox proportional hazards models. Results: The demographic data of patients based on their serum Alb and ASA-S is presented in the Table. The median follow up was 12.4 years (0 - 36.6 yrs). Low serum Alb (<3.4 g/dL) and high ASA-S (3 or 4) were associated with higher early complication rate (43% vs. 33%, p= 0.03 and 40% vs. 28%, p= 0.0001 respectively). In multivariable analysis, low serum Alb level was an independent predictor of RFS (HR 1.35, 95% CI 1.00-1.81) and OS (HR 1.62, 95% CI 1.29-2.04). High ASA-S was an independent predictor of OS (HR 1.45, 95% CI 1.13-1.85), but not RFS. Conclusions: Preoperative low serum Alb and high ASA-S are independently predictive of post cystectomy decreased OS. Low serum Alb is also a risk factor for recurrence after cystectomy. These parameters potentially could be used in nomograms to predict post-cystectomy prognosis. [Table: see text]
PI3KCA mutations in advanced urothelial carcinoma: A potential therapeutic target?
Authors: Molins Joaquim Bellmunt , Werner Lillian , Guix Marta , Guancial Elizabeth Ann , Schutz Fabio Augusto Barros , O'Brien Robert , Stack Edward C. , Loda Massimo F. , Berman David M. , Hirsch Michelle S. , Signoretti Sabina , Gallardo Enrique , Rojo Federico , Ross Robert W , Kantoff Philip , Choueiri Toni K. , Rosenberg Jonathan E. 
Published: March 2020

4582 Background: PI3KCA is frequently mutated in human cancer; however, information is scarce regarding its relevance in urothelial carcinoma (UC). We determined the prevalence of mutation and impact on clinical outcome of PI3KCA uniformly-treated patients with metastatic UC. Impact of PI3K and dual PI3K/mTOR inhibition was tested in vitro in UC cell lines with either H1047R or E545K mutation. Methods: 141 samples from invasive UC were scanned for mutations. Of those, complete clinical data was available from 85 cases treated with platinum-based combination chemotherapy for advanced or metastatic disease. DNA was extracted from FFPE material. Mutation status was determined by iPLEX sequencing and confirmed with hME sequencing. Overall survival (OS) was measured from beginning of treatment for metastatic disease to time of death or censored on the last known alive date. Cox proportional hazard model was used to assess the associations of PI3K mutational status and OS. Growth inhibitory effects of a specific PI3K inhibitor and a dual PI3K/mTOR inhibitor (both from Selleck) on UC cell lines with or without mutations were tested using MTT assays. Results: Mutations in the PI3KCA gene were observed in 14 (10%; 95% CI 6-16%) specimens. E545K was detected in all 14 specimens, though one specimen contained mutation at both E545K and H1047R. Among patients with clinical data, there was no statistically significant association between PI3KCA mutational status and OS (HR for having PI3KCA=0.49, 95% CI [0.15, 1.57], p-value 0.22). Preliminary in vitro experiments showed that cell growth was more potently inhibited with dual PI3K/mTOR inhibitors than with PI3K inhibitors. Conclusions: Mutations in the PI3KCA gene were detected in 10% of invasive UC and did not correlate with OS in patients with metastatic UC treated with platinum-based chemotherapy. PI3K inhibition in vitro impacts UC cell growth, though dual PI3K/mTOR inhibitors may have more significant effects than PI3K inhibition alone.
Second-line treatment of advanced urothelial cancer with paclitaxel and RAD001 (everolimus) in a German phase II trial (AUO trial AB 35/09).
Authors: Niegisch Guenter , Retz Margitta , Thalgott Mark K. , Balabanov Stefan , Honecker Friedemann , Stöckle Michael , Ohlmann Carsten Henning , Boegemann Martin , vom Dorp Frank , Gschwend Juergen , Hartmann Arndt , Ohmann Christian , Albers Peter 
Published: March 2020

4590 Background: Efficacy of second-line treatment after cisplatinum failure in patients (pts) with advanced urothelial cancer is limited. Based on encouraging preclinical data and results from several phase I trials in solid cancers, we evaluated the safety and efficacy of the combination of paclitaxel and RAD001 (everolimus) in these pts. Methods: In this single-arm, multicenter phase II trial, pts failing prior cisplatinum based combination treatment for advanced urothelial cancer were treated with paclitaxel (175 mg/m² i.v., three-weekly) and the mTOR-inhibitor RAD001 (10 mg p.o., once daily). Pts were treated until tumor progression by RECIST criteria or until a maximum of 6 cycles was completed. A one-stage design was used to evaluate the overall response rate (ORR) as primary endpoint. Results: 27 pts (18 men, 9 women; median age 63 (35-76) years; ECOG ≥ 1: 11/27pts, hepatic metastases: 10 pts, Hb<10 g/dl: 8 pts; upper urinary tract: 9 pts, lower urinary tract 15 pts, both: 3 pts) were enrolled between 07/09 and 12/11. As of 01/12, 19 pts are evaluable for the primary endpoint and the toxicity profile (6 pts still on treatment, 1 patient has withdrawn consent). Main toxicities (all CTCAE grades) were anemia (10/19 pts), leucopenia (8/19 pts), and neuropathy (9/19 pts). Grade III/IV toxicities were anemia (4/19 pts) and leucopenia (4/19 pts). No treatment related deaths were observed. Median number of cycles was 4 (1-6). Complete remission (CR) and partial remission (PR) was observed in 0/19 and 3/19 pts, respectively (ORR 16%). Stable disease (SD) was observed in 10/19 pts. Median time-to-progression (TTP) was 2.7 months (95% confidence interval [CI] 1.6 – 4.4), median overall survival (OS) was 6.5 (CI 4.5 – 9.2) months. Conclusions: Frequency and severity of toxicities were acceptable. Using the combination of RAD001 and paclitaxel as second-line treatment for advanced urothelial cancer after cisplatinum-failure, response rates and survival times comparable to vinflunine were observed.
Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial.
Authors: Friedlander Terence W. , Weinberg Vivian K. , Yeung Alex , Burke James , Lamm Donald L. , McKiernan James M. , Nemunaitis John J. , Stephenson Joe , Small Eric Jay , Fong Lawrence , Meng Maxwell V. 
Published: March 2020

4593 Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication-competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3-6 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. No maximum tolerated dose was reached. Urine GMCSF and CG0070 levels were detectable in almost all patients suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. The CR rate for patients with either CIS or Ta tumors was 65% (15/23). Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a complete response. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with inactive Rb and in patients with CIS. Further study in Rb-inactive superficial tumors is warranted.