bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy of irinotecan, paclitaxel, and oxaliplatin (IPO) in relapsed germ cell tumours: A non-cisplatin-based regimen.
Authors: Badreldin Waleed , Chowdhury Simon , Harland Stephen John , Mazhar Danish , Powles Thomas , Wilson Peter , Shamash Jonathan 
Published: March 2020

4529 Background: Cisplatin-based chemotherapy with or without high dose chemotherapy remains the standard approach in managing relapsed germ cell tumors (GCT). The feasibility of IPO was first described in 2006.Non cisplatin-based therapies offer the advantage of differing side effect profiles which may be useful to certain patients.Here we describe the outcome of an expanded cohort of these patients. Methods: The results of 72 consecutive patients were reviewed (18% had metastatic mediastinal GCTs). IPO was used either as 2nd line treatment (n=29) of which 20 had HDCT or 3rd line (n=43) of which 32 had HDCT. IPO consisted of oxaliplatin 100mg/m2, irinotecan 200mg/m2 and weekly pac litaxel 80mg/m2 ( IPO) every 3 weeks for 3-4 cycles with the intention of high dose carboplatin , thiotepa and topotecan as consolidation (HDCT). Results: The 2 year PFS and 3 year OS for the whole cohort was 28.4% (95%CI 17.3-40.5%) and 31.6% (95%CI: 20.1-43.8 %) respectively. The overall response was as follows; CR – 3%, m-ve PR 41%, m+ve PR 18%, SD 17%, PD 20%. In the second line setting, the 2 year PFS was 41.8% (95%CI: 21.7-60.8%) and 3y OS 45.8% (95%CI: 24.2-65.1%). The 2 year PFS according to the IGCCCG2 prognostic score was Intermediate = 34%, High risk =50% and very high risk = 30%. In the 3rd line setting the 2 year PFS was 20.9% (95%CI 9.5-35.4%) and 3 year OS was 23.8% (95%CI 11.7-38.2). For HDCT the 2 y PFS was good risk= 52%, Intermediate =29% and poor risk= 0%. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities were as follows (>5%): neutropenia 35%, thrombocytopenia 18%, infection 15%, diarrhea 11%, lethargy 8%. Conclusions: IPO is a safe, non-nephrotoxic day care regimen which produces encouraging responses particularly in high risk cases. Where cisplatin is contra-indicated this is may be a useful alternative.
Sunitinib objective response (OR) in metastatic renal cell carcinoma (mRCC): Analysis of 1,059 patients treated on clinical trials.
Authors: Molina Ana M. , Zhang Jingbo , Lin Xun , Niculescu Liviu , Korytowsky Beata , Matczak Ewa , Wiltshire Robin , Motzer Robert John 
Published: March 2020

4542 Background: Sunitinib achieves robust OR and improved progression-free survival (PFS) in mRCC patients (N Engl J Med 2007;356:115). A retrospective analysis was performed to characterize the OR rate with sunitinib treatment (Tx) and OR-associated patient features and survival. Methods: Data from six phase II and III trials were pooled from 1,059 patients who received sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the 1st- (n=783; 74%) and 2nd-line (n=276; 26%) Tx settings. Median PFS and overall survival (OS) were estimated by the Brookmeyer and Crowley method, and compared between responders and nonresponders, and early and late responders (response ≤ and >12 weeks, respectively), by a log-rank test. Baseline characteristics were compared by Fisher-exact Test, T-Test, or Wilcoxon Rank-sum Test. Results: Of 1,059 patients, 398 (38%) had a confirmed investigator-assessed OR by RECIST (including 12 with a complete response), of whom 105 (26%), 243 (61%), 314 (79%), and 342 (86%) had a response by 6, 12, 18, and 24 weeks, respectively. Median (range) time to tumor response (TTR) in all patients was 10.6 (2.7–94.4) weeks, which was similar in the 1st- and 2nd-line Tx settings. Responders had better baseline ECOG scores, more favorable risk factor classification based on published MSKCC data, a longer interval since initial diagnosis, more prior nephrectomy, and less presence of baseline bone metastases (all p<0.05). Early responders had more lung metastases (p<0.01). Median PFS (16.3 vs. 5.3 months) and OS (40.1 vs. 14.5 months) were significantly longer in responders vs. nonresponders (both p<0.001), with similar results regardless of 1st- or 2nd-line Tx setting. Median OS did not differ between early and late responders (p=0.1438). Conclusions: OR was achieved in 38% of 1,059 mRCC patients treated with sunitinib and was predicted by favorable pretreatment prognostic factors. Patients with OR had longer PFS and OS. Median TTR was 10.6 weeks, and characteristics and outcome of early and late responders were similar, except for higher frequency of lung metastases among early responders.
Safety and efficacy of MET inhibitor tivantinib (ARQ 197) combined with sorafenib in patients (pts) with renal cell carcinoma (RCC) from a phase I study.
Authors: Puzanov Igor , Sosman Jeffrey Alan , Santoro Armando , Martell Robert E. , Dy Grace K. , Goff Laura Williams , Ma Wen Wee , Fetterly Gerald J. , Michael Shaunita A. , Means-Powell Julie Ann , Chai Feng , Lamar Maria , Strauss Gary M. , Zucali Paolo A. , Chiang Wendy M. , Jarboe Jamie , Schwartz Brian E. , Adjei Alex A. 
Published: March 2020

4545 Background: Inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptor are standard therapy for RCC, and the MET signaling pathway is implicated in tumor angiogenesis. Tivantinib is an oral, selective MET inhibitor. In several tumor models, tivantinib plus sorafenib exhibited synergistic antitumor activity vs single-agent activity. This phase I dose-escalation study assessed the safety of tivantinib plus sorafenib in pts with advanced solid tumors. Methods: Endpoints were safety, the recommended phase II dose (RP2D) of tivantinib plus sorafenib, and antitumor activity. Previously, dose escalation established the RP2D as tivantinib 360 mg twice daily (BID) plus sorafenib 400 mg BID. Extension cohorts enrolled ≤ 20 pts each with RCC or other tumors. Patients were treated until disease progression or unacceptable toxicity. Results: 20 pts (mean age, 60 yr) including 16 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts received treatment at the RP2D (n = 19) or tivantinib 360 mg BID plus sorafenib 200 mg BID (n = 1). 4 pts are still on study. 16 pts (13 with clear cell RCC) received ≥ 1 previous systemic therapy (median, 2; range, 0-4) including VEGF (14 pts) and/or mTOR (5 pts) inhibitors. The most common (≥ 25%) adverse events were rash (65%), diarrhea (45%), alopecia (40%), hypophosphatemia (35%), and fatigue, stomatitis, palmar-plantar erythrodysesthesia syndrome, and pruritus (25% each). Best response was partial response (PR) in 3 pts (all clear cell RCC pts) and stable disease (SD) in 15 pts (11 clear cell, 3 papillary, and 1 clear cell/chromophobe RCC pts). 7 pts with SD had ≥ 10% tumor size reduction. The overall response rate (ORR) and disease control rate (DCR; PR + SD) were 15% and 90%, respectively. Median progression-free survival (mPFS) was 12.7 mo (95% CI, 7.1-14.5 mo). In 14 pts previously treated with a VEGF inhibitor, best response was 2 PR and 10 SD, the ORR and DCR were 14% and 86%, respectively, and mPFS was 12.7 mo (95% CI, 5.3-NR mo). Conclusions: Oral combination therapy with tivantinib plus sorafenib was well tolerated and exhibited preliminary anticancer activity in pts with RCC, including pts pretreated with VEGF inhibitors.
Tasquinimod and survival in men with metastatic castration-resistant prostate cancer: Results of long-term follow-up of a randomized phase II placebo-controlled trial.
Authors: Armstrong Andrew J. , Haggman Michael , Stadler Walter Michael , Gingrich Jeffrey R. , Assikis Vasily J. , Polikoff Jonathan , Denmeade Samuel R. , George Daniel J. , Andreou Cal , Clark William R. , Sieber Paul , Agajanian Richy , Belkoff Laurence , Damber Jan-Erik , Nordle Orjan , Forsberg Goran , Carducci Michael Anthony , Pili Roberto 
Published: March 2020

4550 Background: Tasquinimod (T) is an oral quinoline-3-carboxamide derivative that binds S100A9 protein and has preclinical anti-angiogenic and anti-tumor activity. Between 12/07-6/09, 201 (134 T, 67 Placebo (P)) men with metastatic CRPC were randomized and received treatment once-daily at an initial dose of 0.25 mg/day escalated to 1.0 mg/day over 4 weeks. Placebo patients could cross over to T after 6 months or at disease progression. The primary endpoint of improved PCWG2 criteria-defined progression at 6 months was met (69 vs. 37% of patients (T/P) were progression free) with PFS of 7.6 vs. 3.3 months for pts on T vs. P1 with acceptable toxicity. This abstract provides the first analysis on symptomatic progression, overall survival (OS) as well as a multivariate analysis for PFS and OS. Methods: Survival data were collected between June 2011 and January 2012 with a median time to censoring of 32 months. Survival data was also evaluated in an exploratory multivariate model of known prognostic factors in CRPC. Results: An imbalance of several baseline prognostic criteria favored placebo (e.g. baseline PSA of 29 vs. 19 (T/P)) (JCO 2011;20:4022). Time to symptomatic progression was longer in T treated patients (p=0.039, HR=0.42). Record of death (97 events) or survival >13 months was documented in 182 patients. Median time to death was 34.2 vs. 30.2 months (T/P). Median time to death in the PCWG2 bone-metastatic subgroup (N=92/44) was 34.2 vs. 25.6 months. A multivariate analysis of known prognostic factors including PSA, LDH, PSA kinetics, and hemoglobin demonstrated an adjusted HR for PFS of 0.54 (95% CI 0.37,0.81) and OS of 0.72 (95% CI 0.46,1.12) in the total population and 0.63 (95% CI 0.37,1.07, n=136) in the bone-metastatic group. Conclusions: OS observed after tasquinimod treatment is longer than previously reported in this patient population. The current exploratory data indicates that the prolongation in PFS observed with tasquinimod treatment may lead to a survival advantage in men with metastatic CRPC. A phase III placebo-controlled study (NCT01234311) is ongoing in men with bone-metastatic CRPC powered to detect an OS improvement.
Pretreatment (pre-tx) neutrophil to lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with ketoconazole (keto): Association with outcome and predictive model.
Authors: Sella Avishay , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Neumann Avivit , Peer Avivit , Rosenbaum Eli , Kovel Svetlana , Sinibaldi Victoria J. , Hammers Hans J. , Carducci Michael Anthony , Eisenberger Mario A. , Keizman Daniel 
Published: March 2020

4564 Background: The CYP17 inhibitor keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited vs extensive). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. Results: From 1999-2011, 156 mCRPR pts (median age 69) were treated with keto. 78/156 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-144). Excluded from the analysis were 23 pts without available data on pre-tx NLR, and those with recent (≤1 mos) health event or tx (surgery, steroids, radiation) associated with a change of blood counts. 133 pts were included in the analysis. 62 (47%) had an elevated pre-tx NLR >3. Risk factors associated with PFS (table) were pre-tx NLR >3, prior response to GnRH-a <24 mos and to antiandrogen (AA) <6 mos, and pre-tx PSADT <3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text]
PIK3CA gene alterations in bladder cancer: Analysis of correlative series of transurethral resection (TUR)—Correlation with grade histology and tumor size.
Authors: Castellano Daniel E. , Sepulveda Juan , Martinez-Fernandez Monica , Dueñas Porto Marta , Garcia Escudero Ramon , Villacampa Felipe , de la Rosa Federico , Duarte Jose , Martinez Victor , Paramio Jesus 
Published: March 2020

4584 Background: PI3K pathway involvement in bladder cancer is well documented and activating mutations of the gene have been identified, particularly in tumors of low grade and stage. We have analyzed hot spot mutations and copy number in PIK3CA gene as well as mRNA expression levels in tumor tissue of pts with urothelial cell carcinoma (UCC). Methods: 90 pts were analyzed. In 85 pts, fresh tissue from tumor and adjacent normal tissue was collected. All pts signed an informed consent and basic demoghrapics data were collected. Histology confirmation of UCC was required. PIK3CA alterations were analyzed by quantative-PCR. Results: Patient«s characteristics were: median age 73 years, Ta 45.5%, T1 41.1%, T2 12.2%; high-grade histology 43.4%, low-grade 51,1%, PULMP 4,4%. With a median follow-up of 10.0 months, 21% tumor recurrences were observed. 13% normal tissue and 51,8% tumor samples harbored alterations in PIK3CA gene, including alterations affecting the helical domain (mutations 65%, amplifications 60%, both 21%). According to T stage the distribution was: 10/36 Ta, 26/35 T1 y 6/10 T2. (p<0.05). When analyzing factors related to tumor recurrence, it was found that PIK3CA gene mutations in E542 or E545 had a lower recurrence risk (p-value ²0.045). Differential expression analysis (genome-wide transcriptome analysis/microarray) showed that tumors bearing altered PIK3CA gene are more similar to non-tumoral samples comparing with tumors bearing wtPIK3CA gene. Moreover, overexpressed genes in mutant samples are mainly involved in G-protein and Wnt signaling, whereas underexpressed genes are involved in cell morphogenesis and cell polarity. Conclusions: We observed that PIK3CA gene alterations is an early carcinogenesis event in UCC pts, and more frequently found in larger tumor stages. These data support that PIK3CA status may constitute a good prognostic tool, as well as a therapeutic target in stratified groups for bladder cancer.
External validation of somatic copy number alteration (SCNA) at chromosome 1q23.3 in advanced urothelial carcinoma (UC).
Authors: Riester Markus , Werner Lillian , Molins Joaquim Bellmunt , Selvarajah Shamini , Weir Barbara , Stack Edward C. , Park Rachel S. , O'Brien Robert , Schutz Fabio Augusto Barros , Choueiri Toni K. , Signoretti Sabina , Gallardo Enrique , Rojo Federico , Lloreta Trull Josep , Marchionni Luigi , Hahn William C , Berman David Monty , Kantoff Philip W. , Michor Franziska , Rosenberg Jonathan E. 
Published: March 2020

4585 Background: Advanced UC is associated with multiple SNCAs. To identify SCNA predictors of poor survival in advanced UC, we evaluated SCNAs in two cohorts of high-risk urothelial carcinoma of the bladder. Methods: We obtained DNA copy number data from bladder cancer patients in two independent cohorts [Spanish cohort (n= 93, Agilent aCGH 180k array) and Brigham and Women’s/Dana-Farber (BW/DF) cohort (n = 48, Affymetrix OncoScan FFPE Express 2.0)]. For the BW/DF cohort, we acquired copy number information from 30 primary tumors and 33 metastases. For 12 patients, both primary and matched metastases were available. The GISTIC method was used on GLAD segmented data to identify driver copy number lesions, and the NBC algorithm to identify recurrent breakpoints. Cox proportional hazards models were used to estimate the effect of the identified SCNAs on overall survival, defined as time from start of chemotherapy for metastatic disease (Spanish) or from metastatic recurrence (BW/DF). Copy numbers were incorporated in the Cox models as continuous measures. Statistical significance of optimal cutpoints was estimated with permutation tests. Copy number profiles of primary tumors and metastases were compared with hierarchical clustering. Results: Amplification of 1q23.3 was independently associated with overall survival in both cohorts (Spanish cohort: HR 3.98; 95% 1.64-9.67; p < 0.03; C-statistic 0.54, 95% 0.45-0.65. BW/DF cohort: HR 6.28; 95% 1.84-21.4; p < 0.042; C-statistic 0.62, 95% 0.48-0.76). Amplifications at 22q12.2 were enriched in patients who developed metastasis (p < 0.05). A breakpoint analysis identified possible truncations of ITPR1 (Spanish: 15%; BW/DF: 25%) and PRIM2 (Spanish: 31% BW/DF: 12.5%) in large numbers of samples. For primary tumors with matched metastases, we observed that metastases clustered together with their primary tumors. Conclusions: External validation of the 1q23.3 amplification demonstrates the association of this SCNA with poor outcomes in advanced UC; the identification of the target of this copy number gain is ongoing. Gene truncations and their biological significance require further experimental investigation.
Utilization and predictors of neoadjuvant chemotherapy for muscle-invasive bladder cancer in the Veterans Health Administration.
Authors: Sandhu Gurdarshan Singh , Luo Suhong , Zeringue Angelique , Carson Kenneth Robert , Nepple Kenneth Gerard , Strope Seth A. , Hudson M'Liss A. , Grubb Robert L. 
Published: March 2020

4594 Background: The survival benefit with neoadjuvant chemotherapy for bladder cancer was established in 2003. However, adoption of this paradigm in clinical practice has been slow. We explored the use of neoadjuvant chemotherapy and identified predictors of its use in a contemporary cohort in the Veterans Health Administration (VA). Methods: Using the national VA Clinical Cancer Registry, all patients diagnosed with clinical stage T2-4, N0 or Nx, M0 bladder cancer from 1997 to 2007 were stratified into surgically (radical cystectomy [RC], n=1,211) and nonsurgically managed groups (n=2,125). Receipt of neoadjuvant chemotherapy was defined as chemotherapy treatment up to 6 months before RC as well as initial treatment only with chemotherapy (without subsequent surgery or radiation) in the nonsurgical group. Temporal trends in neoadjuvant chemotherapy use were evaluated with a chi square test. Predictors of neoadjuvant chemotherapy were examined using a multivariable logistic regression model incorporating demographic, socioeconomic, comorbid, pathologic and hospital factors. Results: 6.3% and 8.3% of patients received neoadjuvant chemotherapy in the surgical and non-surgical group, respectively. Analysis of temporal trends in chemotherapy use demonstrated an increase in neoadjuvant chemotherapy use over time (p<0.0001); from 3% (2003 and before) to 14% annually (2007). On multivariable analysis of both groups, older age and more recent diagnosis were predictive of neoadjuvant chemotherapy use (Table). Other covariates did not predict receipt of neoadjuvant chemotherapy. Conclusions: While overall use of neoadjuvant chemotherapy in the VA population with bladder cancer remains low, use thereof is slowly increasing, with a more recent diagnosis most strongly predicting its use. [Table: see text]
Genetic determinants of long-term response to rapalog therapy in advanced renal cell carcinoma (RCC).
Authors: Voss Martin Henner , Hakimi Abraham A. , Scott Sasinya N. , Takeda Shugaku , Liu Han , Chen Yingbei , Motzer Robert John , Berger Michael F. , Hsieh James 
Published: March 2020

4604 Background: Temsirolimus (T) and everolimus (E) are rapalog inhibitors of the mammalian target of rapamycin (mTOR) with efficacy in advanced RCC [NEJM;356(22):227-81; Lancet;372(9637):449-56]. With reported median progression-free survival (PFS) of 5.5 and 4.9 months (mo), respectively, benefit is typically modest, yet a subset of patients (pts) achieves long-term disease control evident by extended PFS. The oncogenomic background for this is unclear. Methods: We analyzed frozen specimens of tumor and adjacent normal kidney from pts with advanced RCC and documented long-term response to T or E, defined as PFS of ≥ 20mo. Samples from pts with PFS ≤ 2mo served as comparators. Specimens were subjected to whole exome sequencing; a targeted next-generation sequencing platform was used for deep sequencing and investigation of copy number variations (CNV) in 230 genes of interest. Results: In 5 pts with long-term response to T [n=3] or E [n=2], histologic subtypes were clear cell [n=3] and unclassified [n=2] RCC. Median number of prior treatments was 2 (1-3). Two pts remain on therapy, 3 have stopped drug for disease progression; treatment duration was 20, 25+, 27, 28, and 28+ mo. Three control pts progressed after 1, 2, and 2 mo on therapy. Mean target coverage was 86x for whole exome and 443x for targeted sequencing. Three of 5 long-term responders harbored acquired somatic mutations and/or CNV in genes encoding for members of the Phosphoinositide 3-Kinase (PI3K) / mTOR pathway. Effects on amino acid sequence and gene function suggest a hyperactive pathway in all 3. For the other 2 long-term responders genomic changes with possible indirect link to the pathway, but no apparent determinants of treatment response were seen. In 3 control patients with rapid disease progression no genomic alterations suggesting hyperactivation of the pathway were seen. Conclusions: In this retrospective discovery set of RCC pts with unusually long response to rapalog therapy, next generation sequencing using pre-treatment tissue specimens revealed plausible oncogenomic determinants of treatment benefit in 3 of 5 cases. These findings provide basis for further biomarker development and studies in a larger sample set are ongoing.