bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of novel metastatic prostate cancer cell lines by “organoid” in vitro culture technology.
Authors: Vela Ian , Gao Dong , Gopalan Anuradha , Sboner Andrea , Undvall Eva , Wanjala Jackline , Iaquinta Phillip , Wongvipat John , Karthaus Wouter , Clevers Hans , Solomon Stephen Barnett , Beltran Himisha , Kossai Myriam , Mosquera Juan Miguel , Rubin Mark A. , Carver Brett Stewart , Scher Howard I. , Sawyers Charles L. , Chen Yu 
Published: February 2017

33 Background: The inability to propagate patient-derived prostate cancer cells in vitro is a major impediment in the mechanistic understanding of tumorigenesis and therapeutic response. In order to generate accurate in vitro models that represent the diversity of in situ prostate cancer, we have developed a three-dimensional “organoid” system to culture metastasis samples and integrated it into our precision medicine workflow of attaining and characterizing pre-treatment biopsies. Methods: Biopsy samples of prostate cancer metastases, both soft tissue and bone, acquired at the time of therapeutic or diagnostic interventions following informed consent and institutional review board approval were obtained from two institutions. Samples were digested in Type II Collagenase (Gibco) and re-suspended in growth factor reduced Matrigel (BD), plated on plastic, and overlaid with prostate culture media (PCM). PCM consists of serum free Advanced DMEM/F12 (Gibco) with multiple growth factors optimized to propagate benign primary prostate cells. Cultures were maintained at 37°C in 5% CO2. Results: In the initial 51 samples, 15 continuous organoid cultures (29%) were established from distinct sites (9 of 32 bone, 6 of 19 soft). Tumor content of the biopsy represents a major determinant of organoid growth. Once established, organoids propagate indefinitely with different kinetics (approximately 48 hours to 1 week doubling time), and can be cryopreserved. Histological analysis shows that the organoids recapitulate the structure of the in situ cancer and genomic analysis using array CGH and whole-exome sequencing (WES) shows the presence of typical copy number alterations including TMPRSS2-ERG interstitial deletion, PTEN loss, CHD1 loss, and AR amplification. WES of two organoid/metastasis pairs shows that the growth conditions do not generate additional mutations. Conclusions: This novel tissue culture technique enables the development of new cell lines derived from metastatic deposits. This advance will facilitate research by availing new and varied cell lines, which will hopefully be more closely aligned to the spectrum of behavior of the clinical disease in comparison to the limited and problematic cell line models currently available.
Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract (TCCU) after failure to one cisplatin-based systemic therapy in clinical practice.
Authors: Gonzalez-Grajera Belen , Puente Javier , Garcia Carbonero Iciar , Mohedano Nicolas , Lopez Criado M. Pilar , Arranz Arija Jose Angel , Gonzalez del Alba Aranzazu , Fernandez Calvo Ovidio , Villalobos Maria L. , Chirivella Isabel , Grande Enrique , Castellano Daniel E. 
Published: February 2017

332 Background: Vinflunine (VFL) is the first agent to show a survival improvement for platinum-refractory patients (pts) with metastatic TCCU in a phase III clinical trial. After EMA approval in September 2009, ESMO (Bellmunt, 2011) and SOGUG (Castellano, 2012) guidelines recommend VFL as second-line therapy. Methods: This is a multicenter and retrospective study to describe the experience with VFL in Spain. Pts with histologically confirmed metastatic TCCU were treated with VFL (280-320mg/m2 every 3 weeks) until progression or unacceptable toxicity. Pts were evaluated according to institutional local follow-up program. Results: From April 2010 to June 2013, we registered 102 pts in fifteen Spanish centers. All patients are evaluable for safety and 98 for efficacy. Median age: 67years (range 45-83), ECOG 0/1/2 previous to VFL (pts%): 31/61/8. Bladder carcinoma was the primary disease site in 84 pts and 46 % of them received cisplatinum-based chemotherapy. Metastatic involvement was: lymph nodes 67.7%, lung 36.4%, bone 28.1%, and liver 21.6%. The median number of cycles of VFL was 4 (1-18). The objective response rate was 25.5% (CR in 2 pts and PR in 23 pts), stable disease in 42.9% and progressive disease in 31.6%. The median follow-up was 6.6 months (0.4 to 43): median progression-free survival 3.9 months (95% CI, 2.3 to 5.5), median time to progression 4.3 months (95% CI, 2.6 to 5.9) and median overall survival 10 months (95% CI, 7.3 to 12.8). At the time of the analysis, 79.4%pts had progressive disease after VFL and 64.7% died. Grade 3/4 adverse events included: nausea/vomiting 13.8% of pts, neutropenia 12.8%, constipation 5.9%, and abdominal pain 4.9%. No toxic death were reported. Conclusions: This retrospective analysis confirms the benefit of VFL in patients with TCCU after failure in a platinum-containing chemotherapy regimen. Results of the randomized trial are reproducible in Spanish Oncology Centers on a daily clinical practice and its toxicity profile results are acceptable and manageable.
Sources of variation in follow-up expenditure after radical cystectomy.
Authors: Vemana Goutham , Vetter Joel , Chen Ling , Sandhu Gurdarshan Singh , Strope Seth A. 
Published: February 2017

335 Background: Follow-up care after radical cystectomy is poorly defined with extensive variation in practice patterns. We sought to determine sources of these variations in care as well as examine the economic impact of standardization of care to guideline recommended care. Methods: Using linked SEER-Medicare data from 1992 to 2007, we determined follow-up care expenditures (time and geography standardized) for 24 months after surgery. Accounted costs included office visits, imaging studies, urine tests and blood work. A multilevel model was implemented to determine the impact of region, surgeon, and patient factors on care delivery. We then compared the actual expenditures on care in the Medicare system (interquartile range) to the expenditures if patients received care recommended by current clinical guidelines. Results: Expenditures over 24 months of follow-up were calculated per month and per patient. The mean and median monthly expenditures were $33 and $21 respectively (minimum $0, maximum $429, 25th to 75th percentile $9 to $43). The total variance of expenditure situated at the surgeon-level and SEER region-level was 9.9% and 4.0% respectively. After accounting for the region, the total variance of expenditure situated at the patient-level and surgeon-level was 14.95% and 7.81% respectively. The assessed cost of guideline follow-up recommendations varied from 0.78-9.05 times the calculated Medicare costs. The guideline recommended cost of follow-up was higher than actual Medicare expenditures in all but one category. Conclusions: While some regional and surgeon-level variations in care were found, most variation in expenditure on follow-up care was at the patient-level, largely based on comorbidity, node positivity, chemotherapy status, readmission rates, and final cancer stage. Standardization of care to current established guidelines would create larger expenditures for the Medicare system than current practice patterns.
Pilot investigation of variants in DNA repair pathways and association with response to platinum-based chemotherapy in bladder cancer.
Authors: Kopp Ryan P. , Stratton Kelly Lynn , Garcia-Grossman Ilana Rebecca , Zabor Emily C. , Ostrovnaya Irina , Thomas Tinu , Gerber Gloria , Alanee Shaheen Riaoh , Schrader Kasmintan A. , O'Donnell Peter H. , Bajorin Dean F. , Joseph Vijai , Offit Kenneth 
Published: February 2017

343 Background: Germline single-nucleotide variations (SNVs) in DNA repair genes may have a role in response to platinum-based chemotherapy in bladder cancer (BC). As a pilot project we created a discovery cohort using an extreme phenotype model of BC response to neoadjuvant chemotherapy; we identified candidate SNVs in DNA repair genes via whole exome sequencing, and sought to replicate these findings in a validation cohort. Methods: We sequenced exomes of a discovery cohort with ≥ cT2 BC and neoadjuvant chemotherapy [6 complete responders (CR, pT0N0 and 1 year disease free interval) vs. 9 non-responders]. We identified SNVs within 377 DNA repair pathway genes. We filtered for SNVs with high impact effects, and moderate impact missense variants. The discovery phase resulted in 16 candidate SNVs which we genotyped (matrix-assisted laser desorption/ionization-time of flight) within a validation cohort of 303 BC patients treated with platinum-based neoadjuvant or first-line chemotherapy. Primary outcome was pathologic (neoadjuvant) or radiographic (first-line) CR, with secondary outcome CR+partial response (PR; RECIST criteria or pathologic downstaging). We used additive genetic model and logistic regression to analyze association between individual SNVs and both CR and CR+PR. Multivariate models included MSK risk score for CR or chemotherapy (cis- vs carboplatin) for CR+PR. Results: We included 303 patients (186 neoadjuvant, 117 first-line; 272 cisplatin, 31 carboplatin), median age 64, including 67 (22%) CR and 153 (50%) CR+PR. Genotyping was adequate for analysis in 14 of 16 SNVs—none were associated with CR. SNVs associated with CR+PR were rs2072454 (EGFR, p=0.031 unadjusted, p=0.035 adjusted for chemotherapy) and rs1805321 (PMS2, p=0.014 unadjusted, p=0.019 adjusted for chemotherapy). Findings were not significant after adjusting for multiple comparisons. Conclusions: Using an extreme phenotype model we identified SNVs in genes of the DNA repair pathway that may have an association with platinum-based chemotherapy response in BC. A larger validation study is required to increase power and reduce the impact of multiple testing prior to confirming significance.
Impact of perivesical lymph nodes on survival after radical cystectomy.
Authors: Hu Brian Robin , Satkunasivam Raj , Cai Jie , Miranda Gus , Daneshmand Siamak 
Published: February 2017

350 Background: Lymph node staging for bladder cancer is dependent upon both location and number. This study characterizes perivesical (PV) lymph nodes (LN) found at radical cystectomy and evaluates their prognostic impact. Methods: We reviewed our Institutional Review Board-approved database from 1971-2009 including all patients who underwent radical cystectomy with pelvic lymphadenectomy for curative intent for urothelial carcinoma. Clinical and pathologic data were obtained. Patients were analyzed in three groups: PV LN+/other LN-, PV LN+/other LN+, and PV LN-/other LN+. Kaplan-Meier curves were used to estimate recurrence free survival (RFS) and overall survival (OS). Multivariable Cox regression (including pathologic T stage, number of positive LN, highest level of positive LN, chemotherapy, and margin status) was performed to evaluate associations between PV LN status and survival. Results: A total of 2,045 patients underwent radical cystectomy for urothelial carcinoma of which 2011 met inclusion criteria. PV LN were identified in 936 (47%) patients, positive in 197 (10%) patients, and represented isolated LN positive disease in 101 (5%) patients. On univariate analysis, positive PV LN were associated with a higher likelihood of extravesical disease (>pT2) when compared with other positive LN (p=0.023). There was no significant difference in RFS or OS when comparing patients with negative PV LN to those with PV LN not identified. On multivariable analysis, patients with PV LN+/other LN+ had a significantly worse RFS (HR 1.75, 95% CI 1.29-2.38, p<0.001) and OS (HR 1.66, 95% CI 1.27-2.19, p<0.001) when compared with PV LN-/other LN+. There was no significant difference in RFS or OS when comparing patients with PV LN+/other LN- to PV LN-/other LN+. Conclusions: PV LN are identified in a significant portion of patients after radical cystectomy with pelvic lymphadenectomy. Positive PV LN, when in combination with other positive LN, portends worse survival even when correcting for the number of positive LN. No significant difference in survival was seen comparing patients with isolated positive PV LN to those with other positive LN. This study highlights the importance of PV LN in pathologic analysis and bladder cancer staging.
Somatic copy number abnormalities (SCNAs) and mutations in PI3K/AKT pathway and prognostic significance for overall survival (OS) in platinum-treated locally advanced or metastatic urothelial cancer (UC).
Authors: Bellmunt Joaquim , Werner Lillian , Riester Markus , Van Hummelen Paul , Rosenberg Jonathan E. 
Published: February 2017

358 Background: An integrative analysis was conducted to identify genomic alterations and mutational status on the gene pathway level that could predict OS in patients (pt) with UC treated with platinum chemotherapy. Methods: DNA was extracted from 94 FFPE samples from invasive UC and screened for mutations and CNAs. Of those, complete clinical data was available from 85 cases. Mutations in the cancer genome were analyzed by a mass-spectrometry based genotyping platform (Oncomap version 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio ≥0.4, or ≤ -0.6 were defined as either having copy number gain or loss and significantly recurrent CNAs across the set of samples was determined using a GISTIC analysis. To better define the co-occurrence pattern of mutations and CNAs, we grouped genes into 3 core signal transduction pathways: (1) TP53 pathway; (2) Abnormalities of in the RTK-RAS-RAF pathway including either ERBB2, FGFR3, MET, FGFR1, KRAS BRAF, RAF1 and NF1; (3) abnormalities on PI3K/AKT pathway including PTEN, PIK3CA, AKT1, TSC1, and MTOR. OS was measured from treatment to time of death or censored. Cox regression was used to assess pathways abnormalities and mutations with outcome. Results: Thirty five samples (41%) harbored mutations on at least one gene, mainly TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). Sixty-six per cent of patients had some sort of copy number variation. PI3K/AKT was the most affected pathway and was associated with shorter overall survival (hazard ratio (HR) =2.3 with 95% CI: 1.3 to 4.2). There was no significant association between mutational status and OS. Combined analysis of SNCA and mutations in the same pathway will be presented. Conclusions: Patients with advanced urothelial cancer receiving platinum chemotherapy have a significantly poor survival which correlated with copy number abnormalities in the PI3K/AKT pathway. This can help to identify patients that can benefit from targeted pathway specific agents.
Using radiologic response to predict prognosis in patients with muscle-invasive bladder cancer undergoing carboplatin-based neoadjuvant chemotherapy.
Authors: Hatakeyama Shingo , Yamamoto Hayato , Okamoto Akiko , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

361 Background: Prognosis and tumor responses of carboplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC) are not well documented. To assess the usefulness of carboplatin-based neoadjuvant chemotherapy, we examined the correlation between radiological responses and pathologic down staging on radical cystectomy (RCx) specimens, disease free survival (DFS), and overall survival (OS). Methods: Between March 2005 and June 2013, we performed carboplatin-based neoadjuvant chemotherapy followed by radical cystectomy in 115 patients with T2-4NxM0 MIBC. After diagnostic TUR biopsy, all participants received two courses of Gemcitabine plus Carboplatin therapy. Baseline and post chemotherapy tumor size from contrast enhanced CT were reviewed. The patients were divided in two groups between responders (CR+PR), and non-responders (SD+PD). RCx and bilateral pelvic lymphadenectomy were performed approximately within a month after cessation of chemotherapy. DFS and OS distributions within radiologic response subgroups were estimated with the Kaplan-Meier method and compared using the log-rank test. To evaluate independent predictor for DFS and OS, age, gender, performance status, pathological T and N stage, down-staging, tumor grade, renal function, and radiological responses were applied by Cox-regression multivariate analysis. Results: No significant differences were observed in patient backgrounds between the groups. Radiologic responses were observed in 75 (65%) patients with 69±24% decrease in responder group, whereas tumor response was 2.8±14% in non-responders. The rate of pathological down staging to <pT2 was 37 (49%) in responders, 5 (13%) in non-responders group. Radiologic response was a strong predictor of DFS and OS. A 5-year advantages of DFS and OS in responders vs. non-responders were 88% and 86% vs. 64% and 69%, respectively (P=0.021 and P=0.013). Multivariate analysis showed radiologic response was the independent factor for DFS and OS. Conclusions: Radiological response post carboplatin-based neoadjuvant chemotherapy is associated with OS in patients with MIBC.
Multicenter sequential phase II study of flavopiridol plus oxaliplatin (Alvocidib) with or without 5-FU and leucovorin (LV) for patients (pts) with refractory germ cell tumors (GCT) including late relapse (LR).
Authors: Feldman Darren Richard , Stadler Walter Michael , Appleman Leonard Joseph , Quinn David I. , Costello Brian Addis , Schwartz Gary K. , Reuter Victor E. , Woo Kaitlyn , Patil Sujata , Fusco Anne , Smith Sloane C. , Carlson Jeremie , Bosl George J. , Motzer Robert John 
Published: February 2017

364 Background: Flavopiridol + FOLFOX showed activity in refractory GCT pts in a phase I trial (Rathkopf, Clin Cancer Res, 2009). This phase II study assessed the efficacy of this regimen in refractory GCT and the necessity of including 5-FU/LV. Methods: Previously treated pts with progressive GCT were eligible if they had received or were not candidates for high-dose chemotherapy (HDCT). Pts on Arm A received flavopiridol 70mg/m2 plus oxaliplatin 85mg/m2. Arm B (flavopiridol + FOLFOX) tested identical doses of flavopiridol and oxaliplatin plus 5-FU (400mg/m2 bolus, then 1800mg/m2 over 48 hours) and LV 400mg/m2. Treatment was every 2 weeks in 6-week cycles. The primary endpoint was response rate (RR) by RECIST. An identical Simon 2-stage design was used for each arm to differentiate between a RR ≥40% vs. ≤20%, with arm B opening only if arm A was ineffective. With ≥3 responses among the first 12 pts, another 13 pts would be enrolled with responses in ≥8/25 pts needed to show efficacy. Tumor biopsies pre-, during, and post-treatment were assessed by IHC for p53, p21, and cleaved caspase-3. Results: Of 36 pts (7 arm A, 29 arm B), 33 had nonseminoma. Primary site was testis in 27 and mediastinum in 7; 22 pts had received prior HDCT and 13 had LR (>2 years), including 2 on arm A and 11 on arm B. Arm A closed early after 0/7 pts responded (2 SD). Of 25 evaluable pts on arm B, 6 achieved a PR, 9 had SD, and 10 had PD. Notably, 5/10 evaluable LR pts on Arm B had a PR, including 1 pathologic CR, 1 PR-negative markers who received radiation (RT) to a residual bone metastasis, and 1 PR-positive markers who received RT to a residual nodal mass. These 3 pts remain disease-free ≥19 months (m) post-chemotherapy and ≥17m post-RT or surgery. Median PFS and OS were 2.3m and 7.3m for all pts and 3.2m and 11.2m for arm B pts. There was 1 treatment-related death due to sepsis. Conclusions: Although neither arm met the prespecified endpoint, flavopiridol plus FOLFOX (arm B) was particularly active in LR pts, with a 50% overall RR, including several durable responses. Further study of FOLFOX with or without flavopiridol is warranted in LR pts. Correlative data will be presented. Clinical trial information: NCT00957905.
An audit of adjuvant carboplatin in patients with stage I testicular seminoma (Anglian Germ Cell Cancer Group, UK).
Authors: Kwan Amy , Shamash Jonathan , Powles Thomas , Ansell Wendy , Chowdhury Simon , Harland Stephen John , Lamont Alan , Wade Robert , Sarwar Naveed , Mazhar Danish , Wilson Peter 
Published: February 2017

366 Background: Patients with stage I testicular seminoma can be managed by surveillance or treated with adjuvant radiotherapy or chemotherapy. Concerns of second malignancies induced by radiotherapy have led to a preference for adjuvant chemotherapy. The TE19 trial demonstrated the non-inferiority of a single cycle of carboplatin, given within 8 weeks of orchidectomy, to adjuvant para-aortic radiotherapy in terms of reduction in recurrence rate. This study also suggested a lower relapse rate if GFR estimation was radionuclide based. Methods: A review of case records of germ cell tumor patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 31/12/2012 was conducted to identify patients with stage I testicular seminoma who received a single cycle of adjuvant carboplatin. Tumor characteristics, clinical management, and patient outcomes were assessed. Results: A total of 336 patients with stage I seminoma who received adjuvant carboplatin were identified. The median age of diagnosis was 38 (range 21 to 78). Median tumor size was 40mm. The rete testis was involved in 131 cases (39%). A radionuclide based estimation of GFR was used in 318 patients (94.6%), the remaining patients GFR was estimated by the Cockcroft-Gault equation. The median time from orchidectomy to receiving chemotherapy was 46 days. Of the 336 patients, 22 relapsed (6.5%), with nine relapsing after 2 years (seven between 24 and 36 months, and wo after 36 months). The median time to relapse was 18 months. There was a trend towards lower progression free survival in patients whose chemotherapy was dosed based on GFR estimation by the Cockcroft-Gault equation. All relapsed patients were successfully treated with combination chemotherapy. Conclusions: These results demonstrate a higher rate of relapse for stage I seminoma patients treated with adjuvant carboplatin compared with the published data from the TE19 study. In addition they confirm that adjuvant carboplatin for treatment of stage I testicular seminoma leads to excellent outcomes in terms of long-term cure. The use of radionuclide based estimation of GFR is advised. Relapses beyond 2 years are not rare and routine cross-sectional imaging beyond this point should be considered.