bluuebunny/crossref_metadata_2025_split huggingface dataset:
A validated 34-gene signature for assessing risk of recurrence in clear cell renal cell carcinoma.
Authors: Rathmell Kimryn , Brooks Samira A , Brannon Angela Rose , Parker Joel S , Fisher Jennifer C , Sen Oishee , Nielsen Matthew Edward 
Published: March 2020

4522 Background: The objective of this study is to create a molecular tool that can be applied widely to clinical specimens using existing transcript signatures for use in clinical risk prediction of clear cell Renal Cell Carcinoma (ccRCC) to improve personalized disease management. Methods: We developed a 34-gene subtype predictor to classify clear cell tumors according to two subtypes, clear cell A (ccA) or B (ccB). The training set consisted of 72 ccRCC microarray-analyzed tumor samples that had previously been classified by unsupervised clustering and logical analysis of data (LAD). The predictor was developed from a panel of genes significantly expressed in ccA and ccB tumors and associated with prognosis. The prognostic value of the algorithm was corroborated in RNA-sequencing data from 379 ccRCC samples from The Cancer Genome Atlas (TCGA) and further validated using the NanoString platform with a cohort of 163 archival fixed samples collected at the University of North Carolina. Results: Risk associated molecular subtypes, ccA and ccB, were classified in TCGA and NanoString cohorts. Subtype classification showed significant prognostic outcomes for overall survival (p<.001), cancer-specific survival (p=.003), and recurrence-free survival (p<.05) and remained significant in multivariate analyses that included age at diagnosis, gender, ethnicity, pathologic stage, and histologic grade. A prognostic model was built for overall and recurrence-free survival for non-metastatic ccRCC patients within the context of subtype and clinical characteristics. Conclusions: The ccA and ccB subtypes significantly added prognostic information to clinical parameters, particularly for non-metastatic ccRCC patients.The subtypes can be used for future analyses involving risk for developing metastatic disease and cancer-specific outcomes. This research was supported with a grant from the American Association for Cancer Research, and the UNC Lineberger Comprehensive Cancer Center Cancer Cell Biology Training Grant.
Association of IGF1R overexpression (OE) with outcome in invasive urothelial carcinoma (UC) of urinary bladder.
Authors: Gonzalez-Ribbon Nilda , Kim Jenny J. , Chaux Alcides , Munari Enrico , Faraj Shiela F. , Ellis Carla , Sharma Rajni , Bivalacqua Trinity , Schoenberg Mark , Carducci Michael Anthony , Netto George J. 
Published: March 2020

4523 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed in several tumors including UC and is currently under investigation as a target of Rx. We here explore IGF1R expression in UC, its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered overexpressed in cases with score 1. Endpoints of the study included overall survival (OS) and disease-specific survival (DSS). Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R OE was found in 62% of UC. No differences were noted between normal urothelium and UC regarding IGF1R OE (74% vs. 60%; P=0.14). IGFR1 OE was more frequent in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). Tumors at stage pT4 overexpressed IGF1R more frequently than tumors at stages pT1-pT3 (71% vs. 29%, P=0.005). No association with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis) was found. OS and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients with tumors overexpressing IGF1R had a lower OS and DSS compared to those without IGF1R OE (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R OE remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: OE of IGF1R was found in 62% of UC. High stage tumors overexpressed IGF1R more frequently than low stage tumors. Further, IGF1R OE was a significant independent predictor of OS and DSS in invasive UC.
Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS).
Authors: Qu Angela Q. , Jacobus Susanna J. , Signoretti Sabina , Stack Edward C. , Krajewski Katherine Maragaret , Rosenberg Jonathan E. , Choueiri Toni K. 
Published: March 2020

4530 Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least >50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p<T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score <0.1 (negative) vs. >0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p=0.146). Those achieving RaR had a significantly longer DFS (p=0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(+) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(+) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(+) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.
Germ cell cancer (GCC): Long-term survival after treatment with bleomycin (B), etoposide (E), and cisplatin (P) in a large cohort.
Authors: Gundgaard Maria Gry , Lauritsen Jakob , Mortensen Mette Sakso , Agerbaek Mads , Holm Niels Vilstrup , Dalton Susanne O. , Johansen Christoffer , Daugaard Gedske 
Published: March 2020

4533 Background: In 1997 the International Germ Cell Cancer Collaborative Group presented a classification dividing patients into a good, intermediate, and poor prognostic group for metastatic GCC with 5-year survival information. However, only a minor part of these patients were treated with today’s standard treatment. We present the first nationwide and population based study of overall survival (OS) and disease specific survival (DSS) in a large cohort of GCC patients treated with BEP. Methods: A nationwide and population based clinical database covering GCC patients diagnosed 1984-2007 was constructed, including 4,683 GCC cases. Through merging with national administrative registers, information on vital status and cause of death for all patients until November 30, 2012, was obtained. Results: The 5-year OS for the whole database cohort was 96%. A total of 1,584 patients were treated with BEP (1,099 patients with primary metastatic disease, 485 patients relapsed from stage I). Until 2001, the standard treatment was 4 cycles of BEP, after 2001 patients with good prognosis had 3 cycles of BEP. Overall survival (OS) and disease specific survival (DSS) with 95% confidence intervals (95% CI) (Table), median observation time was 13.8 years. Conclusions: This cohort study showed improved OS for GCC patients across all prognostic groups since 1997, in particular regarding the poor prognostic group. The present result is based on a large number of cases established in a population based fashion, with long follow up time and unbiased information covering all cohort members including detailed clinical information and vital status of all patients. [Table: see text]
Does chemotherapy improve survival in muscle-invasive bladder cancer (MIBC)? A systematic review and meta-analysis (MA) of randomized controlled trials (RCT).
Authors: Tjokrowidjaja Angelina , Lee Chee , Stockler Martin R. 
Published: March 2020

4544 Background: There is strong evidence that neoadjuvant chemotherapy improves survival in MIBC but its uptake in clinical practice is variable. The benefits of adjuvant chemotherapy are controversial, especially with the recent presentation of 3 RCTs not included in previous MA.We sought to summarise the effects of chemotherapy, both neoadjuvant and adjuvant, on survival in MIBC. Methods: We included published summary data from recent MA and RCTs. Eligible RCTs compared the addition of chemotherapy, neoadjuvant or adjuvant, to local treatment versus local treatment alone. We searched CENTRAL, PubMed, MEDLINE, proceedings of ASCO and clinicaltrials.gov from 2004 to August 2012.The primary outcome was overall survival (OS). Disease-free survival (DFS) and adverse events (AE) were secondary outcomes. Pooled hazard ratios (HR), confidence intervals (CI) and p-values (p) were estimated with fixed effects model. Heterogeneity and subgroup effects were assessed with p-values for interaction. Results: We included 21 RCTs (n=3986), 12 of neoadjuvant (n=3047) and 9 adjuvant chemotherapy (n=939).The addition of chemotherapy significantly improved OS (HR 0.86, 95% CI 0.79 to 0.93, p=0.0004). Separate analyses of neoadjuvant therapy and adjuvant therapy yielded significant results in both subgroups (HR 0.89, 95% CI 0.81 to 0.98, p=0.02; HR 0.75, 95% CI 0.63 to 0.90, p=0.002; respectively; p-value for interaction 0.11). There were larger benefits in DFS (HR 0.77, 95% CI 0.71 to 0.84, p<0.000001), which were also noted with the addition of neoadjuvant and adjuvant therapy (HR 0.80 95% CI 0.73 to 0.88, p<0.00001; HR 0.67 95% CI 0.55 to 0.81, p<0.0001; respectively; p-value for interaction 0.10). The most common AE of grade 3 or 4 were haematological, gastrointestinal and renal impairment with median frequencies of 33%, 15% and 2% respectively in neoadjuvant; and 15%, 21% and 27% in adjuvant trials. Conclusions: Meta-analysis of available randomized trials indicates that chemotherapy, both adjuvant and neoadjuvant, improves survival in MIBC. A direct comparison of these two strategies in a large scale randomised trial is needed to determine which is optimal.
One course of adjuvant BEP in clinical stage I, nonseminoma: Mature and expanded results from the SWENOTECA group.
Authors: Tandstad Torgrim , Cavallin-Stahl Eva , Dahl Olav , Haugnes Hege Sagstuen , Langberg Carl Wilhelm , Laurell Anna , Stierner Ulrika K. , Solberg Arne , Wall Najme , Cohn-Cedermark Gabriella ,   SWENOTECA
Published: March 2020

4553 Background: The SWENOTECA group has since 1998 offered patients with clinical stage I (CSI) nonseminoma (NSGCT) treatment based on a risk-adapted approach. Patients with lymphovascular invasion (VASC+) were recommended one course of adjuvant chemotherapy (ACT) with bleomycin, etoposide and cisplatin (BEP). Patients without lymphovascular invasion (VASC-) had the choice between one course of adjuvant BEP or active surveillance. Methods: From 1998-2010, 491 patients with CSI NSGCT received one course of adjuvant BEP. Following histopathological evaluation 247 patients were classified as VASC+, 239 as VASC- and five patients had uncertain VASC status. All patients were included into a prospective, community-based, multicenter SWENOTECA management program. Initial results from patients treated during 1998-2005 have earlier been reported. We now report the mature data, expanded with patients treated during 2005-2010. Results: The median follow-up was 8.0 years. Eleven relapses were observed. After one course of adjuvant BEP 2.3% of patients relapsed. In regard to VASC status 3.4% of VASC+ and 1.3% of VASC- patients relapsed. The latest relapse was detected 3.3 years after ACT. Ten patients have died, only one due to testicular cancer. The 5 and 10-year overall survival rates were 98.9% and 96.8%, respectively. The 5 and 10-year disease-specific survival rates were 100% and 99.6% respectively. Conclusions: One course of adjuvant BEP reduces the risk of relapse in CSI NSGCT with over 90%. These mature results confirm our earlier results on one course of adjuvant BEP. There is no evidence of late relapses, or chemotherapy-resistance in relapses following ACT. To detect relapses, a follow-up of five years is sufficient.
Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03.
Authors: García-Donas Jesús , Polo Susana Hernando , Guix Marta , Climent Duran Miguel Angel , Mendez Vidal Maria Jose , Jiménez Paula , Leon Mateos Luis , Rodriguez-Moreno Juan Francisco , Moreno Fernando , Segura Eduardo , Duran Ignacio , Maciá Sonia , Arranz Arija Jose Angel , Vazquez-Estevez Sergio , Perez Francisco Javier , Lainez Nuria , Castellano Daniel E. ,   Spanish Oncology GenitoUrinary Group (SOGUG)
Published: March 2020

4587 Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error α = 0.05, power [1 – β] = 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (>6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.
Identification of polo-like kinase 1 (PLK1) in aggressive prostate cancer by paradigm analysis.
Authors: Febbo Phillip G. , Goldstein Theodore C. , Baertsch Robert , Youngren Jack , Newton Yulia , Bivol Adrian , Small Eric Jay , Stuart Joshua M. 
Published: March 2020

5006 Background: Integrative analysis that combines expression data, copy number variation, sequence, and epigenetic data with thousands of known biological interactions can help identify strong biological associations and novel “genotype to phenotype” associations. Methods: We performed multi-dataset differential expression analysis with Statistical Analysis of Microarrays (SAM) and gene set enrichment analysis (GSEA) across 10 publicly-available PCa microarray datasets to identify genes and pathways differentially expressed between local (n=471) and metastatic (n=220) PCa. We used PARADIGM, an integrated pathway analysis method, on PCa tumor samples with mRNA expression, copy number variation, and TMPRSS2:ERG fusion status data to infer differential fusion gene-related “activities” for pathway features (genes, protein complexes, etc) within a “Superimposed Pathway” representing a comprehensive collection of genetic interactions currently containing 20,314 known interactions among 16,362 concepts representing 6916 proteins, 7345 complexes, 1449 families, 55 RNAs, 15 miRNAs and 582 processes. Results: Out of the 7571 genes tested (those genes having data in two or more studies), the meta-analysis on gene expression revealed 210 (1.8% FDR) positively associated with PCa metastasis and 403 (0.94% FDR) negatively associated genes (threshold was p<0.001, 2-tailed Student’s t-test). GSEA highlighted cell proliferation, cell cycle control, and DNA damage repair pathways with metastatic tumors. The PARADIGM analysis identified a network containing 914 features connected by 1137 edges. PLK1 was identified as both highly expressed in metastatic PCa and as one of the fourteen hubs in the largest (596-feature) sub-network identified by PARADIGM. PLK1 was also associated with high Gleason Sum and recurrent disease in independent local PCa datasets. Conclusions: Using an approach pioneered by members of our SU2C/PCF supported PCa Dream Team, integrated analysis across multiple PCa datasets associates PLK1 activity with aggressive PCa and suggests it may provide a novel treatment target for at least a genetic sub-set of advanced PCa.
Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane.
Authors: Petrylak Daniel Peter , Kantoff Philip W. , Mega Anthony E. , Vogelzang Nicholas J. , Stephenson Joe , Fleming Mark T. , Stambler Nancy , Petrini Michaela , Blattman Sara , Israel Robert Joseph 
Published: March 2020

5018 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized within the cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. A phase 1 dose escalation study of PSMA ADC in taxane-refractory mCRPC has been completed. Methods: Patients with progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1 were eligible. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics, PSA, circulating tumor cells (CTC), immunogenicity and clinical progression were assessed. Serum PSMA ADC and total anti-PSMA ADC antibodies were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Subjects who benefitted from PSMA ADC were eligible for treatment in an extension study. Results: 52 subjects were dosed in 9 dose levels. All subjects received prior docetaxel, 6 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. 16 patients reported peripheral neuropathies, including 3 with grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible elevations in liver function tests (LFTs). Antitumor activity was manifested as reductions either in PSA or in CTCs in approximately 50% of patients at ≥ 1.8 mg/kg PSMA ADC. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. There was no accumulation. Conclusion: PSMA ADC in this study was generally well tolerated in subjects with progressive mCRPC, previously treated with taxane. Antitumor activity was seen at doses ≥ 1.8 mg/kg. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose was determined to be 2.5 mg/kg. A phase 2 trial of PSMA ADC in taxane refractory mCRPC has been initiated at 2.5 mg/kg. Clinical trial information: NCT01414283.
Mortality at 120 days following prostatic biopsy: Analysis of data in the PLCO study.
Authors: Boniol Mathieu , Boyle Peter , Autier Philippe , Perrin Paul 
Published: March 2020

5022 Background: With the widespread use of PSA testing for prostate cancer screening in population, more prostate biopsy are being performed and seem set to increase in number. The safety of this diagnostic procedure needs to be ascertained. Only one study evaluated the mortality following prostate biopsy (Gallina et al, Int J Cancer 2008;123:647-52) and reported an increase of 2 deaths per 1,000 biopsies. Our objective was to re-evaluate the risk of death following prostate biopsy in a large, well-conducted randomised trial – the Prostate, Lung, Colorectal and Ovary (PLCO) Study. Methods: We extracted data from the PLCO study on all men participating in the study with a follow-up until 31/12/2009. All biopsies performed since randomisation were included. Cause of death was defined by ICD9 classification. Results: Among 12,300 prostate biopsies, 36 deaths occurred within120 days: 17/8390 in the intervention arm and 19/3910 in the control group. Only 17 deaths had neoplasm listed as the underlying cause of death. Thirty-two deaths out of 9,124 (0.35%) occurred in the positive biopsy group compared to 4 out of 3,176 (0.13%) in the negative biopsy group. In this latest group, this represents 1.3 deaths per 1,000 biopsies. Deaths occurred in all age groups from 55-69 to 70-74, and there was no difference identified in age between study arms (p=0.45) nor between those with a prostate cancer diagnosis and those not (p=0.73). Conclusions: The mortality rate at 120 days following prostate biopsy of 1.3 deaths per 1,000 biopsies, in a population free of cancer, is a serious concern for the computation of benefit risk associated with PSA testing. This figure is in line with the risk reported by Gallina et al (2008) and is now based on a properly monitored population. This prostatic biopsy mortality would occur earlier than any benefit from a screening program and could reverse any potential gain from screening such as recorded in ERSPC study.