bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of dose reduction on survival in patients starting sunitinib (SU) or pazopanib (PA) as first-line for metastatic renal cell carcinoma (mRCC).
Authors: Iacovelli Roberto , Derosa Lisa , Massari Francesco , Verri Elena , Galli Luca , Ciccarese Chiara , Cossu Rocca Maria , Cianci Claudia , Bimbatti Davide , Aurilio Gaetano , Antonuzzo Andrea , Fantinel Emanuela , Cullura Daniela , Ricci Sergio , Modena Alessandra , Falcone Alfredo , Tortora Giampaolo , Nole Franco 
Published: February 2017

553 Background: SU and PA are both VEGFR TKI approved for treatment of mRCC. Previous studies reported that the reduced dose (RD) is not recommended for the beginning of therapy (Motzer et al. 2012) and suggested a direct correlation between dose and effectiveness of therapy (Houk et al. 2010). We aim to investigate if patients (pts) that decreased the dose during treatment have different outcomes compared to those who continue a standard dose (SD). Methods: All pts affected by mRCC who started SU or PA at SD have been included. Pts were divided into two groups: RD and SD, based on whether they reduced the therapy or not. The main reasons for dose change have been collected and the RD group was defined into 2 levels (1st level: SU37.5mg/d, 4/2 or PA 600mg/d; 2nd level: SU25mg/d, 4/2 or PA 400mg/d). Pts were stratified by IMDC prognostic criteria and differences in pts’ characteristics between RD and SD groups were evaluated as well as median PFS and OS. Results: A total of 280 pts have been included. Median age was 62y and 68% was male; 54% had good prognosis, 40% intermediate and 6% poor. First-line was SU in 84% and PA in 16% of cases. A total of 123 (44%) pts decreased the dose to first- (89%) or second-level (11%). The main reasons were hand-foot syndrome (17.9%), diarrhea (15.4%) asthenia (14.6%), mucositis (13.0%) and thrombocytopenia (11.4%). Significant differences between RD and SD groups were the female sex (40% vs. 25%; p = 0.01) and the rate of primary refractory disease (11% vs. 31%: p < 0.001). Median PFS and OS were 12.4 and 34.9 mos, respectively. In RD group, the median time before dose reduction was 3.5 mos. Excluding the primary refractory pts, median PFS was 18.6 and 15.0 mos (p = 0.06) and median OS was 68.0 and 40.7 mos (p = 0.14) in RD and SD group, respectively. In RD group, no differences between 1st- and 2nd-level of dose were observed both in PFS (11.0 vs. 13.1 mos; p = 0.82) and OS (42.8 vs. 36.0 mos; p = 0.78) after reduction. Conclusions: Dose reduction is a frequent event in pts who started a first-line therapy with SU or PA. This study reports that DR does not affect the survival of pts who initially started SU and PA at standard dose.
Comparative effectiveness of pazopanib and sunitinib as first-line therapy for patients with advanced/metastatic renal cell carcinoma in a U.S. community oncology setting.
Authors: Hirsch Bradford Richard , Jiao Xiaolong , Wilson Thomas , Hackshaw Michelle Denise , Jonasch Eric , Ghate Sameer , Perez Jose Ricardo , Vogelzang Nicholas J. 
Published: February 2017

567 Background: The COMPARZ trial demonstrated that pazopanib was non-inferior to sunitinib regarding their efficacy as first line of therapy (LOT) for advanced/metastatic RCC (aRCC). However, no studies have compared the effectiveness of pazopanib to sunitinib outside the clinical trial setting. The purpose of this study was to compare the clinical outcomes of the two therapies in a US community oncology setting. Methods: A retrospective study was conducted using US Oncology’s (USON) iKnowMed electronic health record (EHR) database, supplemented with chart review. Patient eligibility criteria included: ≥ 18 years of age at first diagnosis of aRCC, treated with pazopanib or sunitinib as the 1st LOT between 11/1/2009 – 8/31/2012 in the USON with ≥ 2 office visits. A propensity score (PS) matching was performed to match patients receiving pazopanib to sunitinib. Clinical outcomes including progression free survival (PFS), overall survival (OS) and adverse events (AEs) were compared. Results: A total of 177 patients on pazopanib and 739 patients on sunitinib were identified from the EHR database. After PS matching, 153 pts were included in pazopanib and sunitinib cohort respectively. The mean age, gender distribution, and the Heng disease risk groups were similar between the two cohorts (p>0.05). No significant difference in PFS was observed with pazopanib (median: 9.3 [95%CI, 7.0 to 11.8] months) compared to sunitinib (median: 8.3 [95%CI, 6.4 to 10.9] months, p = 0.43). Similarly, no significant difference was observed in OS for pazopanib (median: 22.3 [95% CI, 16.2 to 31.7] months) compared to sunitinib (median: 26.3 [95% CI, 16.4 to 38.2, p = 0.76] months). AEs (any grade) including diarrhea, hypertension, nausea, vomiting, fatigue were significantly lower in sunitinib (p<0.05) while anorexia was lower in pazopanib (p<0.05). Conclusions: Consistent with the results of COMPARZ, no significant difference was observed in PFS and OS among aRCC patients treated with pazopanib or sunitinib as the 1st LOT in the real world. AEs seemed to be less common with sunitinib, and this may be partially attributed to the limitation of retrospective data.
Randomized phase I/II trial of two schedules of bortezomib and bevacizumab (BBmibmab) in metastatic renal cell cancer: USC trial 4K-05-1.
Authors: Quinn David I. , Wei Denice , Massopust Kristy , Ketchens Charlean , Hu James , Goldkorn Amir , Aparicio Ana , Sadeghi Sarmad , Pinski Jacek K. , Averia Monica , Groshen Susan G. , Dorff Tanya B. 
Published: February 2017

574 Background: VEGF agents are a mainstay of therapy in advanced RCC. Bev has activity in RCC but was licensed with interferon-α, which can produce side effects and reduced QoL. Based on non-overlapping side effect profiles, we studied bortezomib (Bmib), a proteasome inhibitor, with the VEGF ligand monoclonal antibody, bevacizumab (Bmab). Primary objective was to examine safety/toxicity of 2 dose schedules of Bmib with Bmab with secondary aims of efficacy (benchmarked to NCI data) and correlatives. Methods: From 2005 and 2014, 62 RCC patients with clear cell or papillary predominant histology treated with 0-4 prior therapies were screened: 10 screen failed, 4 were ineligible (2 treated, 2 not) leaving 48 eligible patients, of whom 46 were evaluable for safety and efficacy endpoints with 20 in each of the phase II dose schedules. Regimens were randomly allocated, stratified by MSKCC group. Results: Best tolerated doses of Bmib with Bmab 10mg/kg IV q3wks on each regimen were A: 1.3 mg/m2 on D 1, 4, 8 and 11 q3wks & B: 1.8 mg/m2on days 1 and 8 q3wks. MSKCC strata: low, intermediate, high risk in 43, 42%; 48, 49%; 9, 9% for schedules A and B, respectively; other baseline factors were not significantly different between A & B. Overall: nephrectomy 90%; ECOG 0 73%; male 71%; median age 57 years; Caucasian 48%, Hispanic 33%, Black 8%, Asian 10%;. Median cycles both arms: 5. Best RECIST 1.0 response PR: 13%, 13%; SD 52%, 48%; PD 26%, 35%; Reason off therapy: PD 58, 67%; toxicity 25, 17% in arms A, B. Median OS: 33.4, 14.7 months (p=0.69), TTP 11.2, 9.4 months, PFS 7.3, 6.6 months (p=0.61) in arms A, B. Grade 3+ tox: A 14/24 vs. B 13/24, p=1.0. Arm A had numerically more skin toxicities and grade 2/3 hematological tox (Plats and WBCs) compared to arm B but this was not statistically significant. Conclusions: Randomized comparisons of novel agents are feasible in renal cell cancer using risk factor algorithms. This VEGFrTKI contemporaneous series of Bmab based therapy with 2 schedules of Bmib suggests potential better outcomes for schedule A with more frequent dosing of Bmib – further sensitivity analysis is ongoing to determine whether this is explained by histology or therapeutic sequencing or likely to suggest proteasome as a target in RCC. Clinical trial information: NCT00184015.
Histological architectures of clear cell carcinoma and their correlation to clinicopathologic features.
Authors: Kimura Go , Takeda Hayato , Akatsuka Jun , Endo Yuki , Kondo Yukihiro 
Published: February 2017

576 Background: The aim of this study is to clarify the relationship between histological architectures (HA) and clinicopathological features (CF) in clear cell carcinoma (CCC). Methods: Between 1984 and 2014 nephrectomy or partial nephrectomy were performed in 723 renal cell carcinoma cases in our hospital. Among them 603 cases (83.4%) were CCC. We reviewed the pathological reports and found 556 CCC cases had description of HA. The relationship between HA and CF were investigated. Results: HA were as follows: small acinar (SA)/acinar (A) in 453 cases (81.5%), large acinar (LA)/solid (S) in 113 (20.3%), papillary (P) in 54 (9.7%), Cystic (C) in 121 (21.8%) and tubular in 53 (9.5%). By the Spearman rank correlation, significant correlation was observed between HA and tumor grades: SA/A (rho -0.408, p < 0.0001), LA/S (0.567, p < 0.0001), P (0.257, p < 0.0001), C (-0.241, p < 0.0001). Acinar sizes were correlated with tumor grade (0.541, p < 0.0001), tumor size (0.435, p < 0.0001) and local stage (0.414, p < 0.0001). LA/S or P showed low microvessel density evaluated by CD31 immunostaining, which resulted in weaker attenuation in corticomedullary phase of enhancement CT. On the contrary SA had high microvessel density and high attenuation after enhancement. Conclusions: HA is well-correlated with tumor grade, tumor size and local stage, and could be predicted by dynamic CT pattern preoperatively.
The loss of BAP1 protein expression in the first recurrence site of metastasis to predict prognosis.
Authors: Miura Yuji , Inoshita Naoko , Ozaki Yukinori , Tanabe Yuko , Suyama Koichi , Ikeda Masaomi , Okaneya Toshikazu , Takano Toshimi 
Published: February 2017

599 Background: It is well known that the loss of BAP1 protein expression in primary site of clear cell type renal cell carcinoma (ccRCC) is prognostic marker. However, the existence of intratumoral heterogeneity in primary site of ccRCC makes it difficult to assess accurate prognosis. The aim of this study is to investigate the heterogeneity of BAP1 expression in metastatic sites and to evaluate the possibility as a prognostic marker. Methods: We collected samples of both primary and matched metastatic sites of the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for BAP1 and PBRM1 protein expression were performed on at least two tissue microarray (TMA) sections from primary site and at least one TMA sections from metastatic sites. We retrospectively analyzed the association of the IHC with clinical outcomes. Results: 41 primary and metastatic sites were available for this analysis. The most of metastatic sites were lung (68.3%) and lymph node (12.2%). BAP1 protein expression-positive, -negative and -heterogeneity in primary/metastatic sites were 29/29 (70.7/70.7%), 8/11 (19.5/26.8%) and 4/1 (9.8/2.4%), respectively. PBRM1 protein expression-positive, -negative and -heterogeneity in primary/metastatic site were 22/27 (53.7/65.9%), 9/11 (21.9/26.8%) and 10/3 (24.4/7.3%), respectively. The concordance between primary and metastatic site for BAP1 and PBRM1 protein expression was 82.9 and 63.4%, respectively. Median overall survival (OS) from the first recurrence of metastasis in patients with BAP1-positive and -negative in metastatic sites was 97 and 51 months, respectively (p = 0.0275). Median OS from the first recurrence of metastasis in patients with PBRM1-positive and -negative in metastatic sites was 82 and 58 months, respectively (p = 0.44). Conclusions: There is more intratumoral heterogeneity for BAP1 and PBRM1 in primary site than metastatic sites of ccRCC. The loss of BAP1 protein expression by IHC in metastatic sites predicts poor clinical outcome.
The immune landscape of renal cell carcinoma and its association with intratumoral clonality.
Authors: Winer Andrew G. , Senbabaoglu Yasin , Gejman Ron , Ostrovnaya Irina , Kaffenberger Samuel D. , Voss Martin Henner , Coleman Jonathan A. , Russo Paul , Hsieh James , Sander Chris , Hakimi A. Ari 
Published: February 2017

605 Background: Clear cell renal cell carcinoma (ccRCC) is among the most highly infiltrated tumors despite a relatively low mutation burden. Despite success in treating subsets of these patients with immunotherapy, the high immune-infiltration of ccRCC remains a conundrum that has not been sufficiently addressed. Methods: We utilized an original RNAseq-based aggregate immune score (Senbabaoglu Y, bioRxiv, 2015) to compare immune infiltration levels across 20 tumor types profiled in The Cancer Genome Atlas (TCGA) and validated our results with an independent cohort of ccRCC patients (Sato Y, Nat Genet, 2013). We also evaluated the immunogenic effect of intratumoral heterogeneity (ITH) through an analysis of clonal architecture in ccRCC tumors from both of the aforementioned data sets using the SciClone (Miller C, PLoS Comput Biol, 2014) algorithm. Results: We identified ccRCC as an immunogenic outlier that is unique from other highly infiltrated tumors in its exceptional overexpression of antigen presentation machinery compared to normal tissue. In a focused decomposition of immune cell levels within the 415 ccRCC tumors from TCGA, three unique clusters of tumors emerged primarily separated by varying degrees of T cell infiltration; termed (1) T-cell-enriched, (2) heterogeneous, and (3) non-infiltrated groups. These clusters were validated in an independent ccRCC cohort of 101 patients. A comparison of the degree of clonality with immune infiltration levels revealed that tumors with less ITH (i.e. fewer subclones) had significantly higher immune infiltration in both the TCGA and the validation cohort . Conclusions: Our findings provide novel insight into the immune landscape of ccRCC tumors and explore a potential mechanism for the immunogenicity of these tumors. Such information can potentially be used to aid in predicting therapeutic response to immunomodulatory agents.
Front-line management patterns in the prospective metastatic renal cell cancer (MaRCC) registry.
Authors: Harrison Michael Roger , Bhavsar Nrupen Anjan , Wolf Steven Paul , Costello Brian Addis , Stadler Walter Michael , Hammers Hans J. , Vaishampayan Ulka N. , Appleman Leonard Joseph , Tsao Che-Kai , Creel Patricia A. , Samsa Greg P. , Richardson Eric M. , Johnson Kathleen A. , Borham Azah , George Daniel J. 
Published: February 2017

617 Background: Over the past decade, seven agents were approved for metastatic renal cell carcinoma (mRCC) leading to a rapidly evolving clinical landscape. Clinical trials addressing treatment efficacy, sequencing, and other questions may continue to impact management decisions. Furthermore, our prior retrospective experience indicates a significant proportion of pts may not receive systemic therapy in the first year after diagnosis with metastatic disease. This analysis describes contemporary patterns of care in the first 109 real world pts enrolled in a multicenter, prospective, observational registry. Methods: MaRCC Registry will enroll 500 pts from up to 60 US academic (ACAD) and community (COMM) sites with ~2 years of recruitment and ≥ 3 years of follow-up. Key inclusion criteria are age ≥ 18 years and diagnosis of mRCC with no prior systemic therapy (STx) for mRCC at study entry. Pts currently not on STx but who are being observed are permitted. Key endpoints include descriptive characteristics of treatments (e.g. treatment agents, sequence, duration, reasons for therapy choice and discontinuation), treatment effectiveness (e.g. overall response rate, progression free survival, overall survival), quality of life (PROs), medication adherence, and health resource utilization. Results: At data cutoff, 105 pts have been accrued with known STx status; median age 64 (Q1-3 range, 56-70); 66% male; 75% ACAD; 87% clear cell histology; and 31% stage IV at diagnosis. Initial management strategies are shown in the table. The initial management decision after accrual was to defer systemic therapy (Def STx) in 40% (N=44). In ACAD and COMM sites, Def STx percentages were 38% and 48% respectively. Baseline demographics and clinical characteristics were not notably different between Def STx pts and those treated with STx. Conclusions: In our prospective registry, we have identified a large percentage of pts who initially received Def STx. In the context of contemporary pts undergoing investigational and standard of care STx, we will describe the management and outcomes of the Def STx population. [Table: see text]
Missing the mark? Prostate cancer upgrading by systematic biopsy over fusion biopsy.
Authors: Muthigi Akhil , George Arvin Koruthu , Iyer Amogh , Kongnyuy Michael , Kadakia Meet , Chelluri Raju , Mertan Francesca , Frye Thomas P , Kilchevsky Amichai , Sidana Abhinav , Krane Spencer , Su Daniel , Merino Maria J , Turkbey Ismail B. , Choyke Peter L. , Wood Bradford J. , Pinto Peter A. 
Published: February 2017

62 Background: Multiparametric MRI (mpMRI) and fusion biopsy (FBx) detect more high risk prostate cancer (CaP) and less low risk CaP than standard systematic biopsy (SBx). However, there remains a small subset of patients where SBx captures higher grade disease than FBx. We aim to identify potential reasons for failure of FBx biopsy in detection of clinically significant (CS) CaP. Methods: A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by FBx and SBx in the same session from 2007−2014. Patients upgraded to higher risk disease based on SBx results relative to FBx were identified. Independent re−review of MR imaging in this subset was conducted to identify potential proximity between MR targets and SBx region which revealed higher risk CaP. Univariate analysis was performed to determine association of patient, MRI, and pathologic characteristics with upgrading by SBx. Results: We identified 1003 total patients who underwent mpMRI and biopsy, of which 564 were found to have CaP (56.2%). Upgrading based on SBx occurred in 137/564 (24.3%) patients, of which only 55 (9.8%) were to intermediate (high volume 3+4) [N = 37, 6.5%] or high risk CaP ( ≥ 4+3) [N = 18, 3.2%]. 41 of 55 patients (75%) had a lesion identified by mpMRI with FBx in the same sextant in which SBx biopsy revealed intermediate or high risk CaP. On univariate analysis, higher prostate volume (48cc vs 42cc, p < 0.001) and lower percent core involvement (20% vs. 58%, p < 0.001) were associated with upgrading by SBx. Conclusions: MRI rarely misses CS CaP and FBx, if accurate, should reflect the true disease state. Most gleason upgrades by SBx were to low risk, low volume CaP. In patients upgraded by SBx to CS CaP, mpMRI identified a targetable lesion in proximity to the SBx sextant in a majority of patients. FBx failure may be related to suboptimal imaging or biopsy related inaccuracy including registration error, miscalculation of target location, or inadequate lesion sampling. Other possibilities include presence of tumor heterogeneity, multi−focality within the same sextant, or low volume disease. Future studies with biopsy mapping on MRI will provide insight into mechanisms of failure in patients with overlapping target and sextant sampling.
Very small nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Chen Jie-Fu , Ho Hao , Hodara Elisabeth , Go Ann , Ureno Alexander , Kaufman Elizabeth Taryn , Sievert Margarit , Chung Leland WK , Ke Zunfu , Tseng Hsian-Rong , Posadas Edwin M. 
Published: February 2017

64 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastasis (VM) have a poorer clinical outcome in comparison to those without VM. Their clinical course is aggressive and culminates in organ failure as this process is often discovered late in the disease course. There are no existing tests that identify men at risk for VM. Our team has identified an association between the presence of very small nuclear circulating tumor cells (vsnCTCs) and VM. We hypothesized that vsnCTC that can predict the development of VM and monitor the response to anticancer treatment. Methods: In our database we identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using published methods. The vsnCTC counts were related to the presence and development of VM as well as the response to anticancer treatment. Results: Blood specimens were identified from 28 patients who met the eligibility criteria; 16/28 patients presented with VM and 12/28 had bone-only disease at their first CTC enumeration. Five out of 12 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 3/12 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 21/21 VM patients compared to 3/12 non-VM patients. Reduction of vsnCTC count occurred at initiation of anticancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. Conclusions: vsnCTC is associated with the presence of VM and is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment.
Survival outcomes of dose-escalated external beam radiotherapy (DE-EBRT) versus combined brachytherapy for intermediate- and high-risk prostate cancer using the National Cancer Data Base.
Authors: Amini Arya , Jackson Matthew Wayne , Yeh Norman , Waxweiler Timothy V , Jones Bernard , Maroni Paul , Kavanagh Brian D. , Raben David 
Published: February 2017

7 Background: The purpose was to evaluate survival outcomes between dose-escalated external beam radiotherapy (DE-EBRT) versus EBRT plus brachytherapy for intermediate- and high-risk prostate cancer, using the National Cancer Data Base (NCDB). Methods: Patients with cN0M0 prostate cancer treated from 2004-2006, with available data for radiation therapy dose were included. Radiation treatment comparison groups were the following: EBRT alone (75.6-81 Gy) and EBRT (40-50.4 Gy) plus brachytherapy, with EBRT delivered in 1.8-2.0 Gy per fraction. Eligible patients had known T-stage, prostate-specific antigen, Gleason score, and receipt of androgen deprivation therapy. Results: A total of 20,279 patients with intermediate (n = 12,617) and high-risk (n = 7,662) prostate cancer were included; 71.3% (n=14,452) received EBRT alone, 28.7% (n = 5,827) received EBRT plus brachytherapy. Median follow up was 82 months (range, 3-120 months) and median age was 70 years (36-90 years). By multivariate analysis, EBRT plus brachytherapy had a significantly improved survival benefit (hazard ratio [HR], 0.75; p < 0.001) compared to EBRT alone (75.6-81 Gy); this significance remained consistent for both intermediate-risk (HR, 0.73; p < 0.001) and high-risk (HR, 0.76; p < 0.001) when analyzed separately. On subset analysis however, EBRT plus brachytherapy did not have a significant survival improvement (HR, 0.91; p = 0.083) when compared to very high dose EBRT alone (79.2-81 Gy) for all patients combined; this persisted for intermediate-risk (HR, 0.73; p = 0.062) and high-risk (HR, 0.93; p = 0.400) patients when analyzed separately. Conclusions: Patients receiving EBRT plus brachytherapy had improved survival compared to DE-EBRT alone (75.6-81 Gy) for intermediate- and high-risk prostate cancer. When comparing EBRT plus brachytherapy versus very high dose EBRT alone (79.2-81 Gy), this survival advantage disappeared. Given these findings, intermediate- and high-risk prostate cancer patients may benefit from EBRT plus brachytherapy compared with DE-EBRT alone; however, very high doses of EBRT may also be an equivalent option.