bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of systemic spread independent of local extension or nodal disease by venous tumor thrombus in renal cell carcinoma.
Authors: Aboumohamed Ahmed , Digiorgio Lorenzo , Mehedint Diana , Attwood Kristopher , Schwaab Thomas 
Published: February 2017

435 Background: Renal cell carcinoma (RCC) venous extension is a challenging condition. Its prognostic significance is not well established. We investigated possible prognostic correlations between venous extension in RCC, with its various levels, and local extension, lymphatic spread and systemic metastasis; and its impact on progression free survival (PFS) and overall survival (OS). Methods: We analyzed an IRB-approved prospectively-maintained kidney cancer database at Roswell Park Cancer Institute. Patients with venous involvement were identified, classified according to the highest cephalic venous thrombus extension into 3 groups; group 1, renal vein; group 2, infrahepatic; group 3, subdiaphragmatic. Preoperative, postoperative, and pathologic factors were recorded. Patient characteristics were compared between groups using Kruskal-Wallis and Chi-Square tests for quantitative and categorical variables respectively. Results: 711 patients underwent nephrectomy for RCC between 2004 and 2011. Out of 63 patients with RCC and venous tumor thrombus, 55 patients were analyzed in this study who underwent radical nephrectomy and venous thrombectomy. Median age was 63 years and median follow-up was 18.7 months. 37 patients were group 1, 10 were group 2, and 8 were group 3. 1 and 3 year PFS were 66% and 38.5% respectively, and 1 and 3 year OS were 74.2% and 47.4% respectively. There were no statistically significant differences in OS or PFS between different groups. Among several factors examined, venous extension was associated with increased risk of distant metastasis, and that risk did not increase with higher cephalic venous extension (p = 0.011). When patients were categorized by local extension and nodal disease spread, there was no statistically significant association with venous tumor extension (p =0.24 and 0.35 respectively), though they were independently associated with distant spread (p = 0.002 and 0.013 respectively) and OS (p =0.005 and0.03 respectively). Conclusions: Venous tumor extension alone can serve as an independent predictor of distant metastasis in patients with RCC. Our analysis suggests that cephalic venous thrombus extension does not impact patient survival.
The risk of proteinuria with the angiogenesis inhibitor axitinib in patients with cancer.
Authors: Kuei Andrew , Wu Shenhong 
Published: February 2017

439 Background: The use of axitinib, a potent inhibitor of the vascular endothelial growth factor receptor (VEGFR), is associated with proteinuria, which may cause morbidity and treatment interruptions in cancer patients. We performed a systematic review and meta-analysis of published clinical trials to assess the overall risk of severe proteinuria when treated with axitinib. Methods: Potentially relevant studies were identified by searching databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings until June 2012. Eligible studies included prospective clinical trials in cancer patients treated with axitinib containing data on all-grade and/or high-grade proteinuria. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated using the fixed- or random-effects models. Results: A total of 1,671 patients with advanced renal cell carcinoma (RCC) and other solid tumors from 9 studies were included for analysis. The overall incidence of all-grade proteinuria with axitinib was 22.7% (95% CI: 10.4-42.6%). There was no significant difference between RCC and non-RCC patients (p = 0.45), although the incidence in RCC patients was higher (30.0%, 95% CI: 8.4-66.7 vs. 17.5%, 95% CI: 7.4-36.3%). The overall incidence of high-grade (grade 3 or 4) proteinuria with axitinib was 3.8% (95% CI: 2.6-5.7%). In comparison with a control (gemcitabine), axitinib significantly increased the incidence of high-grade proteinuria (3.3%, 95% CI: 1.6-6.5% vs. 0.1%, 95% CI: 0-2.3%; p=0.031). When compared to sorafenib, another angiovsgenesis inhibitor, axitinib has elevated risk of proteinuria but without statistical significance (RR=1.48 for all-grade, 95% CI: 0.92-2.38, p = 0.10; RR=1.81 for high-grade, 95% CI: 0.68-4.85, p = 0.24). Conclusions: There was a significant risk of high-grade proteinuria associated with the use of axitinib in cancer patients. Adequate monitoring and appropriate use of axitinib is recommended to reduce renal complications.
Patient and physician perspective on published therapy management recommendations for TKI-treated patients with a focus on sunitinib: The TheMaPaC project (Therapy Management Patient Consensus).
Authors: Eberhardt-Wetherington Berit , Gall Valerie , Lang Melanie , Schmidinger Manuela , Gruenwald Viktor , Claussen Christina , Wartenberg Markus , Niedtner Rainer , Kalanovic Daniel 
Published: February 2017

445 Background: Optimizing outcomes in RCC or GIST patients (pts) receiving TKI (e.g. sunitinib ([U]) involves therapy management as a key component. Reduction/elimination of adverse events (AEs) by prevention/early intervention may improve quality of life and enable adequate duration of therapy. Published recommendations (RECs) for AE management are heterogeneous and often rely on hypothetical considerations or limited evidence. A collaborative effort of physicians, patients, and Pfizer addresses these issues. An initial analysis of a patient survey on real-life validity of RECs in 27 TKI-treated pts was shown at ASCO 2012 (abstr. 99588). We report an updated combined analysis with an expert survey in 23 physicians experienced in SU use for RCC and GIST. Methods: RECs for AE management in pts receiving SU or other VEGFR-TKIs were retrieved from the literature since 2006 and listed in a questionnaire (QU). For the patient survey, RECs were converted into patient-friendly language, RECs requiring physician intervention/decision were excluded. Pts rated RECs in 5 categories (positive/negative experience [self/others]; no information). Experts rated the RECs according to strength of their consent and own experiences. Results: 27 pts had evaluable QUs. Pts were on SU for 16 months (median). On average, 49% of RECs were rated positive; 44% based on individual experience. 20 RECs were rated positively by >80% of pts. Pts had most positive experiences with RECs concerning pt/physician communication on AEs, care/protection of feet and skin, food preference, hydration, and fatigue. Pts had a preference for RECs with low interference in daily life. RECs rated positive by >80% of pts were supported by most experts. Several RECs supported by most experts were unknown to many pts, including dermatological interventions, dietary counselling, and self-perception. Conclusions: To our knowledge, this is the first patient and expert survey on validity and practicability of published AE management RECs. The data identify useful consensual RECs from real-life perspective. TKI therapy management may be improved by enhanced pt education.
Sunitinib (SU) plus extended courses of irradiated allogeneic lymphocytes (IAL) for patients with metastatic renal cell carcinoma (RCC).
Authors: Stein Mark N. , Huzzy Lien , Anand Monica , Jeyamohan Chandrika , Mayer Tina M. , DiPaola Robert S. , Gharibo Mecide Meric , Strair Roger 
Published: February 2017

464 Background: Treatment of patients with RCC using IAL from a haploidentical donor (sibling/parent), without prior conditioning of the recipient, induced tumor regressions in 3/13 patients with minimal toxicity (Strair J Clin Onc 2003:3785). Responses were not detected until after 2-3 courses, consistent with an immunologic mechanism. We hypothesize that combining the angiogenesis inhibitor SU with IAL will improve outcomes given the potential immune stimulatory benefit of VEGF inhibition and the benefit from preventing clinical progression prior to the development of an immune response in patients with rapid disease progression. Single agent SU has a median PFS of 11mos and response rate of 31%. Methods: Eligible pts with measurable metastatic clear cell RCC, no prior systemic therapy, adequate organ function, no CNS met, and a suitable donor (≥2/6 HLA A, B, DR match, CMV-, HIV-, HepB/C-) received SU 50mg/day in a 4 wk on/2wk off schedule with IAL administration commencing at the start of cycle number 2 of SU. IAL was given once every 8-16 weeks. The primary objective of the study is to determine the PFS of the combination of SU and IAL in 35 patients for 80% power to detect an increase in median PFS from 11 to 18 months. Results: A pre-planned futility analysis was performed. To date 9 pts (7M/2F), median age 63 (range 49-74) have been treated with 29 cycles of DLI. Median number of DLI/pt 2(1-7). 5 pts discontinued DLI due to disease progression, 4 due to loss of donor availability. Median time to disease progression was 41 weeks (range 12-180 weeks), with 4 pts on study for >80 weeks. Response rate (CR+PR): 44% (1/9 CR, 3/9 PR, 2/9 SD, 3/9 PD). DLI was well tolerated with G2 fever in 1pt and G1 fever in 5 pts as the only DLI related AEs. SU related AE lead to SU dose reduction in 8/9 pts. Conclusions: Co-administration of SU and IAL is feasible and safe with no significant IAL related toxicity. Further study accrual is required to determine if SU plus IAL is superior to single agent SU. Clinical trial information: NCT00853125.
Classification of oncocytic papillary renal cell carcinoma.
Authors: Culp Stephen Hembree , Mo Yunchuan Delores , Diolombi Mairo , Cathro Helen P 
Published: February 2017

467 Background: Over the past decade, genitourinary pathologists have increasingly recognized an oncocytic variant of papillary renal cell carcinoma (PRC) that can complicate classification as Type 1 or Type 2 PRC. The International Society of Urological Pathology recently proposed reclassifying oncocytic papillary renal cell carcinoma (OPRC) as a separate subtype. We set out to test the validity of separating oncocytic tumors from other PRC. Methods: 70 consecutive cases of PRC with sufficient tissue for analysis were reviewed from patients undergoing surgery at The University of Virginia (1992 to 2007). All cases were classified by type, including those with oncocytic features. Histologic, clinical, and outcomes data were analyzed based on type and the presence of oncocytic features. Results: A total of 15 (21.4%) tumors displayed oncocytic differentiation, the majority of which were Type 2 tumors (11 or 73.3%) (p < 0.001). The male to female ratio of OPRC cases was nearly 1:1 in contrast to a significant male bias historically seen in PRC. The presence of oncocytic features was significantly associated with higher Fuhrman grade (p < 0.001) and no OPRC tumors were multifocal as opposed to 13 (23.6%) of non-OPRC tumors. At a median follow-up of 79.9 months for the entire cohort, 5-yr disease specific survival (DSS) for OPRC patients was 79.0% which was intermediate between patients with Type 1 (93.4%) and Type 2 (44.4%) tumors. By Cox proportional hazards regression analysis, DSS of OPRC patients was significantly better than Type 2 patients (HR 0.12; 95% CI 0.03, 0.52, p = 0.004), but tended to be worse than Type 1 patients (HR 2.58; 95% CI 0.78, 8.50, p = 0.12). Conclusions: We report the largest cohort of OPRC patients to date. Patients with OPRC demonstrate a survival rate intermediate between that of patients with non-oncocytic Type 1 and Type 2 PRC. Though the majority of OPRC tumors were classified as Type 2 PRC, oncocytic features complicate histomorphologic typing. Therefore, classification of OPRC separately would clarify typing of PRC and improve the validity of Fuhrman nuclear grading for PRC. Our results support separation of OPRC from Type 1 and Type 2 PRC, based on both histomorphologic typing and patient survival.
Outcomes of sunitinib therapy in patients (pts) with metastatic renal cell carcinoma (mRCC) with poor risk features.
Authors: Barroso-Sousa Romualdo , Munhoz Rodrigo Ramella , Fonseca Leonardo Gomes , Fede Angelo Bezerra de Sousa , Linck Rudinei Diogo Marques , Moniz Camila Motta Venchiarutti , Mak Milena Perez , Souza Ciro Eduardo , Hoff Paulo M. , Dzik Carlos 
Published: February 2017

476 Background: Temsirolimus is perceived as the standard of care in pts with mRCC with poor risk features. However, sunitinib (Su) is commonly used in this setting. In this study, we assessed the use of Su in an unselected mRCC population. Methods: Retrospective analysis of 51 pts with mRCC and ≥ 3 poor prognosis features, as determined in the Advanced Renal Cell Carcinoma (ARCC) trial, treated with Su between January 2006 and July 2012. Primary outcome was overall survival (OS). Clinical and laboratory parameters were evaluated, as well as Su-related adverse events (AE). Median time to treatment failure (mTTF) and OS were estimated by Kaplan–Meier methods. On exploratory grounds, univariate, and multivariate analysis using Cox regression model was performed to determine possible prognostic variables. Results: Median age was 60 years (26-89). Most had clear cell histology (98%), 19% prior systemic treatment, and 51% prior nephrectomy. 64%, 15%, and 4% had 4, 5, and 6 adverse prognosis factors respectively. 88% had diagnosis to treatment intervals < 1 year and 45% had KPS scores of < 80. A median of 2 cycles (0–12) were administered. 63% received standard regimen of Su (50 mg/d 4 wk on/2 wk off). Reasons for discontinuation were disease progression (63%) and adverse events (21%). Most grade ≥ 3 AE were fatigue (14%), neutropenia (8%), and stomatitis (8%). 17%, 25%, and 14% developed hypothyroidism, hand-foot syndrome (HFS), and hypertension, respectively. Two therapy-related deaths were observed (one febrile neutropenia and one intracranial hemorrhage). Estimated mTTF and mOS of this cohort were 2.4 and 6.6 months, respectively. Multivariate analysis revealed that in a model adjusted for type of Su regimen, KPS, presence of brain metastasis, and occurrence of HFS, only Su-associated hypothyroidism was significantly associated with survival (respectively, odds ratio [OR] = 0.23; 95% CI = 0.07-0.68). Conclusions: Pts with mRCC with poor risk features treated with Su have an OS, TTF and rates of therapy discontinuation due to AE comparable to clinical trial subsets of similar pts. Our data suggest that the development of hypothyroidism in this setting might be useful as a predictor of OS, and this finding should be further investigated.
Effect of PSA-tricom, a pox-viral vaccine in prostate cancer (PCa), on tumor growth rates within 80 days after initiation in nonmetastatic PCa.
Authors: Gulley James L. , Madan Ravi Amrit , Stein Wilfred Donald , Wilkerson Julia , Dahut William L. , Heery Christopher Ryan , Schlom Jeffrey , Wilding George , DiPaola Robert S. 
Published: February 2017

57 Background: Our understanding of immunotherapies for prostate cancer (PSA-TRICOM, sipuleucel-T, ipilimumab) is incomplete in that such therapies have improved overall survival (OS) without changes in time to progression (TTP) in randomized trials. In an effort to better understand this discrepancy, we evaluated data from studies of PSA-TRICOM. A pox viral vaccine expressing PSA and 3 T-cell co-stimulatory molecules, PSA-TRICOM has demonstrated PSA-specific immune responses and evidence of clinical activity that supported initiation of a currently accruing Phase III trial. An analysis of NCI PCa trials (including a PSA-TRICOM trial) suggests that immune therapies may eventually slow the growth rate (GR) of tumors, leading to unaltered short term TTP, yet improved OS (Stein et al. Clin Can Res. 2011). Methods: PSA-TRICOM was administered to 50 hormone-naïve patients (pts.) with non-metastatic, castration naive PCa in a multi-center trial (ECOG 9802). Pts were treated every 4 weeks for 3 months, then every 12 weeks (preliminary data previously reported, DiPaola, RS et al. ASCO GU 2009). PSA values were used to calculate tumor GR within the first 100 days of treatment. (Pts were given no additional therapies during this time.) As previously described, a two-phase mathematical equation yielded concomitant PSA GR and regression rate constants.(Stein et. al., 2011) Results: See Table. Conclusions: These data suggest that PSA-TRICOM can alter GR significantly within 3 months. If confirmed in future trials, it could explain why vaccines have demonstrated improved OS without improved TTP. A slowing of the GR may not lead to substantial differences in short term TTP, but may enhance OS in the long term. This concept will be evaluated in an international Phase III trial of PSA-TRICOM in minimally symptomatic, metastatic castration-resistant PCa that is currently recruiting pts. Clinical trial information: NCT00108732. [Table: see text]
Modulation of soluble c-Met, bone turnover markers, angiogenic factors, and c-Met in men with mCRPC treated with cabozantinib.
Authors: Corn Paul G. , Varkaris Andreas , Li Ning Tapia Elsa M. , Araujo John C. , Aparicio Ana , Tu Shi-Ming , Zurita Amado J. , Efstathiou Eleni , Qiao Wei , Wen Sijin , Gallick Gary E. , Logothetis Christopher 
Published: February 2017

58 Background: Cabozantinib (cabo) is a multi-TKI against c-Met and VEGFR2. Cabo elicits striking changes in bone scans (BS), reductions in soft-tissue mets, and improves bone pain in mCRPC. This unique response is unlinked from PSA and suggests that targets of Cabo reside in the bone microenvironment. To explore the underlying mechanisms of Cabo activity, we examined changes in soluble c-Met, angiogenic factors, bone specific alkaline phosphatase (BAP), and tumor specific c-Met signaling in men on Cabo. Methods: A phase II cohort of docetaxel pretreated men with mCRPC received Cabo. Response was assessed q6 wks by BS and CT scan. Blood and trans-iliac bone marrow biopsies (BMs) were collected pretreatment and at wk 6. Soluble c-Met was measured by ELISA, angiogenic factors by multiplex immunoassay, and tumor c-Met/phospho c-Met expression by IHC. Results: 21 patients with bony mets were evaluated; 38% also had soft tissue mets. 13/21 (62%) pts experienced an improvement (PRs + CRs) in BS and 2/8 (25%) achieved a PR in soft tissue mets. 12/20 (60%) pts had reductions in BAP on therapy (median reduction 48.5%). VEGFR2 levels decreased in response to therapy (p<0.0001) and VEGF levels increased (p<0.085). Soluble c-Met levels increased on therapy (p<0.009). Pretreatment BMs containing >5% tumor involvement (median 80%) were evaluable for 10 patients, 9 of whom also had a 6 wk BM. High intensity, tumor-specific expression of c-Met was detectable in 8/10 (80%) of pretreatment tumors (median involvement 60%) and increased in 4/9 (45%) pts at 6 wks (median increase 30%). Activated phospho c-Met was detectable in 9/10 (90%) of pretreatment tumors (median involvement 80%) and decreased in 5/9 (56%) pts (median reduction 30%) at 6 wks. Conclusions: The results of our study suggest that changes in soluble markers of c-Met, bone turnover, and angiogenesis are linked to Cabo activity. Analyses of BMs demonstrate high c-Met activation in pretreatment mets and suggest Cabo-mediated inhibition at 6 wks. These data support the hypothesis that c-Met contributes to “driver” signaling networks in mCRPC and suggest that biomarkers of stromal cell function should be prioritized for further study.
Impact of on-study corticosteroid use on efficacy and safety in the phase III AFFIRM study of enzalutamide (ENZA), an androgen receptor inhibitor.
Authors: Scher Howard I. , Fizazi Karim , Saad Fred , Chi Kim N. , Taplin Mary-Ellen , Sternberg Cora N. , Armstrong Andrew J. , Hirmand Mohammad , Forer David , De Bono Johann Sebastian 
Published: February 2017

6 Background: ENZA increased median overall survival (OS) by 4.8 mo (P <0.001, HR 0.63) vs placebo (PBO) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) post-docetaxel in AFFIRM (HI Scher et al, NEJM 2012). Corticosteroids (CS) can activate AR signaling in nonclinical models (J Richards, Can Res 2012). In a multivariate model of AFFIRM data baseline CS use was associated with reduced OS (HI Scher et al. ESMO 2012 abstract 899PD). The impact of CS use during study treatment in AFFIRM was evaluated to test if concomitant CS use is also associated with inferior outcomes. Methods: Pts were randomized 2:1 to ENZA 160 mg/d or PBO. Pts were allowed but not required to take CS. OS was the primary endpoint. In a post-hoc analysis On-study CS use was defined as oral CS user for ≥ 1 day on study. Results: On study CS use was 48% in ENZA and 45% in PBO pts. Prognostic factors were slightly better in the no CS group compared to the CS group. Use of CS regardless of treatment was associated median OS of 11.5 mo (95% CI: 10.5, 13.0) for CS pts vs median OS NM (NM, NM) for no CS pts (HR=0.40; 95% CI: 0.33, 0.48). ENZA was consistently superior to PBO for OS, radiographic progression free survival (rPFS) and time to PSA progression (TTPP), regardless of CS use (Table). Pts on CS had higher rates of grade 3 - 4 adverse events (AE) compared to no CS pts: 63.3% vs 34.4% respectively. Conclusions: In this post-hoc analysis, on study CS use was associated with reduced OS and higher rates of grade 3 -4 AEs in mCRPC pts post-docetaxel. While CS pts had worse outcomes, ENZA was consistently superior to PBO regardless of on study CS use. The inferior outcomes in CS pts may be due to unmeasured confounders or the biologic properties of CS use itself. Clinical trial information: NCT00974311. [Table: see text]
Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.
Authors: Fleming Mark T. , Rathkopf Dana E. , Gibbons Jackie , Peterson Amy C. , Hannah Alison , Forer David , Scher Howard I. , Morris Michael J. 
Published: February 2017

63 Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.