bluuebunny/crossref_metadata_2025 huggingface dataset:
A prospective trial assessing the effects of clamp ischemia during partial nephrectomy on renal function, biomarkers, and structure.
Authors: Ercole Barbara , Torkko Kathleen , Hilton William , Devarajan Prasad , Venkatachalam Manjery A. , Weinberg Joel M. , Parekh Dipen J.
Published: February 2017

367

Background: Tolerance of the human kidney to clamp ischemia (CI) during partial nephrectomy (PN) has been considered to be limited to 20–30 min. We determined the utility of new biomarkers for following renal injury in this setting.

Methods: 40 patients undergoing open PN without ( N=27, avg clamp time 32.3 min, range 15–53 min., 74% > 30 min.) or with cooling ( N=13 avg clamp 48 min. range 30–61 min.) had biopsies of uninvolved areas of the kidney preclamp, during clamping and 5 min. after clamp release, along with serial measurements of standard renal functional parameters plus measurement of serum cystatin C and NGAL, and of urine NGAL, cystatin C, NAG, LFABP, NGAL, KIM-1 and IL-18.

Results: Serum creatinine transiently increased at 24 hours by 21.9±6.4% after warm CI and 27.2±7.9% after cold CI (Ps < .001), but serum cystatin C did not change and plasma NGAL was minimally affected. Urine biomarkers increased irrespective of whether they were factored for creatinine, with particularly large changes in KIM-1 and LFABP, but did not correlate with duration of CI, the change in creatinine at 24 hours, or the use of cold or warm CI. Ultrastructure and staining for actin, phosphotyrosine, B1 integrin, and ICAM-1 showed changes consistent with CI, but much milder than predicted from animal models. Creatinine has remained stable in the patient cohort at up to 18 months of follow-up.

Conclusions: The data indicate that the insult to the clamped kidney from 30–60 minutes of CI under conditions of open partial nephrectomy is well tolerated despite increases of urinary biomarkers, which may in part reflect local effects of the surgery itself, expand indications for PN in the management of renal cancers, and support the use of CI as opposed to more complex procedures for PN.
What is the best treatment option for second line in long responders to the first-line TKI in metastatic renal cell carcinoma (mRCC) patients (pts): TKI-TKI or TKI-mTORi? A European retrospective study.
Authors: Elaidi Reza-Thierry , Beuselinck Benoit , Maj-HES Agnes , Carmier Delphine , Bamias Aristotelis , Debruyne Philip R. , Porta Camillo , Roca Sophie , Oudard Stephane
Published: February 2017

375

Background: The question regarding the benefit of a TKI rechallenge versus switch to an mTOR inhibitor (mTORi) in mRCC pts who responded to a previous line of TKI remains unanswered and is a common dilemma in clinical practice. We report results of a retrospective study to address this question.

Methods: This study retrospectively investigated Duration of Treatment (DT), best radiological response (OR) and predictive factors in pts treated with either TKI-TKI or TKI-mTORi sequences for clear-cell mRCC. Eligibility criteria: 1 TKI in 1st line (L1) followed by another TKI or mTORi as 2nd line (L2). Prior immunotherapy was allowed but not intermediate lines with other drugs. Pts characteristics and Heng’s prognostic factors were collected at each line initiation. Response (resp) was classified with regard to DT and OR using 2 different definitions: def1 = Non Responders (NR): < 4months (m) + PD; Short-Term responders (STR): [4–6]m + SD/PR, Long-term Responders (LTR): >6m + SD/PR, and def2 = NR: < 4m + PD, STR: [4–12]m + SD/PR, LTR: >12m + SD/PR.

Results: 127 pts from 7 European centers were retrospectively analyzed. Based on def1, resp to L1 was: LTR=93, STR=20, NR=14; among LTR pts, 54 received a L2=TKI and 39 a L2=mTORi. Based on def2, resp to L1 was: LTR=59, STR=53, NR=15; among LTR pts, 35 received a L2=TKI and 24 a L2=mTORi. Whether def1 or def2, resp (L1 and L2) was never related to Heng’s score. Among LTR pts at L1, 26 out of 54 were LTR after L2=TKI vs 18 out of 39 after L2=mTORi (p=0.85, Z-test) for def1 and 9 out of 35 were LTR after L2=TKI vs 6 out of 24 after L2=mTORi (p=0.95) for def2 (see table). For both def1 and def2, median DT was 7.2m and 6.9m for L2=TKI and L2=mTORi, respectively (p=0.86 and p=0.95, Log-Rank).

Conclusions: Results suggest that long-term responders on 1st line TKI could benefit both from TKI and mTORi as 2nd line and there is no evidence to favor one sequence over the other.

[Table: see text]
Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy.
Authors: Larkin James M. G. , Blank Christian U. , Bono Petri , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

391

Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval.

Methods: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE.

Results: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.)

Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population.

[Table: see text]
A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.
Authors: Tomita Yoshihiko , Shinohara Nobuo , Mizokami Atsushi , Fujisawa Masato , Hashine Katsuyoshi , Nishikido Masaharu , Nakagawa Masayuki , Akaza Hideyuki , Tsukamoto Taiji , Naito Seiji
Published: February 2017

393

Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1.

Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction.

Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes.

Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.
The usefulness of serum X-linked inhibitor of apoptosis protein (XIAP) for predicting recurrence of renal cell carcinoma.
Authors: Hongo Fumiya , Toiyama Daisuke , Ueda Takashi , Kimura Yasunori , Nakamura Terukazu , Mikami Kazuya , Takaha Natsuki , Miki Tsuneharu
Published: February 2017

396

Background: The X-linked Inhibitor of Apoptosis protein (XIAP) is associated with cell survival by blocking caspase-mediated apoptosis. We have reported the expression and prognostic value of XIAP in human prostate cancer using prostate tissue microarrays (Clin Cancer Res 2007). The expression and prognostic significance of XIAP in renal cell cancer (RCC) has been rarely studied. To our knowledge, no report on the serum XIAP levels from RCC patients has been published. In this study, we examined serum XIAP levels of RCC patients and normal individuals and evaluated its utility as biomarker.

Methods: Peripheral blood samples were obtained from 99 patients (68 men and 31 women, median age; 60.7 years [36–85]) with RCC before surgery. All the patients underwent radical or partial nephrectomy. Blood samples were also collected from 52 healthy controls. The histological grade was as follows: Grade1; n= 5, Grade2; n=72, Grade3; n= 22. The serum XIAP levels were measured by a sandwich enzyme-linked immunosorbent assay. Cut off value was calculated by ROC analysis.

Results: The serum XIAP levels in patients with RCC were higher than those of normal control individuals (328.3 pg/ml vs 156.2 pg/ml, P<0.001). At a median follow up of 33 months (1-105M), tumor with low serum XIAP showed significantly longer progression free survival (PFS) than those with high serum XIAP in Grade 1-2 group (P<0.001).

Conclusions: Serum XIAP level is associated with recurrence and prognosis. These results suggest that it may be used as a novel prognosticator and a potential target for renal cell cancer diagnosis and therapy.
Patients with metastatic renal cell carcinoma treated with everolimus in REACT: Hyperglycemia and hypercholesterolemia and associated outcomes.
Authors: Bono Petri , Gogov Svetozar , Panneerselvam Ashok , Garay Carlos A. , Grünwald Viktor ,   on behalf of the REACT Study Group
Published: February 2017

407

Background: Correlation between specific adverse events (AEs) and clinical efficacy of targeted therapies in the treatment of patients with metastatic renal cell carcinoma (mRCC) has been noted. Subanalyses of REACT (RAD001 Expanded Access Clinical Trial in RCC) evaluated potential association of hyperglycemia and hypercholesterolemia with outcomes in patients with mRCC treated with everolimus (EVE).

Methods: The open-label, international, expanded-access clinical trial REACT (Clinicaltrials.gov: NCT00655252 ) evaluated long-term safety and efficacy of EVE 10 mg/day in patients with mRCC who were intolerant of, or progressed while on, VEGFR-TKI therapy. Based on Common Toxicity Criteria AE v3.0 criteria, all grade 3/4 AEs and any grade 1/2 AEs resulting in study drug modification, temporary interruption, or treatment discontinuation were collected. Subgroup analyses of patients who developed hyperglycemia or hypercholesterolemia of any grade were performed.

Results: There were 1364 patients enrolled in REACT, of whom 78 developed hyperglycemia and 14 developed hypercholesterolemia. Median EVE treatment duration was longer for patients who developed hyperglycemia or hypercholesterolemia than for the overall population (19.14, 19.71, and 14.0 weeks, respectively). Overall, 30.3% of REACT patients remained on EVE for ≥6 months compared with 42.3% and 35.7% of patients with hyperglycemia and hypercholesterolemia, respectively. Best overall response was stable disease in 51.6% (overall) compared with 65.4% of patients with hyperglycemia and 71.4% of patients with hypercholesterolemia.

Conclusions: Most patients with hyperglycemia and hypercholesterolemia remained on EVE longer than the overall REACT population, suggesting these AEs do not lead to permanent EVE treatment discontinuations. Hyperglycemia and especially hypercholesterolemia were observed in low numbers of patients, but may be associated with improved response to EVE treatment and should be further explored as putative biomarkers for mTOR inhibition.
Assessment of a cell-line-derived HIF1α gene signature in tumor tissue from a metastatic renal cell carcinoma (RCC) trial of pazopanib.
Authors: Gagnon Robert C. , Liu Yuan , Choueiri Toni K. , Martin Anne-Marie , Rosenberg Jonathan E. , Signoretti Sabina , Pandite Lini N.
Published: February 2017

408

Background: Microarray and clinical data from a randomized phase II RCC clinical trial were evaluated to examine the HIF1α kidney cancer gene signature developed from cell lines by Shen et al (Cancer Discovery 2011).

Methods: Archival FFPE tumor samples were collected from patients (pts) enrolled in a Phase II RCC study of pazopanib (Hutson, JCO 2009). RNA was isolated and microarray analysis was performed at Response Genetics, Inc. (Los Angeles, CA) using the Affymetrix (Affy) U133 plus Array. Affy data were normalized using the MAS5 algorithm. Genes (n=69) identified from experiments in 10 cancer cell lines were mapped to genes on the U133 array. Patterns of expression (exp) among the mapped genes were assessed using multivariate analyses. Putative patterns were assessed for association with HIF1α gene exp levels, and both patterns and HIF1α levels were assessed for association with response rate (RR) (RECIST), and PFS, using nonparametric and Kaplan-Meier analyses. Gene set enrichment analysis (GSEA) was applied to determine if mapped genes were enriched for HIF1α gene exp.

Results: RNA was available for 46 of 225 patients; baseline characteristics were similar to the overall study. 41/46 patients had VHL heterozygous mutations; 5/46 patients were VHL wild type. HIF1a gene expression was detected in all 46 patients. 64/69 genes were mapped to the Affy platform. For genes which mapped to multiple probes, the probe closest to the 3` end was used. A potential 4 cluster pattern was identified. These clusters were associated with HIF1α gene exp, but neither clusters nor HIF1α gene exp were associated with clinical response to pazopanib.

Conclusions: The observed pattern of gene exp among 46 pts with available data from a Phase II RCC study of pazopanib is consistent with the cell line derived gene set proposed by Shen et al. Patterns are associated with HIF1α exp; neither patterns nor HIF1α exp are associated with clinical response in this small subset of pts. These data support the on-going efforts in bench-to-bedside research.
Time to ADT and chemotherapy initiation for treatment of metastatic prostate cancer (mPC).
Authors: Perlroth Daniella J. , Thompson Stephen F. , Luna Yesenia , Goldman Dana P. , Mozaffari Essy , Lakdawalla Darius N.
Published: February 2017

41

Background: ADT and chemotherapy use in men with mPC may differ across regions in community practice. The extent of variation could indicate whether men with mPC have appropriate access to effective treatments.

Methods: We identified 16,024 men diagnosed with mPC in the Surveillance, Epidemiology, and End Results (SEER) database from 2000-2005 linked to their Medicare claims. Patients were excluded if they had a second cancer or disenrolled from Medicare Parts A or B (n=6,155), or failed to initiate therapy with ADT (n=3,400). We identified demographic and clinical information from SEER and treatments and comorbidities from J-codes and ICD-9 codes in the Medicare claims. We used regression models to estimate the probability of advancement to chemotherapy, the time from diagnosis to first ADT use, and time from first ADT to chemotherapy. Then the patient-level predicted results from these models were used to generate summary statistics by hospital service area (HSA).

Results: There were 6,469 patients remaining after exclusion who were treated with ADT, and 1,198 of those received chemotherapy (19%). The median age was 76 years old, most were white (77%), married (62%), and 50% had 1 other major comorbidity (most frequent was diabetes, 21%). Men who were younger, married, with fewer comorbidities, and higher Gleason scores were statistically more likely to both receive chemotherapy and use it earlier. After adjusting for clinical and sociodemographic factors, the average time to ADT by referral region was 2.7 months but varied from 1.3 to 5.6; probability of progression to chemotherapy averaged 19% but varied from 6% to 30%, and the time from first ADT to chemotherapy averaged 19.7 months but varied from 12.9 to 25.7 months. The difference in time to ADT between regions in the 10th and 90th percentiles of use was 2.6 months, whereas for chemotherapy initiation, it was 12.4 months.

Conclusions: Our results suggest that living in different parts of the country has a substantial impact on how clinically similar patients are treated. There was substantial variation across regions in use of and time to initiation of chemotherapy for men with mPC, but not in ADT use.
The effect of cytoreductive radiofrequency ablation (cRFA) on results of therapy with sunitinib or interferon-alpha (IFN) in metastatic renal cell carcinoma (RCC) patients with a small primary tumor.
Authors: Tsimafeyeu Ilya , Chung Bin , Zart Janie S. ,   KCRB Group
Published: February 2017

414

Background: At least 5% of the patients (pts) with small primary RCC initially present with metastasis. The main objective of this trial was to evaluate the role of cRFA in metastatic RCC pts with small primary tumor treated with immuno- or targeted therapy.

Methods: Three parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials, and included histopathologically confirmed RCC; metastatic measurable disease; size of primary tumor ≤5 cm; good prognosis by MSKCC model; no previous therapy. Study 1: Pts were treated with percutaneous cRFA under CT guide and following IFN, 9 MIU, s.c, 3 tiw. Study 2: Pts received cRFA and following sunitinib in repeated 6-week cycles of 50 mg/day for 4 weeks, followed by 2 weeks off. Study 3: Pts with unresected primary RCC received sunitinib alone. The primary endpoint was a 33% increase in progression-free survival (PFS) over expected 5 months in study 1 and over expected 11 months in studies 2-3 (power 80%; significance .05). Sample size was 38 pts for each study.

Results: Studies were comparable by baseline patient characteristics (age, gender, histology, ECOG PS, number of metastatic sites, primary tumor size). Efficacy data for 114 evaluable pts showed an objective response rate (ORR) of 8% (95% CI 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3; median PFS of 9.1 (95% CI 6.9, 10.2), 13.4 (95% CI 9.8, 14), and 12.7 (95% CI 11.3, 13.5) months for studies 1-3, respectively. ORR and PFS were significantly higher in sunitinib trials comparing with study 1 (P<.01 all differences); no differences were found between studies 2 and 3 (ORR, P=.1; PFS, P=.6). The study 1 met its primary end point, showing that PFS was significantly increased. There were no unexpected toxicities of medical treatment and complications of cRFA.

Conclusions: cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. Cytoreductive ablative technique did not improve PFS in pts treated with sunitinib. Sunitinib was effective in metastatic RCC pts with unresected small primary tumor.
Effect of sunitinib pretreatment on yield from tumor-infiltrating lymphocyte (TIL) cultures in patients with renal cell carcinoma.
Authors: Bex Axel , Guislain Aurelie , van Boven Hester , Blank Christian U.
Published: February 2017

419

Background: Targeted therapies achieve response rates up to 50% in metastatic RCC, but durable complete remissions are very rare. Therefore additional therapeutic options are warranted. Adoptive transfer (ACT) of tumor infiltrating lymphocytes (TIL) has revealed response rates of up to 72% in melanoma patients and may lead to consolidation of responses upon sunitinib in RCC. Recent data suggest that sunitinib influences lymphocyte infiltration and regulatory T cells (Treg) into tumor, dendritic cells (DC), and myeloid derived suppressor cells (MDSC) in animal models, but impaired proliferation and function of human T cells and was unable to improve human DC activity in vitro.

Methods: We compared TIL grown from primary tumors pretreated with 2 courses sunitinib prior to cytoreductive nephrectomy to TIL generated from treatment-naïve RCC. Patients took part in a phase II trial of presurgical sunitinib registered under EudraCT 2006-006491-38 and gave written informed consent. From 6 pretreated primary tumors and 6 untreated controls sterile tumor material was obtained and digested with collagenase, hyaluronidase and DNase to obtain tumor single cell suspension. This TIL/tumor suspension was cultured for up to 25 days in 6000IU/ml interleukin 2 (IL-2) and rapidly expanded by anti-CD3+IL-2 stimulation.

Results: TIL harvested after coculture with tumor cells yielded 36+/−SD fold expansion from non-pretreated tumors versus a 128+/−SD fold expansion from tumors from patients that had been pretreated with sunitinib (p=0.015). Phenotypic analysis of culture product indicated a higher content of natural killer (NK) cells from treatment naïve TIL cultures, while sunitinib pretreatment skewed towards NK T cells. Interferon-gamma-production was not different on a per cell level.Rapid expansion after culture using anti-CD3/IL-2 induced 100-200 fold expansion towards a content of more than 75% T cells with no significant differences between both groups.

Conclusions: Sunitinib in vivo pretreatment improves TIL grow during initial culture and does not impair function or rapid expansion, allowing higher final yield of TIL for ACT studies in RCC.
Sipuleucel-T product characterization across different disease states of prostate cancer.
Authors: Sheikh Nadeem A. , Small Eric Jay , Quinn David I. , Higano Celestia S. , Lin Daniel W. , Wesley Johnna D. , Haynes Heather , Stewart Frances P. , Poehlein Christian Heinrich , Trager James B.
Published: February 2017

42

Background: Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). In the Phase 3 mCRPC trials, antigen presenting cell (APC) activation in sipuleucel-T correlated with overall survival. Here product characteristics of sipuleucel-T were compared in patients (pts) from trials in the neoadjuvant (n=42), asymptomatic or minimally symptomatic mCRPC (n=341), and mCRPC (n=104) disease states.

Methods: Sipuleucel-T comprises 3 treatments approximately 2 wks apart. Cellular composition and APC activation (CD54 upregulation) were evaluated in all courses of sipuleucel-T, and cumulative CD54 upregulation was calculated for each patient. In some studies, cytokines were assayed from culture supernatants and T cell and B cell activation markers were assessed by flow cytometry during manufacture.

Results: Baseline demographics were generally representative of each disease state; neoadjuvant pts were younger with less disease burden; mCRPC pts had the highest disease burden and more frequent prior chemotherapy. While neoadjuvant pts had greater levels of T cells, the patterns of APC activation were similar among all trials, with increased CD54 upregulation at the second and third treatment. The trend for cumulative fold increase in CD54 upregulation was significantly greater in earlier disease pts (neoadjuvant: 35.5, asymptomatic or minimally symptomatic mCRPC: 28.7, mCRPC: 21.8; p<0.0001 (Joncheere-Terpstra test)). During manufacture of the product, lymphocyte activation markers and cytokines consistently showed enhanced expression during the second and third treatments in all disease states. The lymphocyte activation and cytokine profiles were similar between early and later disease state pts.

Conclusions: While cellular composition varied with disease state, manufacture of sipuleucel-T activated APCs in both early and late disease states of prostate cancer, and generated similar T and B cell activation and cytokine production profiles consistent with immunological prime-boost. APC activation tended to be more robust in earlier disease states.
Biomolecular characterization of formalin-fixed paraffin-embedded primary renal tumor specimens.
Authors: Medina Vanessa , Aparicio Gallego Guadalupe , Santamarina Isabel , Valladares Ayerbes Manuel , Antón Aparicio Luis M.
Published: February 2017

421

Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer. It is required a better understanding of signalling pathways involved in renal cells.

Methods: We assessed using immunohistochemistry (IHC) and quantitative real-time PCR (qPCR) with SYBR Green the profile of predictive markers involved in the cascade of events leading to the formation and progression: invasiveness, angiogenesis and antiapoptotic mechanisms. 80 RCC tissues were detected by IHC. RNA of quality only was obtained in 72 (80% clear RCC, 10% papillary RCC and 10% chromophobe RCC) to carry out the study of gene expression through qPCR. A pool of normal kidney-derived RNA samples (N=5) was used as healthy control. GAPDH and YWHAZ were used as reference genes. GenEx software was used for qPCR data processing and analysis. Nonparametric tests (Pearson’s correlation coefficient test and Spearman’s rho test, Kruskal — Wallis and Mann — Whitney) were applied for statistical data analysis (SPSS 19).

Results: p53 showed higher expression in those cases with Furhman grade I (p=0.036). Moreover p53 showed a positive association with VEGF, GLUT1, GLUT4, VEGFR-2 and VHL (r=0.241, sig. level 0.05; r=0.291, sig. level 0.01; r=0.456, sig. level 0.01; r=0.187, sig. level 0.097 and Spearman’s rho=0.269, sig. level 0.05 respectively). Hif1- α, Hif1- β, Notch1 and Notch3 were upregulated in chromophobe RCC (p=0.045, p=0.03, p=0.03 and p=0.02 respectively). Hif1- α and Notch3 were upregulated in clear RCC (p=0.034 and p=0.041 respectively). Spearman’s correlation coefficient showed a strong positive correlation between Nocth1-4 members and their receptors and Hif1-α and β genes. Highlight the correlation found between: Notch1 and Hif1-α (Spearman’s rho = 0.740, significance level 0.01) and Hif1-β and Jagged1 (Spearman’s rho = 0.752, significance level 0.01).

Conclusions: The pathway involving the tumor suppressor gene p53 could regulate tumor angiogenesis. Co-expression of Notch receptors, their ligands and Hif-1 α and Hif1- β subunits may play a role in human RCC. Notch cascade may represent a novel and therapeutically accessible pathway in chromophobe and clear RCC. More detailed studies of these crossing pathways are in progress.
Interleukin-2 (IL-2) chrono-infusion (CHI) in metastatic renal cell carcinoma (mRCC): A phase I/II study.
Authors: Lo Re Giovanni , Santeufemia Davide ADRIANO , Lenardon Oliviero , Talamini Renato , Del Conte Alessandro , Marus Wally , Nicolosi Gianluigi , Mancinelli Paolo , Tumolo Salvatore , Garbeglio Antonio
Published: February 2017

423

Background: The soprachiasmatic nucleus represents the pacemaker coordinating circadian rhythm. Its dysregulation in neoplastic patients (pts) can be an important inducer/promoter of cancer progression. It is a potential mediator of cancer immunosuppressive effect and quality of life (QoL) impairment. CHI allows concentration of time active treatment with possible impact on QoL and immune and hormone set-up. Aim of this study was to evaluate feasibility, dose limiting toxicity and activity of CHI IL-2 in mRCC.

Methods: 22 pts were enrolled, 14 were naive and 8 pretreated (chemo/immunotherapy in 6 and targeted in 6). M/F ratio was 16/6, median age 68 y. IL-2 CHI was administered iv in 8 h (peak 1 am, 9 am, 5 pm) from 2 MUI/m2 with escalated dose ( Fibonacci scale) x 3 days/q 2 wks for 4 cycles. Four maintenance cycles were performed in responsive/stable pts.

Results: from January 2005 to July 2009, out of 22 pts, 3 were treated onto each Le (I-V ) and 7 in the VI. G3-4 toxicity was reported in four pts (hypotension in 2, renal in 2 and diarrhoea in 1) on the VI Le ( DLT 18,6 MUI/m2). Response: 1 CR, 2 PR, 9 SD, 10 PD. ORR was 25%%. DCR on overall/ good-intermediate group (MSKCC) was 54%/69%. Median PFS and OS were 4,5 and 14,5 mos respectively. In a univariate analysis dose Le (4-6 vs. 1-3), PS (0 vs 1-2), gender (M vs F) and cD3, cD4, cD8 count (gain vs drop) were statistically significant for OS. In a univariate analysis age (< 65 y vs. >65y), Motzer score (0-1-2 vs 3) increase/reduction of cD19, cD16, HLA-DR, cD4/cD8, increase/reduction of prolactine, reduction/increase of ACTH-Cortisol showed a trend of survival improvement.

Conclusions: IL-2 CHI aappeared safe in a standard care unit, moderately toxic and active in mRCC. Phase 2 study with dose Le V is now ongoing.
The safety and efficacy of pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer.
Authors: Boleti Ekaterini , Sarwar Naveed , Jones Robert R , Chowdhury Simon , Crabb Simon J. , Shamash Jonathan , Peters John , Oades Grenville , O'Brien Tim S. , Berney Dan , Rockall Andrea , Powles Thomas
Published: February 2017

427

Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting.

Methods: A single arm phase II study (PANTHER 2009-016675-29) evaluated 12–14 weeks of pazopanib prior to planned nephrectomy in untreated patients with metastatic clear cell renal cancer. Patients had MSKCC intermediate and poor risk disease. Pazopanibwas stopped for a minimum of 16 days during nephrectomy. FDG-PET and DCEMRI were performed on a subgroup of patients. The study follows a Simon 2 stage design and we present the results of the initial stage(n=34).

Results: Overall 30 (88%) of patients obtained clinical benefit (by RECIST) prior to surgery. The partial response rate of the primary tumor was 21% by RECIST. No patients became inoperable due to local progression of disease. A nephrectomy was performed in 25 (74%) of patients. The reasons for not having surgery were patient choice (n=5) and progression of disease (n=4). Delayed wound healing, a post operative bleed and a post operative death occurred in 1patient each (4%). The median blood loss, hospital stay and surgical time were 350mls, 7 days and 180mins respectively. FDG-PET and DCE MRI responses were reported.

Conclusions: This interim analysis suggest nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients.
Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Interim safety and quality-of-life (QOL) data from the U.K. early access program (NCT01254279).
Authors: Bahl Amit , Masson Susan , Malik Zafar , Birtle Alison J , Sundar Santhanam , Jones Robert J , James Nicholas David , Mason Malcolm David , Kumar Satish , Bottomley David , Lydon Anna , Chowdhury Simon , Wylie James , De Bono Johann Sebastian
Published: February 2017

44

Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK.

Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included.

Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabazitaxel were completed with 99% relative dose intensity. 83% continued cabazitaxel at the time of safety analysis. 7 patients stopped before completing the full course, 5 of these were due to disease progression. One treatment related death occurred within 30 days of the last cabazitaxel infusion (2.4%). 85% of patients received granulocyte-colony stimulating factor prophylaxis from cycle 1. The proportion of patients reporting no pain or discomfort increased between baseline, cycle 2 and cycle 4 (22.6% to 38% to 50%). Anxiety and depression, mobility and self-care scores from EQ-5D were stable. Median VAS health state increased from baseline (75%) to cycle 4 (79%).

Conclusions: Improvements in pain control and health states were reported during early stages of cabazitaxel treatment. Other EQ-5D QOL measures were stable. Severe toxicity was rare. Results will be updated from final analysis in late 2011.

[Table: see text]
A phase I QTc study of tivozanib in patients with advanced solid tumors.
Authors: Chadha Manpreet Kaur , Infante Jeffrey R. , Cotreau Monette M. , Jacobson Lindsey , Strahs Andrew Louis , Slichenmyer William , Vargo Dennis , Moore Kathleen N.
Published: February 2017

445

Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Preclinical and retrospective electrocardiogram (ECG) analyses suggest no effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the effect of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors.

Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20-30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessing clinical laboratory tests, physical examinations, vital signs, and recording of adverse events.

Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received ≥ 1 dose of tivozanib were evaluable. Preliminary data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented.

Conclusions: Preliminary data suggest that tivozanib 1.5 mg/d over a 21-day period does not cause clinically significant QT/QTc prolongation over baseline, suggesting that its safety and PK profile is similar to that observed in previous studies, including ECG evaluation in a monkey telemetry study.
Efficacy and safety of sequential usage of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC): Cooperative results from Osaka Urologic Oncology Group (OUOG).
Authors: Inamoto Teruo , Uemura Hirotsugu , Nonomura Norio , Nakatani Tatsuya , Matsuda Tadashi , Azuma Haruhito
Published: February 2017

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Background: Data on the efficacy and safety of everolimus (EVE) in Japanese patients (pts) are lacking because only 15 Japanese pts enrolled in the EVE group from the RECORD-1 global study. Efficacy and safety of sequential usage of EVE after other targeted therapies or immunotherapy in Japanese pts were examined.

Methods: We retrospectively reviewed the records of consecutive pts with mRCC (median age 65, M:F 78/22, 78% clear cell) who received salvage EVE at 39 tertiary institutions in Osaka Urologic Oncology Group (OUOG) between 10/09-8/11. Data on safety (NCI-CTC) and efficacy (response assessment, progression-free survival [PFS]) were analyzed. 31% of pts had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential (sunitinib:sorafenib), and 5% no prior therapy. 50% received previous cytokines in addition to targeted therapies.

Results: 172 pts with mRCC were enrolled. Median PFS was 2.8 months. Median time to last follow-up was 3.5 months (range 0.4-15.2 months). 44% continued EVE at last follow-up. 4.7% had partial response (PR) and 51.7% had stable disease (SD) by treating physician assessment. Of 112 pts who discontinued EVE, 46% discontinued EVE due to progressive disease (PD) (median time to PD 3.0 months, range 0.1-15.8 months), 43% discontinued due to adverse events (AEs) (median time to PD 1.5 months, range 0.1-12.6 months), and 0.6% died of PD on treatment. There were no treatment related deaths. The incidence of AEs of all grades was 88.4%. Major AEs were stomatitis (44.2%), thrombocytopenia (30.8%), and interstitial lung diseases (ILD) (22.1%). The incidence of AEs (Grades 3-4) was 52.9%. Serious AEs were anemia (7.6%), ILD (5.8%), and hyperglycemia (4.7%). Time to onset for these AEs was less than one month, showing marked contrast to that of ILD which ranged over several months.

Conclusions: EVE demonstrated clinically relevant activity in Japanese patients with mRCC following PD with other targeted therapies or immunotherapy. Patients prone to serious AEs should be carefully observed for the occurrence of ILD throughout the treatment period.
Translocation renal cell carcinomas: An evolving entity.
Authors: Bambury Richard Martin , Brady Claire , McCarthy Aoife , Fleming Stewart , Mayer Nicholas J. , Power Derek Gerard
Published: February 2017

472

Background: Translocation renal cell carcinomas (RCCs) are a novel, rare and distinct clinicopathological entity. The term refers to RCCs with overexpression of transcription factor E3 (TFE3) due to translocation involving the Xp11 locus or less commonly with overexpression of transcription factor EB (TFEB) due to a t(6:11) translocation. In children it is estimated that these tumours account for 40% of RCCs but in adults this proportion is estimated to be 1-4%. As these neoplasms are only recently recognised, outcome data are premature. We report 2 cases of translocation RCC in an Irish regional cancer centre and describe clinicopathological characteristics and early outcome.

Methods: In our recent practice, 2 renal cell carcinomas were suspected to be translocation tumours based on morphology and immunohistochemical features (RCC+/CK7-/EMA-). Using immunohistochemistry we tested for expression of TFE3 and TFEB.

Results: Both tumours were translocation RCCs. The first case was a 74 year old lady who presented with right upper quadrant pain and had a 9cm right renal mass with no metastatic disease on CT imaging. Radical nephrectomy was performed and histology revealed a pT3aN2, Fuhrman grade 4 renal cell carcinoma with papillary architecture and eosinophillic hyaline nodules within many of the papillae. Staining for TFE3 showed focal nuclear positivity consistent with an Xp11 translocation RCC. She remains disease free 6 months post surgery. The second case was a 46 year old man with an incidental finding of a right renal mass on ultrasound abdomen performed after a new diagnosis of haemochromatosis. Staging CT imaging revealed no metastatic disease and he underwent laparoscopic nephrectomy. Histology revealed a pT1aNx, Fuhrman grade 3 renal cell carcinoma with predominantly alveolar architecture and focal papillary and microcystic areas. Staining for TFEB was positive consistent with a t6:11 translocation RCC. He remains disease free 5 months post surgery.

Conclusions: We report 2 new cases of this rare subset of RCC. The therapeutic implications for patients with these mutations are as yet unclear. We plan to update with ongoing follow-up and identification of new cases to determine the clinical behaviour of these rare cancers in the Irish setting.
Comparison of ERG oncoprotein expression among matched cohorts of African American and Caucasian American patients with prostate cancer.
Authors: Pfister David J. K. P. , Rosen Philip , Young Denis , Petrovics Gyorgy , Chen Youngmei , Dobi Albert , McLeod David , Heidenreich Axel , Srivastava Shiv , Sesterhenn Isabell
Published: February 2017

52

Background: The ERG proto-oncogene is frequently overexpressed in Prostate Cancer (CaP) following genomic fusion, which places ERG under the control of the TMPRSS2 promoter. Recent studies show higher frequency of ERG rearrangement or ERG oncoprotein expression in CaP of Caucasian-American (CA) patients compared to African-American (AA) patients. The frequency of the ERG oncoprotein expression in prostate tumors of matched CA and AA CaP patients is evaluated to better understand the biological basis for differences in prostate cancer between the two populations.

Methods: Ninety-one AA CaP patients were matched for age, Gleason sum and pathologic stage to 91 CA CaP patients. All underwent radical prostatectomy between 1993 and 2010. Whole mount prostate specimens were used for immunohistochemical detection of the ERG oncoprotein by an ERG monoclonal antibody (clone 9FY). Individual foci of tumors were noted as either positive or negative. ERG staining data was linked to dinico-pathologic data.

Results: Fifty-nine of 91 CA patients (64.8%) and 41191 (45.0%) AA patients had at least one focus of tumor positive for ERG in a whole-mount prostate section (p = 0.0073). The index tumor was positive for ERG expression in 55/89 (61.8%) CA and 24/85 (28.2%) of AA patients (p <0.001). Seventy-seven of 183 (42.1%) individual foci were positive in CA versus 511196 in AA (26.0%; P <0.001). There was a trend towards increased biochemical recurrence in CA patients with ERG positive index tumors.

Conclusions: The prevalence of ERG oncoprotein expression is significantly higher among Caucasian- American patients. Differences in pattern of ERG positivity of index and non-index tumors between Caucasian-American and African-American prostate cancer patients and trends towards decreased biochemical recurrence-free survival suggest a more accelerated growth of ERG-positive tumors in Caucasian-American patients. Differences in ERG expression have the potential to delineate biological distinctions of CaP in these patient populations.
Hormonal therapy for localized prostate cancer in Japan: The outcome of J-CaP database.
Authors: Hinotsu Shiro , Akaza Hideyuki , Ogawa Osamu , Oya Mototsugu , Kitamura Tadaichi , Suzuki Kazuhiro , Tsukamoto Taiji , Naito Seiji , Namiki Mikio , Nishimura Kazuo , Hirao Yoshihiko ,   J-CaP Study Group
Published: February 2017

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Background: In Japan, the J-CaP database was established in 2001 when the Japan Study Group of Prostate Cancer (J-CaP Study Group), commenced a study to gather information about hormone therapy administered to Japanese patients and to analyze the outcomes of treatment. From the results of prostate cancer registry conducted by Japanese Urological Association revealed that 45% of localized prostate cancer patients diagnosed in the year of 2000 treated by hormonal therapy in Japan. The J-CaP database is the largest cohort of over 20,000 prostate cancer patients treated by hormonal therapy. Therefore, the objective of the current study was to estimate the outcome of hormonal therapy for the localized prostate cancer patients in the J-CaP database.

Methods: The study cohort included 9,127 men with localized prostate cancer who treated by hormonal therapy. All patients were diagnosed by biopsy as having prostate cancer and began to receive hormonal therapy between January 2001 and December 2003. In this study, initial hormonal treatment contained anti-androgen monotherapy, surgical castration only, LHRH agonist monothrerapy, LHRH agonist plus short-term anti-androgen, surgical castration plus anti-androgen, and LHRH agonist plus anti-androgen. All patients evaluated risk category of D’Amico classification. The percentage of Low-risk, intermediate-risk, and high-risk was 19%, 22%, and 59% of men, respectively. Prognosis analyses were performed using Kaplan–Meier methods. Progression-free survival and overall survival were estimated for each risk classification.

Results: After a median follow-up of 2.9 years (interquartile range, 1.5-5.3 years) and five year progression-free survival of low-risk, intermediate-risk and high risk were 74.5%, 68.1%, and 57.1%, respectively. The five-year overall survival of low-risk, intermediate-risk, and high risk were 90.0%, 87.2%, and 81.8%, respectively.

Conclusions: Comparing the results of radical prostatectomy in US, the five-year progression free survival was 54.6% in high-risk patients. Japanese patients with localized prostate cancer who treated hormonal therapy were comparable outcome of radical treatment in US considering the patients’ risk classification.
Is histoscanning a valid tool to detect prostate cancer in repeat biopsy?
Authors: Epplen Robin , van Essen Julius , Pfister David J. K. P. , Porres Daniel , Heidenreich Axel
Published: February 2017

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Background: Histoscanning is a novel ultrasound-based software programme, which uses back-scattered ultrasound, to detect and visualize prostate carcinoma. It is not clear to date which additive information histoscanning will deliver terms of additive information to ultrasound guided transrectal biopsy as research is scarce.Therefore we aimed to analyze our data on repeat biopsy with histoscanning prior to intervention.

Methods: From Sept. 2009 till present, 61 patients, mean age 62 yrs, that were scheduled for repeat biopsy received Histoscanning prior to intervention. Acquired data were retrospectively processed with Histoscanning software version 2.2 and prostate was divided into a 6 grid pattern. Lesions ≥0,5ml were considered positive. Biopsies were taken according to Vienna normogram and processed by an experienced uropathologist.

Results: Mean number of biopsies prior to repeat was 2. Mean PSA at repeat biopsy was 7,135 ng/ml, mean prostate volume accounted for 45.5 ml. A total of 15/61 men were diagnosed with cancer (24,59%), Gleason Score (Gl.) of 6 n=10, n=2 Gl. 3+4=7, n=2 Gl. 4+4; n=2 Gl. 4+5=9 respectively. A total of 43/834=5.15% positive cores were obtained, averaging 0.7 per person. Mean Volume of Histoscanning lesions per scan: 1,48 ml; no statistical significance can be detected regarding the volume per sextant and a positive core. False positive rate was 90/366=24,6%; false negative rate was 19/366=5,2%. Overall sensitivity was 29,69%, specifity accounted for 73.3%. PPV was calculated at 8.16% and NPV at 92,88%. PSA had no influence on detection rate.

Conclusions: In this highly seleted patient cohort Histoscanning had no beneficial nor additive information on detecting prostate cancer. Further research should has to be done regarding Histoscanning lesions with different histopathological features such as prostatitis and fibrosis.