bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of quantitative gene expression using RT-PCR in the prediction of recurrence risk in resected T1 clear cell renal cell carcinoma (ccRCC).
Authors: Campbell S. , Knezevic D. , Maddala T. , Novotny W. F. , Zhou M. , Aydin H. , Elson P. , Parodi L. , Goddard A. D. , Rini B. I.
Published: February 2017

338

Background: Current pathology and clinical methods do not accurately estimate risk of recurrence in all patients with pT1 ccRCC. Quantitative RT-PCR (qPCR) analysis was performed on resected ccRCC tumors to identify genes associated with recurrence that significantly augment current prognostic tools.

Methods: A retrospective observational cohort consisting of 931 patients (434 T1a, 201 T1b, 296 T2/3) with ccRCC was evaluated. All patients underwent nephrectomy between 1985 and 2003 at Cleveland Clinic and had paraffin-embedded tumor blocks. Patients with inherited ccRCC or inadequate follow-up (< 6 months or no recurrence data) were excluded. qPCR analysis of 732 genes was performed on all patients. Cox Proportional Hazards regression models were used to evaluate the association between gene expression and recurrence-free interval (RFI).

Results: 448 genes were significantly (unadj. p < 0.05) associated with RFI, from which 72 genes were carried forward for further study (Rini, ASCO 2010, #4501). Angiogenesis is the strongest among the pathways represented, from which 3 genes (AQP1, NOS3, PPAP2B) were selected for this analysis. Incorporating these 3 genes, a subset of higher risk patients among those classified as low risk by Leibovich criteria was identified. By Leibovich criteria, 85% of the patients in the cohort with pT1 tumors (< 7.0 cm) were identified as low risk - 7% recurrence at 5 years (95% CI: 5%, 9%). Incorporating these 3 genes, 9% of these patients were found to be at increased risk for recurrence - 19% at 5 years (95% CI: 7%, 21%). For the subset of T1a patients (< 4.0 cm), 98.6% were low risk according to the Leibovich criteria - 7% recurrence at 5 years (95% CI: 4%, 10%). Incorporating the 3 genes, 11% of these patients were found to be at increased risk - 20% at 5 years (95% CI: 7%, 31%).

Conclusions: Addition of 3 angiogenesis-related genes to the Leibovich criteria in patients with pT1 tumors refines stratification of patient risk in a subset of patients. More precise estimation of recurrence risk will help to tailor surveillance and refine inclusion into clinical trials. These genes will be incorporated into an algorithm that requires validation in an external data set.

[Table: see text]
NCI 6896: A phase I trial of suberoylanilide hydroxamic acid (SAHA) and 13-cis retinoic acid in the treatment of patients with advanced renal cell carcinoma (RCC).
Authors: Nanus D. M. , Tagawa S. T. , Dutcher J. P. , Akhtar N. H. , Saran A. , Mazumdar M. , Milowsky M. I. , Gudas L. J.
Published: February 2017

349

Background: Retinoid resistance in RCC inversely correlates with levels of intracellular retinol and retinyl esters suggesting that increasing intracellular levels of all-trans retinoic acid (RA) or enabling RA to become a more potent initiator of transcription will improve RA mediated anti-tumor effects. The combination of all-trans RA and a histone deacetylase (HDAC) inhibitor inhibited renal cancer cell proliferation and tumor growth in a xenograft model more than either drug alone. We performed a phase I clinical trial to evaluate the safety and preliminary efficacy of combining the oral HDAC inhibitor SAHA (vorinostat) plus oral 13-cis RA (isotretinoin) in patients with advanced RCC. Secondary endpoints include analysis of peripheral blood samples to study the effects on retinoid metabolites and retinoid related genes.

Methods: Patients (pts) with metastatic RCC (any histology) who have failed at least two lines of prior therapy were eligible. Vorinostat (300 mg bid x 3 consecutive days per week + isotretinoin co-administered at 0.25 mg/kg, 0.375 mg/kg, or 0.5 mg/kg PO bid x 3 days per week in cohorts using standard 3+3 dose escalation. Dose limiting toxicity (DLT) was defined as any grade > 3 toxicity during the first cycle.

Results: 14 pts have enrolled on the trial of which 12 are evaluable for toxicity (6 cohort 1; 3 cohort 2; 3 cohort 3) and 11 for tumor response. Common grade 1-2 toxicities included fatigue and GI effects (nausea, diarrhea, anorexia). One pt on dose-level 1 experienced a DLT (grade 3 depression). One patient experienced a partial response and 10 patients had stable disease lasting a median of 4 months (range 2–10 mos). Three patients progressed with brain metastases in the setting of stable systemic disease for at least 6 months. Pharmacokinetic and correlative studies examining expression of retinoid related genes are ongoing.

Conclusions: The recommended phase II dose is vorinostat (300 mg bid) + isoretinoin (0.5 mg/kg PO bid) 3 days per week. The combination of vorinostat and isotretinoin was well tolerated, and there was evidence of antitumor activity in this heavily pretreated population of patients with refractory metastatic RCC.

[Table: see text]
Use of percent positive biopsy cores to predict prostate cancer–specific death in patients treated with dose-escalated radiotherapy.
Authors: Qian Y. , Feng F. Y. , Halverson S. , Blas K. , Sandler H. M. , Hamstra D. A.
Published: February 2017

35

Background: The percent of positive biopsy cores (PPC)-considered a surrogate of local disease burden-has been shown to predict biochemical failure (BF) after external beam radiation therapy (EBRT), but most series have used conventional dose RT. Dose-escalated RT has been demonstrated to improve prostate cancer outcomes, but the value of PPC is unclear in the setting of RT doses high enough to decrease local failure.

Methods: A retrospective evaluation was performed of 651 patients treated to ≥75 Gy with biopsy core information available. Patients were stratified for PPC by quartile, and differences by quartile in BF, freedom from metastasis (FFM), cause specific survival (CSS), and overall survival (OS) were assessed using the log-rank test. Receiver operated characteristic (ROC) curve analysis was utilized to determine an optimal cut-point for PPC. Cox proportional hazards multivariate regression was utilized to assess the impact of PPC on clinical outcome when adjusting for risk group.

Results: With median follow-up of 62 months the median number of cores sampled was 7 (IQR: 6–12) with median PPC in 38% (IQR: 17%-67%). On log-rank test, BF, FFM, and CSS were all associated with PPC (p < 0.005 for all), with worse outcomes only for the highest PPC quartile (>67%). There was no observed difference in OS based upon PPC. ROC curve analysis confirmed a cut-point of 67% as most closely associated with CSS (p<0.001, AUC=0.71). On multivariate analysis after adjusting for NCCN risk group and ADT use, PPC>67% increased the risk for BF (p<0.0001, HR:2.1 [1.4–3.0]), FFM (p<0.05, HR:1.7 [1.1 to 2.9]), and CSS (p<0.06 (HR:2.1 [1.0–4.6]). When analyzed as a continuous variable controlling for risk group and ADT use, increasing PPC increased the risk for BF (p < 0.002), metastasis (p < 0.05), and CSS (p < 0.02), with a 1–2% increase in relative risk of recurrence for each 1% increase in the PPC.

Conclusions: For patients treated with dose-escalated RT, the PPC adds prognostic value but at a higher cut-point then previously utilized. Patients with PPC >67% remain at increased risk for failure even with dose-escalated EBRT and may receive benefit from further intensification of therapy.

No significant financial relationships to disclose.
Effect of genitourinary cancer mortality calculated using the potential years of life lost (PYLL): Trends from 1972-2006 based on a report from the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Heshmat S. , Moore P. C. , Kamel M. , Moussa O. , Bissada N.
Published: February 2017

350

Background: We aim to illustrate the potential years of life lost (PYLL) and the average years of life lost (AYLL); secondary to genitourinary cancer in US during the period from 1972-2006 utilizing the Surveillance, Epidemiology and End Results (SEER) database, and illustrate the trends in the PYLL over this time period.

Methods: PYLL were calculated to assess premature mortality trends in US for ureter, urinary bladder, kidney and renal pelvis, penis, testis, and prostate cancers. AYLL is the average of the differences between the actual ages at death and the expected remaining years of life for each person who died of cancer. Calculations were made based on the SEER cancer mortality data.

Results: There were a total of 7,733,235 PYLL in both men and women secondary to urogenital cancer in US in the period from 1972-2006. In both males and females, the greatest PYLL were for kidney and renal pelvis cancer related mortality. In both sexes no improvement in PYLL secondary to ureteral and bladder cancer related mortality was observed. In males the greatest reduction in PYLL was in testicular cancer followed by prostate cancer.

Conclusions: PYLL and AYLL are two powerful tools that reflect the impact of cancer related mortality on society. There has been an increasing trend in PYLL related to urogenital cancers over the last 35 years for both males and females. Kidney cancer had the highest increase in PYLL among both genders and more efforts are needed to address its progression.

No significant financial relationships to disclose.
The economic and clinical costs of chronic kidney disease following radical and partial nephrectomy in the management of small renal masses.
Authors: Chang S. L. , Cipriano L. E. , Harshman L. C. , Chung B. I.
Published: February 2017

353

Background: Postoperative chronic kidney disease (PCKD), defined as a glomerular filtration rate of < 60mL/min/1.73m2, is a recognized adverse outcome after extirpative therapy for small renal masses (SRM, ≤ 4cm). We quantified the long-term economic and clinical costs of PCKD following radical and partial nephrectomy for the management of SRM.

Methods: Using a Markov model, we evaluated open and laparoscopic approaches for radical and partial nephrectomy in the treatment of SRMs. The base case was a 65-year old healthy individual with a unilateral SRM and normal renal function. We used a 3-month cycle length, lifetime horizon, societal perspective, and 3% discount rate. The costs, quality of life adjustments, and transition probabilities were estimated from the literature, Medicare, and expert opinion. Health outcomes were measured in quality-adjusted life-years (QALY) gained and costs in 2008 U.S. dollars. The model was tested with sensitivity analyses.

Results: The average discounted lifetime outcomes are listed in the Table. There were minimal differences between the open and laparoscopic approaches. PCKD led to a substantial increase costs and decrease in health outcomes. The impact of PCKD was indirectly associated with age.

Conclusions: Partial nephrectomy provides cost-savings and improved health outcomes compared to radical nephrectomy in the management of patients with SRMs. Both procedures incur significant economic and clinical costs due to the development of PCKD. A discussion about the potential for PCKD should be incorporated into the informed consent for surgical treatment of SRMs.

[Table: see text]

No significant financial relationships to disclose.
Effect of salvage radiofrequency ablation on local control of recurrent renal cell carcinoma.
Authors: Psutka S. P. , Daha A. , Gervais D. , Feldman A. S.
Published: February 2017

355

Background: Radiofrequency ablation (RFA) has emerged as a safe and efficacious option to manage small renal cell carcinoma (RCC) in patients for whom comorbidities preclude surgical treatment. Salvage surgical excision of disease recurrence after ablative therapy is often complicated by extensive perinephric fibrosis. There are no reports in the literature which assess salvage RFA (sRFA) of recurrent disease (RD). The aim of this study was to assess the overall efficacy, complications, and safety of sRFA.

Methods: Between 1998 and 2008, 313 patients underwent RFA for RCC. RD was defined as detectable new enhancing tissue in the prior RFA-cavitation site after a documented complete response. We retrospectively compared patients who developed RD (RD+, n = 15, 5.1%) with patients who remained disease free after a complete response (RD−, n = 296, 95%), assessing tumor characteristics (size, location, biopsy pathology), complications, and disease-free survival. Mean follow-up was 3 years (SD 2.1).

Results: RD+ and RD− groups did not differ significantly in age, gender, or tumor type. In tumors < 4cm, 3.3% were RD+. In tumors >= 4cm, 9.6% were RD+ (p<0.0001). RD+ groups were more likely to have central tumors (20% vs. 5.7%, p = 0.04). Mean time to disease recurrence was 1.47 years (SD 0.75, 0.5-3.5 yrs). Of the 15 patients with RD, 7 patients underwent sRFA, 6 patients elected observation due to comorbidities precluding further treatment, one patient received chemotherapy for widespread metastases and one patient underwent salvage partial nephrectomy, which was aborted due to extensive tumor burden and perirenal fibrosis. There were no complications related to sRFA. Of those who underwent sRFA, local recurrences were successfully ablated in 100% of cases with a single salvage RFA treatment. None of these sRFA cases developed locally recurrent disease at an average of 3 years follow-up.

Conclusions: RD after RFA remains challenging to treat due to the significant comorbidities of the patients who are candidates for ablative treatment of RCC. RD was more likely to occur in centrally located tumors, > 4cm in size. Salvage RFA successfully can achieve local control in these patients without increased rates of complications.

No significant financial relationships to disclose.
Cytokine and angiogenic factor (CAF) profiling for identification of markers associated with response to cediranib in metastatic renal cell carcinoma (mRCC).
Authors: Zurita A. J. , Khajavi M. , Mulders P. , Yan S. , McKee K. S. , Tran H. T. , Pike L. , Mookerjee B. , Jurgensmeier J. , Heymach J.
Published: February 2017

362

Background: Cediranib is a highly potent and selective signaling inhibitor of vascular endothelial growth factor (VEGF) receptors−1, −2, −3 and c-Kit. In a phase II trial, patients (pts) with mRCC were randomized 3:1 to treatment with cediranib or placebo to primarily assess the difference in change in tumor size at 12 weeks. Cediranib resulted in a significant reduction in tumor size vs. placebo (Mulders et al. ESMO. 2009). Here we investigated soluble biomarkers in serum and concentration changes during treatment.

Methods: Pts received cediranib 45 mg/day PO or placebo for the first 12 weeks on treatment. At that time (or upon progression if earlier), treatment was unblinded and pts on placebo were given the option of receiving cediranib. Serum was collected from 61 pts at baseline (BL; cediranib 46, placebo 15), from 50 pts on day (D) 28, and from 45 pts on D84. Multiplex bead suspension arrays and ELISA were used to measure CAF concentrations including VEGF, placental growth factor (PlGF), sVEGFR-2, PDGFbb, HGF, MMP-9, multiple chemokines and interleukins (IL). The objectives of this exploratory analysis were to assess whether baseline CAFs were associated with changes in tumor size after 12 weeks of treatment and whether CAF levels changed while on treatment.

Results: Of 39 CAFs available at BL, lower than median (‘low') concentrations of IL-10, VEGF, PlGF, stem cell factor (SCF), and monokine-induced by interferon-gamma (MIG) were associated with larger decreases in tumor size than high concentrations (independent of treatment arm), whereas the opposite trend was observed for IL-5 and TRAIL. Consistent with inhibition of VEGF signaling, cediranib treatment resulted in changes over time in VEGF (increase), sVEGFR-2 (decrease) and PlGF (increase) concentrations. In addition, SCF, a c-Kit ligand and M-CSF decreased, while VCAM-1 and TRAIL increased during cediranib treatment.

Conclusions: Candidate CAFs associated with response to cediranib in mRCC such as IL-10 and VEGF were identified. Patients treated with cediranib showed distinct CAF changes compared with placebo. These results require independent validation in a larger trial.

[Table: see text]
Extracellular proteases in renal cell carcinoma.
Authors: Lipe B. , Ernstoff M. S. , Gui J. , Seigne J. D. , Schned A. , Petrella B.
Published: February 2017

363

Background: Tumor growth and metastasis relies on extracellular matrix remodeling, which is primarily mediated by the matrix metalloproteinase (MMP) family of enzymes. Extracellular matrix metalloprotease inducer (EMMPRIN, E) is a glycoprotein also implicated in tumor progression and has been shown to function in concert with MMPs. MMPs and E are highly expressed on the surface of many malignant tumors, including renal cell carcinoma (RCC). We investigated whether MMPs and E represent molecular prognostic factors in RCC.

Methods: Protein expression was evaluated in 77 patients with immunohistochemical analysis of a tissue microarray (TMA) consisting of two tumor samples and an adjacent normal renal sample from each patient. Tumors represented on the TMA were clear cell (57), chromophobe (9), papillary (4), oncocytomas (3), clear cell with sarcomatoid differentiation (2), and metastatic (2). Protein expression scores were correlated with clinical outcomes to determine prognostic significance by univariate and multivariate analyses.

Results: Using univariate analysis of all RCC tumors, membranous E correlated with overall survival (OS), metastasis-free survival (MFS), size, stage and overall 5-yr survival. Cytoplasmic E correlated with OS, MFS, size, grade, stage and 5-yr survival. Membranous MT1-MMP correlated with MFS, and endothelial MMP-2 correlated with grade. In multivariate analysis, membranous E was an independent indicator of stage, whereas cytoplasmic E was an independent indicator for size, stage, grade and MFS. In the clear cell population, membranous MT1-MMP correlated with OS and MFS, and endothelial MMP-2 correlated with grade in univariate analysis. In multivariate analysis, membranous MT1-MMP was an independent indicator for MFS.

Conclusions: We identified EMMPRIN as an independent prognostic indicator for size, grade, stage, and MFS in RCC. While MT1-MMP and MMP-2 both significantly correlated with disease outcome in the clear cell RCC population, only MT1-MMP was an independent prognostic factor for MFS. We conclude that MMPs and E mediate important steps in RCC progression. Further investigation is warranted using larger datasets and a prospective study to determine the strength of the prognostic significance of these findings.

No significant financial relationships to disclose.
Utilization of partial nephrectomy at a cancer center in the modern era.
Authors: O'Malley R. L. , Kowalik T. , Hayn M. H. , Collins T. B. , Underwood W. , Kim H. L. , Schwaab T.
Published: February 2017

370

Background: Analyses of population-based databases have demonstrated a striking under-utilization of partial nephrectomy (PN) despite its superiority in functional outcomes. Disparities in treatment patterns exist in the community and at some tertiary centers, based on age, gender and some comorbidities. The goal of the current study was to determine predictors of PN utilization at a cancer center in the modern era.

Methods: An institutional renal tumor database was used to identify patients who were potential candidates for elective PN (solitary tumors ≤ 7cm, baseline creatinine ≤ 1.5 mg/dL and a normal contralateral kidney). We estimated the effects of hypothesized predictors on the likelihood of undergoing radical nephrectomy (RN) versus PN by univariable (UV) and multivariable (MV) logistic regression. Variables included were: age, gender, race, smoking status, Charlson comorbidity index, body mass index (BMI), preoperative creatinine, year of surgery (YOS), radiographic tumor size, and whether diagnostic biopsy was performed.

Results: Of the 244 patients identified, 64% underwent PN and 37% underwent RN between August 2004 and June 2010. The cohort was composed of 11% non-Caucasians, 59% males and 22% current smokers with a mean age, BMI and tumor size of 61 years, 31 kg/m2 and 3.5cm, respectively. Of the cohort, 17% underwent biopsy. On UV analysis advanced age, larger tumor size, earlier YOS and Caucasian race all predicted RN (OR 1.03 CI 1.02-1.06, OR 2.09 CI 1.70-2.58, OR 0.56 CI 0.46-0.70, OR 0.36 CI 0.13-0.99, respectively). On MV analysis using all variables, tumor size and YOS remained independent predictors (OR 2.89 CI 2.11-3.95, OR 0.44 CI 0.33-0.59, respectively). Renal cell carcinoma (RCC) on biopsy was also independently predictive on MV analysis (OR 0.37 CI 0.14- 0.97).

Conclusions: Predictors of PN utilization at a cancer center differ from previous analyses and include decreasing tumor size, more recent YOS and RCC on biopsy. Appropriately, age and gender (when comorbidity is included) are not predictors of type of surgery. The significance of RCC on biopsy as a predictor of PN is unclear but may represent co-varying selection bias for lesions that are both accessible to biopsy and more appropriate candidates for PN.

No significant financial relationships to disclose.
Incidence of benign pathologic lesions at nephrectomy for renal masses presumed to be stage I renal cell carcinoma in Japanese patients: Impact of sex, age, and tumor size.
Authors: Fujii Y. , Saito K. , Iimura Y. , Yasuda Y. , Koga F. , Masuda H. , Yonese J. , Ishikawa Y. , Fukui I. , Kihara K.
Published: February 2017

374

Background: The widespread use of modern imaging techniques has resulted in the increased detection of small, asymptomatic renal tumors. Some recent studies from Western countries have reported that the incidence of benign lesions is approximately 15% in patients undergoing definitive surgery for renal masses presumed to be clinical stage I renal cell carcinoma (RCC). The high level of noncancerous lesions is, to some extent, due to the fact that no imaging feature can accurately distinguish either oncocytoma or lipid-poor angiomyolipma (AML) from RCC. This study attempts to determine the incidence of benign pathologic findings for such renal masses in Asian patients.

Methods: Between 1991 and 2009, 711 consecutive patients (218 women and 493 men) underwent partial (n=206) or radical (n=505) nephrectomy for renal masses presumed to be stage T1N0M0 (T1a/T1b= 503/208) sporadic RCC on preoperative imaging in two Japanese centers. The mean size of the lesions was 3.3 cm (range 0.3-7.0). The pathologic features were reviewed by an experienced pathologist.

Results: Of the 711 masses, 53 (7.5%) revealed benign pathologic findings. Twenty-two (3.1%) were AMLs, 13 (1.8%) were oncocytomas, 8 (1.1%) were complicated cysts, and 10 were others. Twenty-eight (12.8%) of the 218 females and 25 (5.1%) of the 493 males had benign lesions (p=0.0005). Of the 357 patients aged 60 years or younger, 37 (10.4%) had benign lesions while only 16 (4.5%) of the 354 patients over 60 years did (p=0.024). Forty six (9.2%) of the 503 T1a and 7 (3.4%) of the 203 T1b masses were benign (p=0.0071). A multivariate logistic regression model showed that sex, age and tumor size were all independently predictive of benign histology, particularly of AML.

Conclusions: The present incidence (7.5%) of benign lesions in presumed clinical stage T1N0M0 RCC masses at nephrectomy was lower than the incidence of approximately 15% previously reported from Western countries, probably because of the low incidence of oncocytomas in Japanese patients. Female gender, young age and small tumor size are all independently predictive of benign lesions, particularly of AML in Japanese patients.

No significant financial relationships to disclose.
Percutaneous radiofrequency ablation therapy as a first choice for renal tumor in patients with von Hippel-Lindau disease.
Authors: Uematsu K. , Saika T. , Kanbara D. , Kobayashi Y. , Gobara H. , Hiraki T. , Mimura H. , Kanazawa S. , Nasu Y. , Kumon H.
Published: February 2017

375

Background: Forty percent of patients with von Hippel-Lindau (VHL) disease have multifocal, bilateral renal cell carcinoma (RCC). The advent of ablative therapy has allowed many of these tumors to be approached percutaneously. Probe-based radiofrequency ablation (RFA) have recently been shown to be feasible nephron-sparing therapies for RCC, and have been proposed as first-line treatments for patients with VHL. We evaluated the feasibility, safety and therapeutic effects of RFA for VHL patients.

Methods: We reviewed the outcomes of VHL patients with RCC treated by RFA from 2003 to 2010. Follow-up consisted of serum creatinine measurement, physical examination and serial contrast enhanced computerized tomography or magnetic resonance imaging.

Results: The 42 tumors of 15 patients (23-70 years old, median 40) received a total of 43 RFA treatments to a 7 to 28 mm renal tumor (median 16). Seven of the patients had bilateral renal tumors. Tumor enhancement was eliminated and the renal function was preserved after the treatment in all tumors. There were no major complications related to the procedures though eight of small subcapsular hematomas, one of hematuria, one of small urine overflow, and one of nausea were seen after RFA. There was no recurrence after RFA during a mean follow-up period of 28.9 months (range 4.0-89.0, median 20.0 months). The overall recurrence-free survival rate was 100%. There was also a 100% metastasis-free and disease specific survival rate in the cohort.

Conclusions: The result of the present study showed percutaneous RFA was a feasible, safe, and promising therapy for the treatment of VHL patients with RCC.

No significant financial relationships to disclose.
Second primary cancers and their prognostic significance in patients with renal cell carcinoma.
Authors: Hauke R. J. , Tarantolo S. R. , Batra S. , Chakraborty S.
Published: February 2017

377

Background: To study the overall and site specific risk and prognostic significance of second primary cancers (SPC) in patients diagnosed with renal cell carcinoma (RCC).

Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for all patients with RCC as the first cancer and one or more SPC (1973-2006). SPC diagnosed within 1 month of diagnosis of RCC or at autopsy/death were excluded. Deidentified information was obtained to analyze the effect of SPC on overall survival (OS) of RCC patients.

Results: A total of 3,795 patients with RCC and ≥ 1 SPC were identified. The ratio of observed/expected cases (O/E ratio) of RCC and ≥ 1 SPCs was 1.18 (95% C.I. 1.15-1.22), significantly greater than the general population (p<0.05). The overall age-adjusted rate of SPC was 0.6 per 100,000 and rate of SPCs was higher in males and in blacks. The O/E ratio of SPCs was significantly higher in younger patients (6.6 vs. 1.3 and 1.13 for those aged <30, 30-59 and ≥60 yrs respectively), in blacks (1.38 vs. 1.15 in whites), for larger tumors (1.3, 1.2 and 1.05 for tumors <5cm, 5-<10cm and ≥10cm in diameter), and those who did not receive radiation. The risk was similar for both genders. There was variation in the site-specific risk of SPC depending on age at time of RCC diagnosis, gender, race, size of the tumor and presence or lack of radiation therapy. Patients with SPC had longer OS than those with RCC as the only primary tumor on univariate but not multivariate analysis. Older age (≥60yrs), radiation therapy, and a short interval (<12 mo) between the diagnosis of RCC and a SPC were associated with significantly shorter OS in RCC patients with SPC on multivariate analysis.

Conclusions: Our comprehensive analysis of SPCs in patients with RCC as the first primary malignancy using SEER data suggests that about 10% of RCC patients develop SPC and that several patient, tumor and treatment-related factors affect the risk of SPC at specific sites. Further, SPC can adversely influence the prognosis of patients with RCC, especially those >60 years old, receiving radiation or diagnosed with a SPC within 1 year after RCC diagnosis. These results may have significance in planning surveillance strategies to improve the survival of patients with RCC.

No significant financial relationships to disclose.
Correlation of hypothyroidism with survival in metastatic renal cancer patients treated with sorafenib or sunitinib.
Authors: Riesenbeck L. , Bierer S. , Hoffmeister I. , Koepke T. , Hertle L. , Thielen B. , Herrmann E.
Published: February 2017

379

Background: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su).

Methods: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodtyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH.

Results: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (PFS) (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Twenty-one of 66 (31.8%) patients developed hypothyroidism during treatment, which was associated with a positive prognosis (p=0.032). In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.018) and hypothyroidism (p=0.01) were independent prognostic parameters.

Conclusions: The development of hypothyroidism during treatment might be useful as a clinical predictor of PFS for mRCC patients undergoing treatment with targeted agents.

No significant financial relationships to disclose.
Recurrence and survival following preoperative sorafenib for advanced renal cell carcinoma.
Authors: Rathmell K. , Cowey C. L. , Grigson G. , Watkins C. , Wallen E. , Nielsen M. E. , Pruthi R. , Godley P. A. , Whang Y. E. , Kim W. Y.
Published: February 2017

384

Background: The impact of neoadjuvant or preoperative therapy in the setting of advanced renal cell carcinoma on recurrence-free or survival outcomes is not known.

Methods: 28 patients with renal cell carcinoma were treated with preoperative sorafenib in a prospective pilot study (LCCC 0603). Patient files were reviewed a median of 885 days (2.42 years) following nephrectomy. Records were evaluated for 13 patients with nonmetastatic disease for development of recurrence, and for 15 patients with stage IV disease for survival.

Results: For the nonmetastatic patients, only 2 patients had developed recurrent disease, one underwent metastectomy and remains in surveillance and the other is on second line systemic targeted therapy. A median recurrence-free survival has not been met after a median 2.5 years. For stage IV disease patients at a median follow up of 2.3 years, a median survival has also not been reached. Four patients are deceased, one patient is lost to follow up, and 10 remain alive. Treatments for metastatic disease included continued sorafenib, high dose interleukin-2, sunitinib, pazopanib, temsirolimus, and everolimus. Some stage IV patients have also enjoyed prolonged treatment-free intervals ranging from six months to over two years, with biopsy confirmed, but indolent disease.

Conclusions: Although these data are descriptive, these observations are suggestive that preoperative therapy with sorafenib is unlikely to accelerate the growth of grossly metastatic or micrometastatic disease. Further studies are needed to determine whether preoperative therapy is valuable in improving recurrence-free or overall survival endpoints.

[Table: see text]
Use of C-reactive protein to predict perinephric or renal sinus fat invasion in patients with clinical T1N0M0 renal cell carcinoma.
Authors: Iimura Y. , Saito K. , Fujii Y. , Ishioka J. , Iwai A. , Numao N. , Okada Y. , Koga F. , Masuda H. , Kihara K.
Published: February 2017

385

Background: Indication of nephron sparing surgery (NSS) for renal cell carcinoma (RCC) has been extending, as NSS can be considered for not only cT1a but also cT1b tumors. However, some cT1 diseases have pathological perinephric or renal sinus fat invasion. It is useful to know the probability of the presence of fat invasion before surgery, but diagnostic ability of imaging studies such as CT for predicting pT3a disease is limited. Therefore, estimation of the risk for pT3a disease in cT1 RCC patients could be helpful. C-reactive protein (CRP) has been shown to be a strong prognostic factor in RCC patients, reflecting tumor aggressiveness. We evaluated the predictive ability of preoperative CRP for pT3a disease in cT1N0M0 RCC patients.

Methods: Of consecutive 386 patients treated with radical nephrectomy for cT1a-bN0M0 RCC, 82 were excluded due to hemodialysis, inflammatory disease, bilateral synchronous renal tumors, synchronous other malignant disease or loss of each data. The remaining 304 patients constituted the current study cohort. Cut off point of CRP was 3 mg/L. Associations were analyzed between pT3a and preoperative factors including age, sex, BMI, laterality, tumor size, CRP, hemoglobin, platelet, LDH, ALP, calcium and albumin. We developed a multivariate model for predicting pT3a disease in cT1 RCC.

Results: Of the 304 patients, 28 (9%) had pT3a disease. Of 43 patients with elevated CRP level, 10 (23%) had pT3a disease. In contrast, of the remaining 261 patients with non-elevated CRP level, 18 (7%) had (p=0.002). Univariate and then multivariate analyses identified age (p=0.021), tumor size (p=0.007), and CRP (p=0.024) as independent and significant predictors for pT3a disease. Incorporating these three factors, we developed a predictive model for pT3a disease with predictive accuracy of area under the ROC curve of 0.772.

Conclusions: Preoperative CRP is an independent predictor for pT3a disease in cT1 RCC along with age and tumor size. The model could be useful to estimate the risk of the probability of fat invasion before surgery, especially NSS.

No significant financial relationships to disclose.
Renal cancer treatment in Spain: An online survey.
Authors: Duran I. , Sanchez Maurino P. , Garcia-Donas J. , Berthold D. R.
Published: February 2017

397

Background: Renal cancer incidence has increased in the last decades. Many treatment options have also been developed in this period. Knowledge about oncologists' attitudes in the management of this disease could help to implement better treatment protocols.

Methods: An online survey about therapeutic options for renal cancer was developed by an expert committee. Oncologists with expertise on the treatment of genitourinary malignancies that fulfilled all inclusion criteria in Spain were listed (n=200) and 80 were randomly selected to complete the survey. Survey items considered renal carcinoma management in the daily clinical practice. The questionnaire posed multiple tests, protocols, or therapeutic options.

Results: From the 80 selected oncologists, 53 responded to the online survey (66% response rate). The mean number of newly diagnosed cases per year was 201 (SD: 12) patients of whom 15 corresponded to renal carcinoma. Seventy nine per cent of participants reported to apply a protocol for treatment decisions, being the NCCN recommendations the most frequently followed (54.7%). Surprisingly, local or European recommendations were scarcely used. When asked about management of metastatic disease, most physicians (83%) reported that they would use sunitinib as the preferred first line treatment for good or intermediate prognosis patients. If further treatment would be required, 69.8% (n=37) and 79.2% (n=42) of oncologists would recommend a change in the mechanism of action by switching to an mTOR inhibitor (everolimus) for first and further relapses, respectively. Regarding the management of first line non-clear cell histologies, almost half of the physicians would utilize a TKI, while 38% would prefer an mTOR inhibitor.

Conclusions: NCCN are the most frequently followed recommendations. There is agreement among oncologists about which treatment should be used for renal carcinoma after first line treatment failure by switching the mechanism of action of the selected treatment. The management of non-clear cell patients remains a matter of debate with no consensus among the participants.

No significant financial relationships to disclose.
Prognostic factors and survial of advanced renal cell carcinoma with predominant sarcomatoid histology.
Authors: Park I. , Lee J. , Ahn J. , Lee D. , Song C. , Hong J. , Kim C. , Ahn H.
Published: February 2017

400

Background: Sarcomatoid renal cell carcinoma (SRCC) is known to have aggressive clinical course and poor response to treatment. Very limited data of clinical feature, prognostic factor, and survival are available for advanced disease with predominant sarcomatoid histology. We evaluated clinical features, response to treatment, and prognostic factors for survival.

Methods: Between 2001 and 2010, 30 patients with metastatic or recurrent RCC with predominant sarcomatoid histology (sarcomatoid component 30% or more for resected kidney or exclusive sarcomatoid carcinoma on needle biopsy) were treated at our institution. We reviewed these patients' records to identify clinical and pathologic features which could affect survival. The role of nephrectomy and systemic therapy on patient outcome was also investigated.

Results: There were 20 male and 10 female patients with a median age of 58 years (range, 43–83). Twenty patients had initially metastatic disease and 16 patients (53%) had ECOG performance status (PS) of 0–1. The most frequent metastatic site was lung (57%) followed by bone (43%) and distant lymph nodes (23%). Fourteen (70%) out of 20 patients with initially metastatic disease underwent primary nephrectomy and six patients also underwent metastasectomy. The median % of sarcomatoid component was 80% (range, 30–100%). All patients (N=10) who received immunotherapy had progressive disease as their best response and only one out of 5 patients treated with sunitinib or everolimus had a partial response. With a median follow-up duration of 22 months, the median survival was 3.6 months (95% CI, 0∼7.5) with 6-month survival rate of 43%. Only ECOG PS had impact on survival (P<0.001: ECOG=0, 14.1 months; ECOG=1, 7.4 months; ECOG=2, 3.2 months, and ECOG=3, 1.64 months). Survivals for initially metastatic disease were not significantly different whether patients underwent nephrectomy or not (2.0 months vs. 3.4 months, HR=0.62, 95% CI, 0.16–2.44 after correcting for potential prognostic factors).

Conclusions: Patients with SRCC have a fulminant clinical course and the majority of patients had disease progression irrespective of any treatment. Only performance status dose have impact on overall survival.

No significant financial relationships to disclose.
Anti-VEGF drugs combined with gemcitabine-based chemotherapy in treatment of metastatic collecting duct carcinoma.
Authors: Guo J. , Cui C. L. , Chi Z. H. , Si L.
Published: February 2017

403^

Background: Collecting duct carcinoma (CDC), accounting for less than 1% of kidney cancer, demonstrates an aggressive course and extremely poor prognosis. There are still no standard treatment regimens for this disease at present. Sunitinib and sorafenib, two protein tyrosine kinase inhibitors, have been used in treatment of renal cell carcinoma mainly by inhibiting vascular endothelial growth factor receptor (VEGFR). However, the combination of anti-VEGF drugs with gemcitabine-based chemotherapy has not been tested in CDC treatment.

Methods: From Jun 2008 to Aug 2010, six patients (5 males and 1 female) with metastatic CDC, ECOG PS ≤ 2 and adequate organ function were enrolled in the trial. Four patients received sorafenib (400mg bid) and two received sunitinib (37.5mg Qd), all in combining with gemcitabine (1.0 g/m2 d1,8) and cisplatin (40 mg d1-3) Q28d. A mean of 2.3 cycles (range 1-4 cycles) was given. Performance status 0-2 was allowed. Tumor assessments and radiological evaluations were conducted every 4 weeks.

Results: The median age was 41.5 years (range 28-60 years). All patients received prior nephrectomy. The sites of metastases included lung (4/6), skeleton (3/6), mediastinal lymph node (2/6), and liver (1/6). The therapy was well tolerated with grade 3-4 toxicities: neutropenia (4/6), thrombocytopenia (2/6), hand-foot syndrome (1/6) and rash (1/6). One patient had partial response, four had stable disease, and the disease control rate was 83.3% (5/6). The median progression-free survival was 3.5 months (range 1-6+ months), and the median overall survival was 6.5 months (1-15+ months) with the median follow-up of 6.5 months. No drug related deaths occurred.

Conclusions: The combination of anti VEGF drugs and gemcitabine based chemotherapy are well tolerated. This treatment regimen demonstrates modest antitumor activity and may cause progression-free survial benefit in patients with CDC.

[Table: see text]
Candidate biomarkers in renal cell carcinoma.
Authors: Seliger B. , Lichtenfels R. , Recktenwald C. , Dressler S. , Atkins D. , Stevanovic S.
Published: February 2017

405

Background: Renal cell carcinoma (RCC) represents a heterogeneous disease with widely varying prognosis. Therefore, the screening for biomarkers, which allow the diagnosis as well as the assessment of the individual risk of disease progression and mortality are a prerequisite for the selection of patients for different modes of therapies and the implementation of individually tailored surveillance protocols.

Methods: Various proteome-based technologies such as 2DE-based proteomics, PROTEOMEX or ligandomics in combination with mass spectrometry have been applied. Bioinformatic data mining led to the categorization and priorization of the respective target lists. Selected candidate targets were further independently verified by qRT-PCR, Western blot and/or immunohistochemistry.

Results: A large series of differentially expressed/immunoreactive proteins have been identified in clear cell RCC when compared to normal kidney epithelium. With the different approaches distinct sets of potential candidate targets were defined and categorized into different protein families and functions and according to their cellular localization. Moreover, the limited sharing rates between the respective target lists demonstrate their complementarity. Some selected markers were further validated by qRT-PCR, Western blot analysis and/or immunohistochemical stainings of tissue micro arrays comprised of RCC lesions of different TNM classification and histology revealing distinct expression pattern in regard to the RCC subtype, tumor grading,staging or additional molecular features. Using the ligandomics approach proteins have been identified, which were able to mount an immune response in vitro.

Conclusions: Some candidate markers might have the potential to be used as diagnostic and prognostic factors if not as novel targets for therapy and thus could be employed for the expression profiling of a larger series of RCC patients.

No significant financial relationships to disclose.
Prognostic impact of post-prostatectomy PSA slope determined with a novel, nucleic acid detection immunoassay (NADiA ProsVue) for total PSA.
Authors: Moul J. W. , Semmes O. J. , Vessella R. , McDermed J. E. , Lilja H.
Published: February 2017

47

Background: ProsVue is an investigational PSA immunoassay whose reporter antibody is labeled with a synthetic DNA sequence. RT-PCR detects the DNA signal indicating the PSA concentration. Pilot studies showed ProsVue slope (least-squares linear slope of 3 post-RP PSA values) to correctly classify prostate cancer (PC) patients (pts) with no evidence of disease (NED) and clinical progression (CP) using a 2 pg/mL/month (mo) decision threshold. In a retrospective, multicenter clinical trial, we evaluated potential prognostic value of ProsVue slope at this decision threshold.

Methods: 392 PC pts having RPs 11/1991 to 8/2001 were studied. Eligibility required first post-RP PSA <100 pg/mL, full pathologic and radiographic data and 3 frozen serum samples drawn 6 weeks to 19.4 mo post-RP. Adjuvant radiotherapy (RT) and/or hormone therapy (HT) was not allowed. CP was documented by positive imaging, biopsy results or PC-related death. Efficacy of ProsVue slope as a prognostic test for NED/CP at a 2 pg/mL/month decision threshold was determined and also examined with regards to Gleason score (GS), pre-RP PSA and final pathology stage.

Results: Median (range) of pre-RP PSA was 6.3 (0-60.6) ng/mL and post-RP GS was 7.0 (4-10). 73 pts received neoadjuvant HT. Pathologic stage was pT0-2 (228), pT3 (147), pT4 (17); 116 pts had positive margins and 8 had positive lymph nodes. The 3 PSA values were drawn after a median of 4.9, 8.6 and 12.8 mo and showed median values of 10.7, 23.0 and 50.7 pg/mL, respectively. Calculated sensitivity, specificity, PPV and NPV for a 2 pg/mL/mo ProsVue slope were 75.0%, 96.6%, 81.4% and 95.2%, respectively. Median follow-up (f/u) was 10.5 years. There were 40 deaths (14 from PC).

Conclusions: ProsVue provides information previously unknown in post-RP pts. ProsVue slope ≤2pg/mL/mo in the first year is highly associated with NED over long-term f/u. Potential clinical utility may include predicting pts not requiring long-term oncologic f/u and predicting a need for post-RP adjuvant RT. ProsVue slope may become a new paradigm for identifying those patients at reduced risk for recurrence of prostate cancer post-RP. Further studies are planned to address these questions.

[Table: see text]
Use of speed and extent of PSA response during the first three cycles of docetaxel chemotherapy in metastatic castrate-resistant prostate cancer to predict overall survival.
Authors: Goody R. B. , Mitchell D. M. , McAleese J. , O'Sullivan J. M.
Published: February 2017

48

Background: Docetaxel chemotherapy has an established role in the management of metastatic castrate-resistant prostate carcinoma (CRPC). With an overall survival benefit demonstrated with second line agents, identifying non-responders to docetaxel at an early stage would allow timely consideration of therapy change.We wished to assess PSA response rates to sequential cycles of docetaxel chemotherapy to determine after which cycle men should be considered nonresponders.We also wished to assess if previous therapy with diethylstilbestrol (DES) influenced subsequent response to docetaxel.

Methods: Retrospective case review of all men with CRPC receiving docetaxel chemotherapy between January 2007 and April 2010 at our institution was performed. PSA immediately prior to cycle 1 (baseline) and subsequent cycles were noted and evaluated for response compared to baseline PSA.

Results: 86 men with a median age of 65 years (47-81) received an average of 5 cycles (1-10) of docetaxel chemotherapy. 67 (77%) had a documented fall in PSA below baseline during chemotherapy with 56 (65%) and 43 (50%) having a PSA response of >30% and >50% respectively. A PSA level lower than baseline was seen in 54%, 63% and 72% of men after cycles 1, 2 and 3 respectively. Limited PSA falls below baseline were seen in 3 (3.4%) and 2 (2.3%) men after cycles 4 and 5 respectively. All PSA responses of >50% had occurred by the start of cycle 4. Of the 14 men who had received DES prior to starting docetaxel, only 3 (21%) had >50% reduction in PSA. The median overall survival for men achieving a PSA response >50% below baseline was 20 mths and was significantly better than the median overall survival of 10mths for those with no PSA response >50% (p<0.0001). Site of metastatic disease also correlated with survival.

Conclusions: In our population, men who fail to document a PSA response to the first 3 cycles of docetaxel chemotherapy are highly unlikely to do so after this time. Response defined as a fall below baseline and the extent of PSA decline below baseline are all correlated with survival. More modest PSA responses are seen in men pre-treated with DES than those who have not received DES.

No significant financial relationships to disclose.