bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of post-operative complications and prolonged length of stay following cytoreductive nephrectomy.
Authors: Gershman Boris , Moreira Daniel M. , Boorjian Stephen A. , Lohse Christine M. , Cheville John C. , Costello Brian Addis , Leibovich Bradley C. , Thompson Robert Houston
Published: February 2017

420

Background: Cytoreductive nephrectomy (CN) has been associated with significant morbidity, but there is little data identifying patients at increased risk. We evaluated the association of clinicopathologic features with early post-operative complications and prolonged length of stay (pLOS) among CN patients. Methods: We identified 294 patients treated with radical nephrectomy for M1 renal cell carcinoma between 1990 and 2009 at the Mayo Clinic. All complications within 30 days of surgery were reported using standardized methodology according to the Clavien classification. Associations with the presence of any early complication and pLOS (defined as ≥8 days, the top 25th percentile) were evaluated using logistic regression models. Results: Thirty-five (12%) patients experienced at least one early complication and 15 (5%) patients experienced at least one Clavien grade ≥3 early complication. The median LOS was 6 days (IQR 5-7), and 68 (23%) patients had a pLOS. On univariate analysis, liver metastases, symptomatic presentation, intraoperative transfusion, and pathologic nodal stage were significantly associated with both early complications and pLOS (Table). Two multivariate models were constructed. In Model 1 (limited to pre-operative features), only liver metastases (p<0.01) were associated with early complications while liver metastases (p=0.01) and open approach (p=0.02) were associated with pLOS. In Model 2 (all variables included), liver metastases (p=0.01), intraoperative transfusion (p<0.01), and high nuclear grade (p<0.01) were associated with early complications while intraoperative transfusion (p<0.01) and positive nodes (p=0.05) were associated with pLOS. Conclusions: CN was associated with a low incidence of early post-operative complications, particularly Clavien ≥3 complications. Presence of liver metastases and intraoperative transfusion were independently associated with increased risk of both complications and pLOS. [Table: see text]
Whole-exome sequencing (WES) predicting two extreme phenotypes of response to VEGF-targeted therapies (VEGF-TT) in patients with metastatic clear cell renal cell carcinoma (mRCC).
Authors: Fay Andre Poisl , Van Allen Eliezer Mendel , Murray Bradley , Albiges Laurence , Signoretti Sabina , Ho Thai Huu , Hakimi A. Ari , Mickey Suzanne S , Stanton Melissa L. , Bellmunt Joaquim , McDermott David F. , Atkins Michael B. , Garraway Levi A. , Kwiatkowski David J. , Choueiri Toni K.
Published: February 2017

422

Background: There is significant variability in the response to VEGF-TT in mRCC with no validated predictive biomarkers. We hypothesized that whole exome analysis might identify markers of response and resistance to VEGF-TT in mRCC. Methods: mRCC patients who received first-line sunitinib or pazopanib and were in two extreme phenotypes of response were identified. Extreme responders (ER) were defined as PR or CR for ≥3 years (n=10) and primary refractory patients (PRP) were defined as PD within the first 3 months of therapy (n=10). WES was performed in pre-treatment specimens and established Broad Institute analytical pipelines were utilized to identify point mutations and copy number alterations across the exome. ER (n=4) and PRP (n=4) who were part of TCGA project for clear-cell RCC were included in this analysis. Nonsense, missense and indel mutations in established or novel RCC genes were investigated. Results: IMDC prognostic scores were not significantly different between the two groups. VHL mutations were observed at similar frequency in ER and PRP, overall 57%. Mutations in PBRM1 were identified in 7 ER (50%) vs. 1 PRP (7%) (p=0.03). In addition, mutations in TP53 were only found in PRP (p=0.09). No other gene had mutations that were associated with either response or primary refractory disease (Table). Conclusions: In this pilot study, PBRM1 mutations were associated with extreme response to VEGF-TT. However, this was exploratory, and multivariable analysis was not performed. Analysis of additional patient samples is ongoing to confirm or refute this association. If true it suggests that epigenetic effects of PBRM1 mutation may contribute to response to VEGF-TT in mRCC. [Table: see text]
Evaluation of the effects of neoadjuvant pazopanib for renal cell carcinoma on intratumor genetic heterogeneity.
Authors: Ferguson Jed , McKibben Maxim , Parker Joel S , Wallen Eric , Wood Christopher G. , Powles Thomas , Rathmell Kimryn
Published: February 2017

425

Background: The prevalence of intratumoral genetic heterogeneity in renal cell carcinoma (RCC) has recently been elucidated, and the clinical implications are currently under investigation. The effects of neoadjuvant pazopanib on intratumoral genetic heterogeneity in RCC are unknown. Methods: With IRB approval and informed consent, 5 patients with clinically localized clear cell RCC were treated with pazopanib chemotherapy for ≥8 weeks prior to radical nephrectomy. Prior to treatment, the tumors were sampled by percutaneous core biopsy for histologic and genetic analysis. Peripheral leukocytes were collected for wild-type genetic analysis. Following nephrectomy, tumors were sampled for histologic and genetic analysis. DNA was extracted from all samples and ultra-deep multiregion exome genetic sequencing was performed to identify genetic mutations. Mutant allele frequencies were calculated and compared between pre- and post-pazopanib samples. Hierarchical cluster analysis was performed to evaluate intra- and inter-tumoral heterogeneity, and the fraction of private mutations was tabulated to evaluate change in clonality after pazopanib treatment. Results: Patients age ranged from 52 to 75, and tumors ranged from T2 to T4 (all cN0M0). Percent change of tumor volume after treatment ranged from -10% to -33%. Hierarchical cluster analysis of genetic mutations revealed that all pre- and post-pazopanib sample pairs clustered more closely with each other than with the other tumors, suggesting that intertumoral heterogeneity overshadowed intratumoral heterogeneity. Important genetic mutations in RCC (such as VHL, PBRM1, and SETD2) were highly represented in our dataset, thus validating our approach. After pazopanib, total numbers of mutations as well as the fraction of private mutations decreased in all tumors, showing an increased clonality with pazopanib therapy. Conclusions: RCC is highly genetically heterogeneous. However, this heterogeneity decreases with neoadjuvant pazopanib. These data have implications for the accuracy of percutaneous biopsy to predict tumor biology, and begin to reveal insights into the biologic and genetic response of these tumors to pazopanib.
Long-term response in metastatic renal cell carcinoma patients receiving first-line therapy with VEGF TKIs.
Authors: Tantravahi Srinivas Kiran , Patel Shiven B. , Ravulapati Sowmya , Batten Julia A. , Merriman Joseph , Stenehjem David D. , Agarwal Neeraj
Published: February 2017

436

Background: A subset of metatstatic renal cell carcincoma (mRCC) patients (pts) on first-line (1st) vascular endothelial growth factor inhibitors (VEGF TKIs) will have a long-term response (LTR) defined as a progression free survival (PFS) of >18 months (mos) on continuous therapy, and may be candidates for intermittent VEGF TKI therapy. Methods: From our institutional dataset of mRCC pts, we identified pts receiving 1st VEGF TKIs and who achieved a LTR. Data on clinical characteristics and survival outcomes were compared between those with LTRs and rest of the patients (control). Continuous and categorical variables were assessed by Wilcoxon rank sum and chi-square, respectively; and survival outcomes were compared by log-rank tests. Results: Of 89 pts, 24 (33%) had LTRs, of whom 5 pts have discontinued treatment (range 1-5 years) without subsequent disease progression, and 4 pts took treatment breaks for 3-9 mos. Baseline pts or disease characteristics were not predictive of LTRs (Table). Conclusions: A subset of mRCC pts receiving 1st VEGF TKIs achieve a LTR, and are not currently identifiable by baseline clinical characteristics including prognostic risk categorization. Identification of biomarkers predictive of LTR may allow intermittent or even deferred therapy with VEGF TKIs minimizing toxicity and cost. [Table: see text]
Management and outcomes of patients with renal medullary carcinoma (RMC): A multicenter retrospective study of 39 patients.
Authors: Shah Amishi Yogesh , Karam Jose A. , Rao Priya , Jonasch Eric , Rathmell Kimryn , Matin Surena F. , Vaishampayan Ulka N. , Heng Daniel , Plimack Elizabeth R. , Guancial Elizabeth A. , Fung Chunkit , Lowas Stefanie Rose , Lim Zita D. , Wood Christopher G. , Tannir Nizar M.
Published: February 2017

438

Background: RMC is a rare and aggressive neoplasm that afflicts primarily young black patients with sickle cell trait. Our primary objective is to report the outcomes of RMC patients through a collaborative initiative. Methods: After IRB approval, we retrospectively reviewed records of RMC patients treated from 2000-2013 at 7 academic institutions. Overall survival (OS) was calculated from RMC diagnosis to date of death. Descriptive statistics were used. Results: A total of 39 patients were included. Median age was 27.8 years and 29 (74%) were males. 38 (97%) had sickle cell trait. Median renal tumor size at presentation was 5.8 cm (range 3.4-11.4 cm). 3 patients presented with stage I disease, 13 with stage III disease, and 23 with stage IV disease. 22 patients had ECOG PS 0-1 and 17 had ECOG PS 2-3. The most common metastatic sites at diagnosis were lymph nodes in 27 and lung in 13. 26 patients (66.7%) had a nephrectomy. Pathologic stage was pT1-2 in 6 and pT3-4 in 20. 23 of these patients (88.5%) had positive lymph nodes at RPLND. 7 patients received preoperative systemic therapy. Median duration of pre-op therapy was 16 weeks (range 12-27 weeks). 1 patient had CR, 3 had PR and 3 had SD as best response to pre-op therapy. All patients received at least 1 line of systemic therapy. Median OS was 12.2 months. One patient had clinical CR with preoperative chemotherapy, near path CR on nephrectomy, and is currently NED at 27.4 mos. 5 patients are alive to date, though no patients have survived past 37 months. Conclusions: Patients withRMC have a grave prognosis. Nephrectomy (upfront or delayed) was associated with improved OS, even in patients with poor PS, though poor PS patients should be considered for upfront chemo. More effective therapies are desperately needed to improve patient outcomes. [Table: see text]
Cost analysis of an initial observation approach in metastatic renal cell carcinoma from a prospective study.
Authors: Parekh Hiral D.
Published: February 2017

439

Background: A prospective observational study of metastatic renal cell carcinoma (mRCC) prior to initiation of systemic therapy has been conducted. (Rini et al., ASCO 2014, abst 4520). A direct cost analysis was undertaken in mRCC patients from this trial matched to historical control mRCC patients treated with immediate systemic therapy. Methods: Histologically-confirmed, asymptomatic mRCC patients without prior systemic treatment were enrolled and followed until starting initial systemic treatment on a prospective trial. Patients underwent clinic visits and radiographic evaluation every 3 months for year 1, every 4 months for year 2, then every 6 months until treatment was initiated per physician discretion. Control mRCC patients who received immediate systemic therapy were matched for age, gender, Heng risk criteria and length of follow up. After clinical review, non mRCC-related encounters were excluded from final analysis. The direct cost of inpatient and outpatient visits plus associated laboratory analysis and imaging studies were compared between the 2 groups using the Wilcoxon signed rank test. Results: Seventeen matched pairs were included in the final analysis. The median (range) number of hospital admissions was 1 (range, 0-6) for the observation group and 1 (range, 0-5) for the immediate therapy group (p=1.0). The median (range) number of outpatient visits in the observation group was 17 (range, 6-39) and 19 (range, 4-59) in the immediate therapy group (p=0.47). In aggregate, the direct costs for the observation group were 30.6% less for outpatient visits and 21.9% less in total (outpatient plus inpatient visits) as compared to the immediate therapy group (p=0.19 for both). Conclusions: Initial observation as a management strategy for a subset of mRCC patients is associated with a non-significant aggregate decrease in direct costs compared to patients requiring immediate treatment. Further study is required to evaluate costs associated with different management strategies over the lifetime of mRCC patients.
MRI/US fusion-guided biopsy to detect clinically significant prostate cancer in the central gland correlating with index lesion.
Authors: Fascelli Michele , Frye Thomas P , George Arvin Koruthu , Abboud Steven , Chelluri Raju , Ho Richard , Sankineni Sandeep , Merino Maria J , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A.
Published: February 2017

44

Background: Central gland (CG) prostate cancers (CaP) are reported with lesser incidence and smaller tumor volume compared to the peripheral zone (PZ). Index tumor lesions defined by highest grade may be missed when in the CG. MRI/US fusion-guided biopsy allows targeting of lesions, potentially identifying cancer outside the traditional TRUS biopsy template. Methods: Retrospective review of 1,003 patients who underwent multiparametric MRI (mpMRI) found 2,119 suspicious lesions. Targets were biopsied and stratified by zonal distribution, CG or PZ. Cancer detection rates (CDR) were tabulated by location and correlated with PSA, Gleason score, prostate volume and MRI suspicion. Results: Fusion-guided biopsy targeted lesions in the central (711, 34%) or peripheral (1408, 66%) prostatic zones. CDR was similar between zones: 35.2% CG compared to 33.6% PZ (Table). CDR of clinically significant disease (Gleason >4+3) was similar in the CG and PZ despite higher prostate volume in those with CG lesions. In contrast to TRUS biopsy, upgrading occurred in 18.5% of CG patients versus 13.3% PZ (p=0.024). 36.6% (77/210) of CG lesions represented the highest risk lesion on MRI, translating to 13% (77/592) of the biopsy-proven CaP cohort. Conclusions: CG cancers occur at a similar frequency as PZ CaP. CG lesions were more likely to be upgraded from TRUS biopsy, frequently representing the index lesion. In upgraded patients, CG targets constituted the index lesion in a third of all males. MRI/US fusion-guided biopsy identifies clinically significant disease of the CG not captured on traditional biopsy. [Table: see text]
Overall survival (OS) in renal cell carcinoma (RCC) before and after the introduction of targeted therapies (TTs): A Norwegian population-based study (2000–2011).
Authors: Klepp Olbjorn Harald , Johannesen Tom Børge , Oldenburg Jan , Torgersen Knut Martin , Kowalski Jan , Solli Oddvar , Sandin Rickard , Beisland Christian
Published: February 2017

443

Background: The Renal Comparison study in Norway (RECON) is a retrospective non-interventional study of OS in all patients diagnosed with RCC and metastatic (m)RCC before and after the introduction of TTs. Methods: Using data from two national health registries, Cancer Registry of Norway (diagnosis and cause of death) and Norwegian Prescription Database (all dispensed drugs), we assessed OS in RCC and mRCC patients diagnosed during two periods after (2009–2011 and 2006–2008) and one period before (2000–2005 [RCC]; 2002–2005 [mRCC]) the introduction of TTs and factors influencing OS in mRCC. Multivariate analysis was performed using a Cox proportional hazards model, including estimation of adjusted HR. The regression model included the covariates age, gender, geographic region, nephrectomy status, diagnostic period and TT prescription. Results: In total, 2,176, 1,887, and 3,233 RCC patients were identified in 2009–2011, 2006–2008 and 2000–2005, respectively, of whom 2,160 (30%) had mRCC. From 2006 to 2011, TT use in mRCC patients significantly increased from 21% to 56% (p<0.01); sunitinib was the most frequent first-line treatment (93%). RCC patients diagnosed in 2009–2011 and 2006–2008 had a significant improvement in OS compared with patients diagnosed in 2000–2005 (median OS: not reached and 76 vs. 49 months, respectively; both p<0.001 [log-rank]). Similarly, a significant OS improvement was shown in mRCC patients diagnosed in 2009–2011 and 2006–2008 compared with 2002–2005 (median OS: 11.0 and 8.0 vs. 6.0 months, respectively; both p<0.001 [log-rank]; with adjusted HR [95% CI] of 0.77 [0.68–0.87] and 0.87 [0.78–0.98], respectively). Factors significantly associated with longer OS in mRCC were (HR, 95% CI): younger age (0.98, 0.98–0.99), female gender (0.88, 0.79–0.97), prior nephrectomy (0.49, 0.43–0.55) and TT prescription (0.58, 0.51–0.65). Significant regional variation was also shown. Conclusions: A significant OS improvement was shown in RCC and mRCC patients following the introduction of TTs. This advance has continued into the later TT era and, although multifactorial in origin, the contribution of TTs in mRCC is highly likely.
Association and prognostic impact of peripheral blood counts with tumor programmed death ligand one expression.
Authors: Lewis Daniel , Joseph Richard Wayne , Serie Daniel , Eckel-Passow Jeanette , Ho Thai Huu , Cheville John C. , Kwon Eugene D. , Thompson Robert Houston , Leibovich Bradley C. , Parker Alexander S.
Published: February 2017

447

Background: Components of the peripheral blood counts (PBC) are associated with poor prognosis in patients diagnosed with non-metastatic clear cell renal cell carcinoma (ccRCC). Related to this, higher tumor expression of programmed death ligand one (PDL1) is also associated with poor ccRCC prognosis. Herein, we utilize a large cohort of patients undergoing nephrectomy for localized ccRCC to evaluate the association of PBC with tumor expression of PDL1. Secondarily, we examine the association of PBC and relapse free survival (RFS) after adjusting for age and PDL1 expression. Methods: Through chart review, we obtained PBC values at time of nephrectomy for patients enrolled in the Mayo Clinic Renal Registry from 1990-2009 who were treated for localized (M0) ccRCC including the following: hemoglobin (HGB), white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), and platelets (PLT). We determined tumor PDL1 expression as a continuous variable (% of positive PDL1 tumor cells) using the 5H1 antibody on archived tissues. We analyzed the correlation of PBC values with PDL1 expression as a continuous variable using a linear estimate. To evaluate the association of PBC values with RFS after adjusting for PDL1 expression, we employed multivariate Cox regression models. Results: A total of 706 ccRCC patients had available PDL1 expression and PBC. PDL1 expression was inversely associated with HGB (linear estimate of -0.02, p<0.001) and positively associated with platelets (linear estimate 1.73, p<0.001) whereas there was no association with PDL1 with WBC, ANC, AEC, or AMC. After adjusting for age and PDL1 expression, a higher HGB (HR=0.87, p<0.001), higher ALC (HR 0.68, p=0.003), and higher AEC (HR 0.12, p=0.002) were all associated with improved relapse free survival. Conversely, higher PLT was associated with decreased RFS (HR 1.002, p<0.001). Conclusions: PDL1 expression is associated with decreased HGB and increased PLT at the time of nephrectomy. After adjusting for PDL1 expression and age, higher HGB, ALC, and AEC are associated with improved RFS, while higher platelets are associated with decreased RFS.
Immune cell repertoire in patients with metastatic renal cell carcinoma: Data from prospective clinical trial.
Authors: Damarla Vijay , Elson Paul , Wood Laura S. , Sybor Sylvia , Rayman Pat A. , Wong Yu Ning , Plimack Elizabeth R. , Finke James , Rini Brian I.
Published: February 2017

452

Background: Immune dysfunction is documented in renal cell carcinoma (RCC) patients and likely influences tumor progression. An ongoing prospective trial of observation in metastatic RCC patients prior to systemic therapy is investigating circulating immune cell populations. Methods: Asymptomatic patients with low volume metastatic disease were enrolled and followed until starting initial systemic treatment. Peripheral blood specimens were collected at baseline and again at 3, 6, 9, 12, 16, 20, and 24 months, and then every 6 months until initiating systemic therapy. Immune parameters measured included CD3+ and CD4+ INF-γ producing T cells (INF-γ+ T), CD4+CD25+FoxP3+ regulatory T-cells (Treg), CD33+HLADr-CD15+CD14- neutrophilic myeloid-derived suppressor cells (N-MDSC), monocytic M-MDSC, total MDSC, and lineage-negative MDSC. Similar immune parameters were recorded for treatment-naïve patients prior to immediate systemic therapy (sunitinib or pazopanib, n=34) and healthy volunteers (n=22) on separate IRB-approved protocols. The immune data was analyzed using Wilcoxon rank sum and signed rank tests and proportional hazards models. Results: Forty patients enrolled in the observation study had immunologic data. 25 patients (62%) started systemic therapy, and 15 (38%) continue observation. The observation group had lower baseline levels of MDSC, N-MDSC, M-MDSC, Tregs and higher levels of CD3+INF-γ+ T cells, CD4+ INF-γ+ T cells, and lineage negative MDSC compared to the immediate treatment group, although higher MDSCs and lower Tregs compared to healthy controls. The impact of baseline parameters on the duration of observation revealed that lower Tregs (p=0.003) were associated with a longer time on observation. There were no significant changes in immune parameters of observation patients over the length of observation. Conclusions: Metastatic RCC patients with indolent disease have low levels of Treg and MDSC, and a relatively preserved immune cell repertoire compared to patients requiring immediate therapy. Lower baseline Tregs may be associated with a longer length of observation.
Everolimus (EVE) versus temsirolimus (TEM) after first-line treatment with VEGF TKI in patients with metastatic renal cell carcinoma.
Authors: Patel Shiven B. , Agarwal Neeraj , Hsu JoAnn , Tantravahi Srinivas Kiran , Gill David , Vuong Winston , Batten Julia A. , Stenehjem David D. , Pal Sumanta Kumar
Published: February 2017

460

Background: Given the lack of affordability with an oral drug like EVE and/or preference in some patients (pts), TEM has been used after disease progression on a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). However, efficacy of TEM and EVE in this setting has not been evaluated in a randomized trial. Methods: Pts who were treated with a first VEGF TKI for metastatic renal cell carcinoma (mRCC) and then treated with either EVE or TEM upon progression were identified from two institutional databases. Survival estimates of progression free (PFS) and overall survival (OS) were assessed from initiation of second-line (2nd) treatment by Kaplan-Meier methodology. Results: 90 pts were eligible that received either EVE (n=59; 66%) or TEM (n=31; 34%) in 2nd setting. Pts and disease characteristics were similar in both groups. Median PFS was not different, but OS was significantly improved with EVE (Table). Conclusions: After progression on a 1st VEGFTKI, 2nd EVE and TEM have similar efficacy in terms of PFS, but OS was significantly higher with EVE. Data need further validation in a larger cohort. [Table: see text]
Clinical features of metastatic renal cell carcinoma patients with intrinsic resistance to sunitinib: A Korean multicenter study.
Authors: Kim Jung Hoon , Won Young-Woong , Kim Seung Tae , Park Se Hoon , Lee Soonil , Lim Sung Hee , Hwang In Gyu , Oh Sung Yong , Ji Jun Ho , Lee Ji Yun
Published: February 2017

462

Background: In a subset of patients with metastatic renal cell carcinoma (RCC), primary resistance to first VEGF targeted therapy is not fully understood, and the optimal treatment approach for these patients is still controversial. This study was aimed to characterize the primary sunitinib resistant patients and associated predicting factors. Methods: A total of 134 patients with recurrent or metastatic RCC, who were initially treated with sunitinib, consecutively selected from 4 centers in Korea, between January 2008 and March 2013. Patients in whom progressive disease (PD) was the best response during treatment with sunitinib were included in the primary sunitinib resistant group. Results: Among 134 patients, 33 (25%) patients primary resistant to sunitinib with a median age of 59 years (range, 28-78) were identified. Most patients had clear cell histology (94%) and good ECOG performance status (0, 1) (82%). According to MSKCC risk, 25% of patients were at favorable risk, 72% at intermediate risk, and 3% at poor risk. Univariate analysis revealed that poor performance status (ECOG≥2), elevated LDH, neutrophilia, and higher number of distant metastatic disease (≥3) and bone or hepatic metastasis were significant factors associated with intrinsic resistant disease. Neutrophilia (OR=7.4, p=0.015) and more than three distant metastatic disease (OR=3.6, p=0.031) were independently significant risk factors of predicting intrinsic resistant disease on multivariate analysis. There was statistically significant difference with regard to overall survival (median, 11.7 vs. 31.1 month; p=0.001) and progression free survival (median, 2.4 vs. 12.5 month; p<0.0001) between the patients with and without intrinsic resistance. Conclusions: Intrinsic resistance to sunitinib treatment is associated with a dismal prognosis in metastatic RCC patients. Along with above predicting clinical features, more understanding of the underlying mechanism and molecular biomarkers for detecting the intrinsic resistant disease are needed.
Identification of tumor biomarkers for sunitinib in advanced renal cell carcinoma (RCC).
Authors: Dai Hongyue , Fishman Mayer N. , Ching Keith A. , Williams James Andrew , Teer Jamie K. , English Patricia A. , Zhang Yonghong , Murray Brion W. , Kumar Naveen , Huntsman Shane , Berglund Anders E. , Dalton William S. , Matczak Ewa , Martini Jean-Francois
Published: February 2017

470

Background: Sunitinib is a standard of care for advanced RCC. Despite efforts to identify predictive molecular markers for patient selection, none are available, likely due to multiple resistance mechanisms. Using the Total Cancer Care (TCC) database, which integrates patient clinical, molecular, and biospecimen data, we devised a tumor genomics and transcriptomics experiment to identify differences between RCC patients who derive prolonged clinical benefit from sunitinib versus those who are resistant. Methods: A discovery set of 34 RCC patients treated with sunitinib at the approved regimen were identified in the TCC database (n=16 treated for ≤6 months, having primarily discontinued for reasons other than tolerability; n=18 treated for ≥18 months). Tumor samples were analyzed by whole exome sequencing (WES) and by parallel 400-gene expression profiling. Following gene mutation identification and supervised gene expression analysis, molecular differences between the two groups were identified and tested for potential association with treatment duration. Results: Of the 34 cases identified, 24 remained for analysis following sample QC failure and clinical review (n=10 and 14 treated for ≤6 and ≥18 months, respectively). Gene expression analysis revealed a 37-gene signature associated with treatment duration: MAPK8 (JNK1) was a leading candidate biomarker (Pearson correlation with log [treatment duration]=–0.70; p=0.06 after Bonferroni multiplicity correction). Pathway-based WES analyses identified 25 potential variants of interest, none remaining statistically significant after correction. However, following genome-wide analysis, a single variant in an intronic region of ING3 was statistically associated with treatment duration (p=0.02). Conclusions: Activation of the PI3K/AKT pathway was a marker of resistance to sunitinib. In contrast, activation of the angiogenic, NOTCH, or JAK-STAT pathways was, to some degree, associated with sensitivity to therapy. However, neither VHL alteration nor lack of expression, nor alteration in chromatin-rearrangement genes, was associated with sunitinib treatment duration. These findings require further validation in a larger and independent cohort.
Association of chronic co-morbidities with long term survival with metastatic renal cell carcinoma (mRCC).
Authors: Campbell Matthew T. , Shah Amishi Yogesh , Nautiyal Kirtan Das , Hashemi Neda , Corn Paul Gettys , Pagliaro Lance C. , Jonasch Eric , Tannir Nizar M.
Published: February 2017

472

Background: Since the introduction of targeted therapy, patients (pts) with mRCC are living longer. Cumulative toxicities of sequential targeted therapies remain an area largely unexplored. Methods: A retrospective review of consecutive mRCC pts evaluated at MDACC from 1/1/2001 to 12/31/2008 was conducted. We characterized pts who lived >4 yrs with metastatic disease. In the table below, de novo hypertension (HTN) refers to new onset HTN on VEGF or mTOR targeted therapy (TT), HTN exacerbation refers to HTN in pts with already documented HTN on TT, HTN exacerbation after de novo HTN refers to pts who had exacerbations during subsequent TT after de novo HTN on TT. Descriptive statistics were used. Results: 205 pts with evaluable initial data were characterized for baseline co-morbidities listed in the table below; 37 pts did not have adequate follow up. Of the remaining 168 pts, 12 were managed with surgical resections only and did not receive any systemic therapy, 12 pts received systemic therapy (Tx), but not TT, and 144 received TT: 142 pts (84.5%) received at least 1 VEGF-directed agent, 115 pts (68.5%) received multiple VEGF-directed agents, 75 pts (44.6%) received mTOR inhibitors. Conclusions: Development of HTN and HTN exacerbations are markers of treatment efficacy. The long-term survivors identified in our series had high rates of HTN, hyperlipidemia, hypothyroidism, and VTE. Toxicity cost is an important aspect of long-term survivorship and warrants continued study. [Table: see text]
Rho GDP dissociation inhibitor beta ARHGDIB in renal cell cancer.
Authors: von Klot Christoph A. J. , Dubrowinskaja Natalia , Hennenlotter Jörg , Kramer Mario W. , Merseburger Axel S. , Stenzl Arnulf , Peters Inga , Tezval Hossein , Kuczyk Markus A. , Serth Juergen
Published: February 2017

474

Background: Rho GDP dissociation inhibitor 2 (ARHGDIB) is an important mediator of cellular signaling. The expression of ARHGDIB correlates with tumor growth and metastasis in a variety of non genitourinary cancers, however the role of ARHGDIB in renal cell cancer (RCC) has not yet been evaluated. Methods: Tissue samples from 106 patients undergoing surgery for RCC were obtained. The expression of ARHGDIB mRNA in normal kidney tissue and in corresponding cancer tissue was analyzed by means of quantitative real time PCR. Differences in mRNA expression levels were assessed using paired two-sample tests. Associations of relative mRNA expression levels and clinicopathological parameters were statistically analyzed using an univariate logistic regression model. Relative mRNA expression levels in healthy renal tissue compared to cancerous tissue from the same kidney was assessed using a paired t-test. Results: When comparing 74 tissues from kidney tumors with adjacent histologically normal appearing paired tissues, mRNA expression of ARHGDIB was significantly higher in the tumor tissue (p < 0.001). Paired analysis did not only show significantly higher mRNA expression levels for ARHGDIB over all RCC but also for the subgroup with clear cell RCC (ccRCC). The mRNA expression of ARHGDIB was also more pronounced in ccRCC when compared with papillary RCC (p < 0.001). When looking at clinicopathological parameters in univariate logistic regression analysis ccRCC was significantly associated with nodal involvement (p = 0.03) and also with tumor grade (p = 0.05). For all RCC there was no association with clinicopathological parameters. A bivariate Cox regression model, adjusted for metastatic status (p = 0.001), tumor diameter (p = 0.043), state of advanced disease (p = 0.030) and lymph node metastasis (p = 0.006) identified ARHGDIB mRNA expression as a candidate positive prognosticator for RFS. Conclusions: Increased ARHGDIB mRNA expression is significantly associated with RCC tissues. Higher relative expression observed within tumor tissues represents a candidate prognosticator for better RFS of patients.
The impact of rhabdoid differentiation on prognosis in patients with grade 4 renal cell carcinoma.
Authors: Zhang Ben Yiming , Cheville John C. , Thompson Robert Houston , Boorjian Stephen A. , Lohse Christine M. , Leibovich Bradley C. , Costello Brian Addis
Published: February 2017

494

Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p<0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p<0.001) and grade 3 RCC with necrosis (HR 1.62; p<0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.
Outcomes of patients with late relapse metastatic renal cell carcinoma treated with targeted therapies: A single-institution experience.
Authors: Mandalapu Kamal Kishore , Matrana Marc Ryan , Poosarla Teja
Published: February 2017

498

Background: Approximately 20-30% of patients (pts) with renal cell carcinoma (RCC) develop recurrence after treatment of localized disease. Of these pts, the great majority recur within the first few years following surgery. Rarely, late recurrences are seen after 5 years of disease free survival. The outcome of metastatic RCC has improved markedly with targeted therapies (TT). Little data are available about outcomes of pts with metastatic RCC from late recurrences who are treated with TT. Methods: We retrospectively reviewed records of consecutive pts with metastatic RCC who had late recurrence >5 years and were treated with TT between 11/1/2006 and 11/1/2013. All the pts had prior nephrectomies. Outcomes were tabulated using basic statistical techniques. Adverse events (AEs) were graded using CTCAE v4.0. Results: 24 pts (100% clear-cell, median age 69 years, 83% males, all with prior nephrectomies) met inclusion criteria with late recurrence >5 years. 79% had favorable risk and 21% intermediate risk by MSKCC criteria. 11 pts died. Estimated median overall survival time for all pts was 50.2 months (95% CI: 23.93–NR) .The 3-year overall survival rate was 71.78% (95% CI: 47.98-84.77). The median number of sequential TT received was 2 (range 1-4). Median time on first line TT was 20.7 months. 45% of pts received pazopanib in the frontline setting, 29% received sunitnib, and 25% received sorafenib. 68% received TT in the second-line and subsequent settings. Common adverse events of TT included fatigue (52%), diarrhea (36%), hypertension (36%), anorexia (28%), hair and skin changes (24%), increased liver function tests (20%), nausea/vomiting (16%), and 95% of adverse events were grade 1/2. Conclusions: In this retrospective study, pts diagnosed with metastatic RCC after disease free interval >5 years have prolonged survival when treated with TT. Overall survival and 3-year survival rates were better than historical controls. Adverse events were mild/moderate and manageable.
Predicting pulmonary metastases among patients with indeterminate pulmonary nodules with renal cell carcinoma.
Authors: Adibi Mehrad , Kenney Patrick , Thomas Arun Z. , Devine Catherine E , Karam Jose A. , Wood Christopher G.
Published: February 2017

505

Background: Indeterminate pulmonary nodules (IPN) are of uncertain significance in renal cell carcinoma (RCC) patients. We sought to determine the natural history of IPN in patients undergoing radical nephrectomy and to identify clinical variables associated with the development of lung metastases. Methods: We reviewed all radical nephrectomy patients at a single institution from 2005 – 2009 who had ≥1 IPN on chest computed tomography (CT) within 6 months prior to surgery and no evidence of distant metastates. All chest CTs were re-reviewed by a radiologist who was blinded to outcomes to independently determine number, size, location of nodules and whether the IPN appeared concerning for metastases based on nodule size, tissue density, and morphology. Univariate and multivariate Cox regression was used to assess associated predictive factors. Results: Of 258 patients with IPN, 73 (28%) developed pulmonary metastases. Median follow−up was similar in the groups at 36 months. Patients who developed pulmonary metastases had significantly poorer survival compared to those who did not (3-year DSS 54.5 versus 86.5 months, p<0.001), and 39 (53%) developed pulmonary metastases at the same location as the largest IPN. On univariate analysis, larger renal tumor diameter (HR 1.12, p<0.001), number of pulmonary nodules CT (HR 1.12, p 0.001), presence of hilar lymphadenopathy on chest CT were associated with both lung metastasis development and cancer-specific mortality. After adjusting for age, performance status, comorbidities, histology, and smoking status, higher tumor grade (HR 5.11, p 0.007), presence of tumor thrombus above the diaphragm (HR 4.38, p 0.013), perinephric (HR 4.29, p 0.002) or renal sinus (HR 2.16, p 0.045) fat invasion, and a chest CT concerning for metastasis by the radiologist (HR 2.91, p<0.001) were associated with development of pulmonary metastases. Conclusions: RCC patients with IPN who develop pulmonary metastases have a significantly poorer outcome. Independent predictors of developing lung metastases include tumor grade, presence of tumor thrombus above the diaphragm, perinephric or renal sinus fat invasion, and a chest CT concerning for metastasis.
Long-term survivorship in patients (pts) with metastatic renal cell cancer (mRCC): A retrospective study from the MD Anderson Cancer Center (MDACC).
Authors: Campbell Matthew T. , Shah Amishi Yogesh , Hashemi Neda , Nautiyal Kirtan Das , Corn Paul Gettys , Pagliaro Lance C. , Jonasch Eric , Tannir Nizar M.
Published: February 2017

510

Background: The overall survival (OS) of pts with mRCC has improved since the introduction of targeted therapies (TT). We sought to characterize the baseline characteristics, management, and outcomes of pts who survived > 4 yrs from date of diagnosis of metastatic disease (Met Dx). Methods: We retrospectively reviewed medical records of consecutive pts who were diagnosed with mRCC and evaluated at MDACC from 1/1/2001 to 12/31/2008. Descriptive statistics and Kaplan-Meier methods were used to estimate OS times. Results: For 729 mRCC pts identified, median OS was 2.3 years (95% CI: 2.1, 2.5); 219 (30.0%) pts have survived >4 yrs, and 167 (22.9%) pts have survived >5 yrs. For pts diagnosed in the cytokine era (2000 to 2004) median OS was 2.3 yrs (95%CI: 2-2.6) compared to median OS 2.4 yrs (95%CI: 2.0-3.0) for pts diagnosed in the targeted era (2005-2008). Of the 219 pts, 205 pts had adequate baseline information. Conclusions: Since 2000, approximately 30% of mRCC pts have survived >4 yrs and 23% have survived >5 yrs. Patients spent more time on treatment in the targeted compared to the cytokine era. Understanding the health problems and costs long-term survivors face is essential to devise therapeutic and coping strategies. [Table: see text] [Table: see text] [Table: see text]
Societal costs after renal cancer surgery.
Authors: Chang Peter , Renehan Peter , Taylor Kimberly , Dovirak Ostap , McAnally Kyle , Carneiro Arie , Crociani Catrina , Percy Andrew , Wagner Andrew A
Published: February 2017

512

Background: The hospital costs of radical or partial nephrectomy for treatment of confirmed or suspected renal cell carcinoma have been well described. We sought to estimate a previously unreported societal cost of renal cancer surgery by assessing surgery-related time off work (TOW) taken by patients and their caretakers. Methods: To a cohort of 315 subjects enrolled in an IRB-approved prospective renal quality-of-life study who underwent radical or partial nephrectomy at our institution, we administered an occupational survey asking subjects to recall employment status, physical demands at work (sedentary, moderate activity, heavy lifting), income by tax bracket, surgery-related TOW (in days), and caretaker assistance. We excluded subjects who underwent cytoreductive nephrectomy. We estimated potential wages lost using individual income and TOW, and used logistic regression to assess for factors predictive of TOW > 30 days. Results: Of the 108 subjects who responded to the survey, 69 were employed at time of surgery. 4 subjects did not return to work after surgery, all of whom were older than 65. 12 subjects were excluded per the above-described criteria, leaving 53 subjects with complete occupational information. Mean (SD) age was 54. The majority (54%) of subjects had sedentary jobs. Subjects’ time off work ranged from 14 to 88 days; mean (SD) and median (IQR) TOW was 38 (17) and 34 (26-45) days, respectively. Mean potential wages lost for TOW was $10,371 (SD=$7,966). 23 (43%) subjects had at least one caretaker take TOW (mean/median caretaker TOW: 10/5 days, respectively) to assist in post-operative recovery. On univariate and multivariable analysis, age, work physicality, type of surgery (radical vs partial nephrectomy), surgical approach (minimally invasive vs open), income bracket, post-operative complications, or caretaker assistance were not significantly associated with taking > 30 days off from work. Conclusions: Despite advances in minimally invasive surgery, most patients take over one month off from work after renal cancer surgery. Incorporating these societal costs may allow for more comprehensive cost-effectiveness analyses in renal cancer care. Future directions include assessing TOW prospectively in a larger, more diverse cohort.
Does the extent of pelvic lymph node dissection affect long-term survival in men undergoing radical prostatectomy after radiation for adenocarcinoma of the prostate?
Authors: Huynh Danny Long , Henderson Alex , Pokala Naveen
Published: February 2017

67

Background: Salvage prostatectomy (SP) in radiation resistant prostate cancer is feasible in select patients that do not have metastatic disease. The correlation between the extent of pelvic lymph node dissection (PLND) and long-term survival in SP has not been clearly established. This study evaluates the role of PLND on long-term survival outcome in men that underwent radical prostatectomy (RP) following radiation. Methods: SEER 18 registry was searched for patients that underwent RP following radiation for adenocarcinoma of the prostate between 1988 and 2010. The patients were analyzed for demographics, grade and stage, pelvic lymph node status, nodal yield and survival. Patients with metastatic disease, more than one primary cancer and unknown stage were excluded. Results: 364 men were identified. Mean age was 63.6 years and 86.3% were white. Grade differentiation was well (n=12), moderate (n=198), poor (n=150) and unknown (n=4). The T stage was pT2 (n=178), pT3 (n=90) and pT4 (n=96). PLND was performed in 78.6% (n=286) of the patients. The nodal yield was 0-5 (n=75), 6-10 (n=45) and >10 (78). For the 40 patients with positive nodes (PN), 25 (62.5%) had 1 PN, 8 (20%) had 2 PN and 7 (17.5%) had >2 PN. The 10 and 20-year overall survival (OS) was 77.5% and 37.3% and cancer specific survival (CSS) was 88.6% and 72.7%, respectively. The CSS at 20 years was >70% for all grades and stages. On comparison, there was no significant improvement in survival for PLND vs. no PLND (p=0.14) but there was a trend toward improved CSS for patients undergoing PLND. There was no significant improvement (p=0.89) in survival for increasing total nodal yield. CSS at 20 years for N0 and N1 patients was 75% and 65%, respectively. Patients with 0 or 1 PN had similar 20 year CSS of ~75%. Patients with 2 PN had the worst survival with CSS of 30% at 15 years. Conclusions: Good long-term survival can be achieved with RP following radiation therapy. Patients who have node positive disease have similar long-term outcomes to patients that are node negative. However, patients with 2 PN have the worst survival. PLND status and extent of nodal dissection does not significantly confer a survival advantage.