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In the last few years, enhanced understanding of the biology of clear cell renal cell carcinoma has led to the development of molecular signaling inhibitors, which, with their superior anti-tumor activity demonstrated in randomized clinical trials, have led to a paradigm shift in the treatment of advanced renal cell carcinoma from cytokine-based therapy to signaling-inhibitor therapy. Relevant therapeutic signaling pathways that have emerged are VEGF receptor and mammalian target of rapamycin pathways, and signaling inhibitors sunitinib, sorafenib, temsirolimus and, most recently, everolimus are approved by the FDA for treatment of advanced renal cell carcinoma in the USA. Newer agents with promising anti-tumor activity are in continued development, as are efforts to uncover additional therapeutic targets. Currently, the optimal use of available agents, such as sequence and combination strategies, as well as their role in the adjuvant and neoadjuvant setting, remain unclear and investigative efforts are underway.

BACKGROUND: It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE: To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). DESIGN, SETTING, AND PARTICIPANTS: Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). RESULTS AND LIMITATIONS: All patients with LNM had worse PFS (p=0.001) and OS (p

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]

BACKGROUND: The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.OBJECTIVE: To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.DESIGN, SETTING, AND PARTICIPANTS: Retrospective data from patients with synchronous mRCC (n=1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.RESULTS AND LIMITATIONS: Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (pCONCLUSIONS: CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times PATIENT SUMMARY: We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.

Advanced bladder cancer, both muscle-invasive localized disease and metastatic disease, is managed with systemic chemotherapy. Cisplatin-based multi-agent chemotherapy remains the cornerstone for systemic therapy. MVAC (methotrexate-vinblastine-doxorubicin-cisplatin) has been most rigorously studied, both neoadjuvantly and for palliation of metastatic disease. For metastatic disease, cisplatin-gemcitabine (GC) has compared favorably to MVAC due to improved tolerability with similar efficacy. GC has been adopted as standard therapy. Neoadjuvant chemotherapy for muscle-invasive bladder cancer improves survival among those patients eligible to receive cisplatin. Adjuvant chemotherapy is difficult to administer effectively given morbidity of radical cystectomy, and studies have shown mixed results about its benefit. Non-cisplatin regimens have been investigated but remain experimental and reserved for those not candidates for cisplatin in the metastatic setting. While multiple agents have been studied after metastatic disease progression after cisplatin-based therapy, there remain no FDA-approved therapies for the second line. Future trials with anti-VEGF therapy and immunotherapy are actively being investigated. This review examines the systemic therapy available to oncologists with current evidence and future directions.

Purpose The clinical implications regarding the use of statins in patients with end-stage renal disease (ESRD) undergoing hemodialysis are explored. Summary The majority of the evidence reviewed from randomized controlled trials and recent meta-analyses suggest that there is minimal to no benefit of statin therapy for reducing the risk of coronary heart disease (CHD), including cardiovascular events and mortality, for statin-naive patients undergoing hemodialysis. The Kidney Disease Outcomes Quality Initiative (KDOQI) 2003 dyslipidemia guidelines recommended that patients with ESRD receive a statin to reach a goal low-density-lipoprotein (LDL) cholesterol concentration of

In the past decade, metastatic renal cell carcinoma (mRCC) treatment underwent significant advancement that resulted in an unprecedented improvement in the prognosis of this disease. This review will provide an updated review of currently approved treatment options, namely antiangiogenic and immunotherapy, as well as treatment guideline recommended by the National Comprehensive Cancer Network (NCCN). We will summarize studies ongoing in determining prognostic and predictive biomarkers in maximizing therapeutic benefit in the treatment of this disease. Lastly, we will discuss promising agents in clinical testing.

Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non-clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.

GC (cisplatin and gemcitabine) and MVAC (methotrexate, vinblastine, Adriamycin [doxorubicin], and cisplatin) have been the standard systemic chemotherapy in advanced urothelial carcinoma. These regimens have shown significant response rates in this patient population. Nevertheless, disease does recur with most patients who unfortunately do succumb to the disease. Research efforts are focused in several different areas of therapy, targeted therapy, and immunotherapy. Further efforts include those in improving understanding of the molecular biology of urothelial carcinoma which may lead development of biomarkers that may enhance therapeutic index. This paper reviews recent advances in the treatment and ongoing study of molecular biology of urothelial carcinoma.

Castration-resistant prostate cancer is a disease that is fatal in virtually all patients. Docetaxel chemotherapy became the standard front-line agent based on the results of the TAX327 trial in 2004, with a survival advantage of 3 months achieved over mitoxantrone. Over the past few years, an improved understanding of the molecular biology of castration-resistance has resulted in expansion of the treatment armamentarium for advanced prostate cancer with the emergence of novel: androgen receptor-directed therapies, cytotoxic chemotherapies, as well as immunotherapies. Four different agents have very recently gained approval by the US FDA for the treatment of castration-resistant prostate cancer and this review will summarize the development, mechanism of action and safety and efficacy of these agents as demonstrated in preclinical, as well as clinical studies.

Biomarkers that predict response or toxicity to antiangiogenic therapy are sought to favorably inform the risk/benefit ratio. This study evaluated the association of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) genetic polymorphisms with the development of hypertension (HTN) and clinical outcome in metastatic clear cell renal cell carcinoma (MCCRCC) patients treated with sunitinib.Sixty-three MCCRCC patients receiving sunitinib (50 mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. A panel of candidate VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) were evaluated for associations with the development of hypertension and clinical outcome.VEGF SNP -634 genotype was associated with the prevalence and duration of sunitinib-induced hypertension (as defined by systolic pressure ≥150 mmHg and/or diastolic pressure ≥90 mmHg) in both univariable analysis (P = .03 and .01, respectively) and multivariable analysis, which adjusted for baseline BP and use of antihypertension medication (P = .05 and .02, respectively). Patients with the GG genotype were estimated to have a greater likelihood of being hypertensive during treatment compared with patients with the CC genotype (odds ratio of 13.62, 95% confidence interval [CI] 3.71-50.04). No single VEGF or VEGFR SNPs were found to correlate with clinical outcome. However, the combination of VEGF SNP 936 and VEGFR2 SNP 889 were associated with overall survival after adjustment for prognostic risk group (P = .03).In MCCRCC patients treated with sunitinib, VEGF SNP -634 is associated with hypertension and a combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes is associated with overall survival.

BACKGROUND We sought to determine the change of PSA doubling time (PSADT) and its association with disease progression during intermittent androgen deprivation (IAD) therapy for prostate cancer. METHODS Data were retrospectively analyzed in 96 patients with biochemically relapsed prostate cancer (BRPC) treated with IAD since 1995. IAD consisted of LHRH-agonists ± antiandrogen given usually at PSA threshold (ng/ml) of 10–20, for 6–9 months. Cycles were repeated until the development of castration resistance. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify outcome-associated variables. RESULTS Patients received a mean of 2.8 treatment cycles over a mean follow-up time of 71 months. Fifty-seven (59%) remain on treatment and 39 (41%) developed PSA refractoriness (n = 8) or positive scans (n = 31). First off treatment interval PSADT (median 2.3 months) was significantly shorter than the baseline (median 7.34) but remained stable in subsequent cycles. Off treatment interval PSADT adjusted for testosterone recovery (median 3.7) was significantly longer than that based on all PSA determinations (median 2). Factors associated with disease progression were pre-treatment PSADT (≥6 vs.

New dental graduates compete for house surgeon positions every year, despite little being known about the work experience gained from such posts. The main objectives of this study were to identify the nature of house surgeons' work experiences, their continued professional development (CPD) opportunities and the impact of hospital experience on their future career pathways.A questionnaire was mailed to all 31 New Zealand dental house surgeons (response rate 100%).The majority of house surgeons (77.4%) found hospital work enjoyable, with nearly all (93.5%) perceiving themselves as better clinicians from their experience. Oral surgery, restorative dentistry, special needs dentistry and removable prosthodontics were the most commonly practised areas. The average weekly number of working hours was 42.3 hours for a normal week and 61.8 hours for an on-call week. Stress levels during on-call work were significantly higher than during day-to-day hospital work (p0.05). Departmental seminars were reported to be the most common form of CPD available at hospitals (74.2%), followed by hands-on clinical training (61.3%). More than half of the house surgeons (58.1%) planned to pursue a specialist career, with nearly 13% wishing to return to a New Zealand hospital in the future.A dental house surgeon position remains an attractive choice and offers an enjoyable experience for young graduates. Hospitals provide ample CPD opportunities and appear to play an influential role in a house surgeon's career pathway.

Protein arginine N-methyltransferase (PRMT) dimerization is required for methyl group transfer from the cofactor S-adenosyl-L-methionine (AdoMet) to arginine residues in protein substrates, forming S-adenosyl-L-homocysteine (AdoHcy) and methylarginine residues. In this study, we use Förster resonance energy transfer (FRET) to determine dissociation constant (K(D)) values for dimerization of PRMT1 and PRMT6. By attaching monomeric Cerulean and Citrine fluorescent proteins to their N-termini, fluorescent PRMTs are formed that exhibit similar enzyme kinetics to unconjugated PRMTs. These fluorescent proteins are used in FRET-based binding studies in a multi-well format. In the presence of AdoMet, fluorescent PRMT1 and PRMT6 exhibit 4- and 6-fold lower dimerization K(D) values, respectively, than in the presence of AdoHcy, suggesting that AdoMet promotes PRMT homodimerization in contrast to AdoHcy. We also find that the dimerization K(D) values for PRMT1 in the presence of AdoMet or AdoHcy are, respectively, 6- and 10-fold lower than the corresponding values for PRMT6. Considering that the affinity of PRMT6 for AdoHcy is 10-fold higher than for AdoMet, PRMT6 function may be subject to cofactor-dependent regulation in cells where the methylation potential (i.e., ratio of AdoMet to AdoHcy) is low. Since PRMT1 affinity for AdoMet and AdoHcy is similar, however, a low methylation potential may not affect PRMT1 function.

Von Hippel-Lindau syndrome (VHLS) is an autosomal dominant familial cancer syndrome arising from germ-line inactivation of the VHL gene on the short arm of chromosome 3. VHLS manifests in a myriad of hyper-vascular tumors of both benign and malignant nature. Incidence of VHLS is roughly 1 in 36,000 live births and has over 90% penetrance by the age of 65. Improved understanding of the natural history and biology of VHLS has led to the introduction of screening protocols, early interventions and improved treatments, all of which resulted in a substantially improved prognosis for this disease. Further details regardingvariegated molecular pathways and mechanisms ofVHLS are emerging with the subsequent advent of novel treatment protocols that are currently in clinical trials.

Angiogenesis is central to the growth of normal tissues and tumors. Inhibiting this pathway has been a strategy for drug development for tumors not responsive to most agents used in chemotherapy. Notably, signaling mediated by vascular endothelial growth factor (VEGF) is a key target because aberrant signaling via this pathway is frequently associated with neoangiogenesis in tumors. The drug-discovery effort to blunt VEGF signaling has led to the approval of bevacizumab and several receptor tyrosine kinase inhibitors (TKIs) that have shown efficacy in the clinical management of breast, colorectal, lung, and kidney cancer. Understanding the genetic variability in VEGF and VEGF receptor has led to identifying genotypic variations (single nucleotide polymorphisms [SNPs]) associated with treatment outcome and toxicity. Notably, identification of SNPs in VEGF associated with angiogenesis inhibitor treatment-induced hypertension and outcome provides exciting opportunities for personalized medicine to improve outcome and reduced toxicity with these novel TKIs.

Von Hippel-Lindau syndrome (VHLS) is an autosomal dominant familial cancer syndrome arising from germ-line inactivation of the VHL gene on the short arm of chromosome 3. VHLS manifests in a myriad of hyper-vascular tumors of both benign and malignant nature. Incidence of VHLS is roughly 1 in 36,000 live births and has over 90% penetrance by the age of 65. Improved understanding of the natural history and biology of VHLS has led to the introduction of screening protocols, early interventions and improved treatments, all of which resulted in a substantially improved prognosis for this disease. Further details regarding variegated molecular pathways and mechanisms of VHLS are emerging with the subsequent advent of novel treatment protocols that are currently in clinical

Background: Sunitiinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) that is widely used in the front line setting for the treatment of advanced renal cell cancer. As with other targeted agents, there is a significant heterogeneity in the clinical response to sunintib and a biomarker which would predict patients' response up front would be an invaluable tool in the clinical management of patients (pts) afflicted with this disease. In this regard, whole genome methylation array was performed between sunitinib responders and nonresponders to identify differentially methylated genes between these two subsets of pts. Methods: mRCC pts. who received sunitinib therapy with available frozen nephrectomy tissues and clinical data were identified. Responders (RES) were identified as patients with progression free survival (PFS)of >11 months (mos) and nonresponders (NRES) as those with PFS Results: Thirteen pts treated with sunitinib for mRCC with available frozen nephrectomy tissues as well as clinical data were identified. Five were selected for each RES and NRES cohort as described above. Three pts had PFS that ranged between 3-11 mos (INT). All pts. In RES had clear cell subtype. Two of the NRES group were of non-clear cell type. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of Conclusion: In this study, DENND2D was significantly hypermethylated in sunitinib RES vs. NRES in mRCC pts. Technical and clinical validation of DENND2D and the other 4 differentially methylated genes are planned as is immunohistochemistry study of DENND2D to evaluate downstream effects of methylation. Citation Format: Jenny Kim, Mariette Labots, Henk Verheul, Michael Carducci, Shahnaz Begum, George Netto, Mohammad Hoque. Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer patients (pts). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A18.

Retinal neovascularization is a leading cause of human blindness. However, little is known concerning the molecular mechanisms controlling retinal neovascularization in vivo. Here we provide evidence that exposure of a collagen type IV cryptic epitope detected by monoclonal antibody (mAb) HUIV26, delineates sites of vascular bud formation and represents one of the earliest structural remodeling events required before vessel out-growth. Exposure of these cryptic sites was inhibited in matrix metalloproteinase (MMP)-9-deficient but not MMP-2-deficient mice implicating MMP-9 in their exposure. Retinal endothelial cell interactions with the HUIV26 epitopes induced endothelial cell migration, which was blocked by mAb HUIV26. Importantly, subcutaneous administration of mAb HUIV26 potently inhibited retinal angiogenesis in vivo. Taken together, these findings suggest a novel mechanism in which MMP-9 facilitates exposure of HUIV26 cryptic sites, thereby promoting retinal endothelial cell migration and neovascularization in vivo.

Objective To assess the insulin-like growth factor-1 receptor (IGF1R) expression in urothelial carcinoma (UC) and its prognostic role in relation to clinicopathologic parameters. Methods A total of 100 cases of invasive UC were evaluated using tissue microarrays. Membranous IGF1R staining was evaluated using immunohistochemistry. A scoring method analogous to that of HER2 expression in breast carcinoma was used, and the highest score was assigned in each tumor. IGF1R was considered overexpressed in cases with score ≥1. Results We found IGF1R overexpression in 62% of invasive UC. IGF1R overexpression was associated with race ( P = .04) and pT category ( P = .03). Median follow-up was 29 months (range, 0.5-212). Progression rate was 60%, and overall mortality and cancer-specific mortality rates were 69% and 51%, respectively. In invasive UC, IGF1R overexpression was significantly associated with overall mortality and cancer-specific mortality (Mantel Cox P = .0002 and P = .006, respectively). IGF1R overexpression was associated with increased hazard ratios (HRs) for overall mortality (HR = 2.63, P = .001) and cancer-specific mortality (HR = 2.45, P = .01), independently and after adjusting for clinicopathologic features and treatment modalities. Conclusion We found IGF1R overexpression in 62% of bladder UC. More importantly, IGF1R overexpression was a significant predictor of overall mortality and cancer-specific mortality, suggesting its potential role as a prognosticator in UC of bladder.

Aim: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging activity in mRCC. This trial assessed immunomodulatory activity, antitumor response, and safety of nivolumab in patients (pts) with mRCC. Methods: 91 pts received nivolumab IV Q3W: previously treated pts (1-3 prior therapies; ≥1 anti-angiogenic agent) received 0.3 (n = 22), 2 (n = 22), or 10 mg/kg (n = 23); untreated pts received 10 mg/kg (n = 24). Fresh biopsies and serum were obtained at baseline (BL) and at nivolumab cycle 2 day 8 (C2D8; biopsy) and cycle 4 day 1 (C4D1; serum). The primary objective assessed immunomodulatory activity of nivolumab on serum chemokines (CXCL9, CXCL10) and tumor T cell infiltrates from BL to posttreatment. Secondary/exploratory objectives included safety, antitumor activity (ORR, RECIST 1.1; PFS), BL and treatment-induced changes in PD-1 ligand (PD-L1) expression (Dako immunohistochemistry assay; PD-L1 positivity: >5% tumor membrane staining at any intensity) and association of clinical activity with BL PD-L1 expression. Results: T cell infiltrates increased by a median of 70% (CD3 + ; range 53-220%) and 88% (CD8 + ; 61-257%) from BL to C2D8. Mean increase from BL to C4D1 was 180% for CXCL9 and 79% for CXCL10. In evaluable pts ORR was 17% (15/90); 18% previously treated, 13% untreated pts. Median duration of response was 64 weeks; 6 (43%) responses are ongoing. PFS rate at 48 wks was 18% (16/90). Grade 3-4 AEs occurred in 15% (14/91): colitis and elevated AST (n = 2 each), diarrhea, elevated ALT and pneumonitis (n = 1 each). Of 56 evaluable pretreatment biopsies, 18 (32%) were PD-L1+. ORR was 22% (4/18) for PD-L1+ pts vs 8% (3/38) for PD-L1–. In 5/27 (19%) matched biopsy pairs PD-L1 expression increased >5% by C2D8. Conclusions: In this prospective study, changes in biomarkers were consistent with PD-1 inhibition, evidence of nivolumab's immunomodulatory effects in serum and the tumor microenvironment. Nivolumab demonstrated antitumor activity and manageable safety in pts with previously treated or untreated mRCC. Responses were numerically higher in PD-L1+ pts, but also present in PD-L1– pts. Disclosure: T. Choueiri: Ad Board: Pfizer, Novartis, GSK, Bayer, Aveo Research: Pfizer; M.N. Fishman: I have received funding for research trials from Bristol Myers Squibb; B. Escudier: I have received compensation for consultation/ advisory position to the following: Bayer, Pfizer, Novartis I have received honoraria from the following: Bayer, Roche, Pfizer, Genentech, Novartis, AVEO, GSK; W.M. Stadler: University of Chicago/I has received funding for research from Bristol Myers-Squibb; J.L. Perez-Garcia: I have received funding for research from Bristol Myers Squibb; M.R. Harrison: I have consulted/worked in advisory role to: Novartis, AVEO, Exelixis, Bayer; I have received honoraria from: Novartis, Prometheus; I have received funding for research from: BMS, Argos, Exelixis, Pfizer, Exelixis; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; L. Appleman: I have received funding from Bristol Myers-Squibb; L. Fong: I have received funding for research from Bristol Myers-Squibb; C.G. Drake: Sponsored Research: Aduro Biotech, BMS, Janssen, I have consulted to: BMS, Compugen, Dendreon, Pfizer, Roche/ Genentech, NexImmune; L. Cohen: I am an employee of Bristol Myers Squibb; S. Srivastava: I am an employee of Bristol Myers Squibb; M. Jure-Kunkel: I am an employee of and have stock or other ownership interest in BMS; Q. Hong: I am an employee of and have stock or other ownership interest in BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; M. Sznol: I have received personal Fees from BMS, Amgen, Medimmune, Genentech, Symphogen, Nektar, Anaeropharma, Immune Design, Merus, Lion Biotechnologies, Kyowa-Kirin, Astra-Zeneca-Medimmune. All other authors have declared no conflicts of interest.

470 Background: The neutrophil to lymphocyte ratio (NLR) is a marker of host inflammation and appears to have prognostic value in many solid tumors. We have found in a pilot RCC study that a NLR > 2.5 was predictive of a lower likelihood of response to TT on a multivariable analysis. Here we aim to explore the added value of the NLR to improve the prognostic value of the established IMDC criteria (Heng et al JCO 2009). Methods: We included patients from 7 consortium sites where NLR data was available for patients treated with TT and compared NLR cutoff 2.5 (i.e. low vs. high NLR) and adjusted using proportional hazards regression for the known poor prognostic criteria (listed in Table). Results: Data from 859 patients were included. NLR values were: Mean 4.98, Median 3.51, Mode 2.5, 95%CI 1.42 – 14.0. Using Cutoff 2.5 Median overall survival (OS) is 30.4 months (95%CI 24.9-37.0, n= 237) vs. 15.7 months (95%CI 13.0-17.2, n=622); log-rank p value

396 Background: The role of cytoreductive nephrectomy is unclear in patients with synchronous metastases from renal cell carcinoma (RCC) in the age of targeted therapy. Methods: Comparisons were made between patients treated with targeted therapy who had a CN versus not and adjusted using proportional hazards regression for known poor prognostic criteria (IMDC criteria Heng et al JCO 2009). Results: 2569/3245 (79%) mRCC patients received a nephrectomy. Patients who had nephrectomy before the diagnosis of metastatic disease were excluded (n=1634). Among the remaining patients, 935 patients had a CN and 676 patients did not have nephrectomy. All patients received targeted therapy with the majority receiving first-line sunitinib 72%, sorafenib 15%, temsirolimus 5%, bevacizumab 3%, pazopanib 3%. Patients who had CN had better IMDC prognostic profiles versus those without (favorable/intermediate/poor in 9%/63%/28% vs 1%/45%/54% p

The extracellular matrix (ECM) plays a fundamental role in the regulation of normal and pathological processes. The most abundantly expressed component found in the ECM is collagen. Triple helical collagen is known to be highly resistant to proteolytic cleavage except by members of the matrix metalloproteinase (MMP) family of enzymes. To date little is known concerning the biochemical consequences of collagen metabolism on human diseases. This is due in part to the lack of specific reagents that can distinguish between proteolyzed and triple helical forms of collagen. Here we used the technique of Subtractive Immunization (SI) to generate two unique monoclonal antibodies (MAbs HUIV26 and HUI77) that react with denatured and proteolyzed forms of collagen, but show little if any reaction with triple helical collagen. Importantly, HUIV26 and HUI77 react with cryptic sites within the ECM of human melanoma tumors, demonstrating their utility for immunohistochemical analysis in vivo. Thus, the generation of these novel MAbs not only identify specific cryptic epitopes within triple helical collagen, but also provide important new reagents for studying the roles of collagen remodeling in normal as well as pathological processes.

4566 Background: There exists a significant heterogeneity in the clinical response to sunitinib among pts treated for mRCC and, thus, a biomarker which would predict pts’ response up front would be an invaluable tool in the clinical management of these pts. In this regard, whole genome methylation array was performed between 2 extreme groups: sunitinib responders (RES) and non-responders (NRES) to identify differentially methylated genes between these subsets of pts. Methods: mRCC pts who received sunitinib therapy with available frozen nephrectomy tissues (stored at -80°C) and clinical data were identified. RES were identified as pts with progression free survival (PFS) of > or =11 months (mos) and NRES as those with PFS < or = 3 mos. After DNA extraction and quality assurance according to standard protocol, whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit - Illumina. Data normalization was achieved by subset-quantile within array normalization (PMID: 22703947). Differentially methylated regions were identified using logit transformed Beta values, using an F-test after shrinking variance via empirical Bayes (PMID: 21118553). Results: Total of 13 pts who received sunitinib therapy with available frozen nephrectomy tissues were identified. Of the 13, 5 pts qualified for each RES and NRES cohort as described in methods section. All pts in RES group had clear cell subtype. Two pts of the NRES group were of non-clear cell subtype. The QC plots showed that all arrays were successful. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of

4523 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed in several tumors including UC and is currently under investigation as a target of Rx. We here explore IGF1R expression in UC, its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered overexpressed in cases with score 1. Endpoints of the study included overall survival (OS) and disease-specific survival (DSS). Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R OE was found in 62% of UC. No differences were noted between normal urothelium and UC regarding IGF1R OE (74% vs. 60%; P=0.14). IGFR1 OE was more frequent in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). Tumors at stage pT4 overexpressed IGF1R more frequently than tumors at stages pT1-pT3 (71% vs. 29%, P=0.005). No association with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis) was found. OS and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients with tumors overexpressing IGF1R had a lower OS and DSS compared to those without IGF1R OE (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R OE remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: OE of IGF1R was found in 62% of UC. High stage tumors overexpressed IGF1R more frequently than low stage tumors. Further, IGF1R OE was a significant independent predictor of OS and DSS in invasive UC.

416 Background: Preliminary data support that B7H1 expression is associated with objective response (OR) to anti-PD-1 antibody treatment in multiple solid tumors. The aim of this study was to retrospectively evaluate a possible association between B7H1 expression and clinical response to sunitinib therapy in mRCC patients. Methods: mRCC patients receiving sunitinib therapy (50mg 4/2) were identified and data regarding patient characteristics and clinical outcome to sunitinib were recorded. Immunohistochemistry (IHC) staining of B7H1 was done on pretreatment formalin fixed paraffin embedded (FFPE) tissue sections according to available protocol at Hopkins. IHC scorings were done by 2 independent pathologists who were blinded to outcomes and a 3rd pathologist was used if there was a discrepancy between the first 2. Association of B7H1 expression with OR was assessed using Fisher’s exact test. Progression free survivals (PFS) were estimated using the Kaplan-Meier method and compared using log-rank test. Multivariate analyses were performed using logistic regression and Cox regression. Results: 20 cases were identified of which 18 had available FFPE for IHC analysis. 78% were male; median age was 55 (range 35-79); 72% ECOG PS of 0; 94% had prior nephrectomy; 89% were therapy naïve. 50% were intermediate risk category according to Heng criteria and the rest were poor risk. 55.6% (10/18) were positive for B7H1 expression (>5% positive cell membranous staining). 30% of B7H1 positive patients had OR whereas 50% of B7H1 negative patients had OR (p = 0.63). Median PFS were 19.3 and 6.2 mos for B7H1 negative and positive groups, respectively (p = 0.56). In multivariate models, B7H1 expression was neither associated with OR (odds ratio = 0.54, 95% CI = 0.07-4.23, p = 0.56) nor PFS (hazard ratio =1.06, 95% CI = 0.34-3.34, p = 0.92) after adjusting for Heng risk classification. Conclusions: In this study, B7H1 expression was not associated with clinical outcome to sunitinib therapy in metastatic RCC patients.

280 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed (OE) in several tumors including bladder cancer and is currently under investigation as a target of Rx. Here we explore IGF1R expression in urothelial carcinoma (UC), its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered OE in cases with score 1. Endpoints of the study included overall survival and cancer-specific survival. Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R was OE in 62% of UC. No differences were noted between normal urothelium and malignant counterparts (74% vs. 60%; P=0.14). IGFR1 was more frequently OE in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). pT4 tumors OE IGF1R more frequently than pT1-pT3 tumors (71% vs. 29%, P=0.005). No association was found with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis). Overall survival (OS) and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients whose tumors OE IGF1R had a lower OS and DSS compared to those whose tumors did not OE IGF1R (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R overexpression remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: Overexpression of IGF1R was found in 62% of UC. High stage tumors OE IGF1R more frequently than low stage tumors. More importantly, IGF1R overexpression was a significant independent predictor of OS and DSS.

TPS2613 Background: With the enhanced understanding of the immune response to a tumor, new immunotherapeutic agents may expand treatment options for metastatic renal cell carcinoma (mRCC). The programmed death-1 (PD-1) receptor is upregulated by activated lymphocytes, and upon binding to its ligands, inhibits lymphocyte function. In a phase 1 study of the anti-PD-1 monoclonal antibody BMS-936558, encouraging antitumor activity has been observed in patients with previously treated mRCC. Responses occurred in extensive mRCC and were durable in many patients. Here we describe an exploratory study to investigate the immune-regulatory activity of various doses of BMS-936558 in patients with metastatic clear-cell RCC. Methods: Eighty patients with metastatic clear-cell RCC will be enrolled in this open-label, parallel group, randomized study. Patients who have received prior treatment with ≥3 therapies, including ≥1 anti-angiogenic therapy, will be enrolled in Arms 1-3 (~20 patients per arm); 20 treatment-naïve patients will be enrolled in Arm 4. BMS-936558 will be administered every 3 weeks until disease progression or unacceptable toxicity at 0.3 mg/kg (Arm 1), 2 mg/kg (Arm 2), and 10 mg/kg (Arms 3 and 4). Patients in the 0.3-mg/kg group may escalate to 2 mg/kg if not responding. Tumor assessments will occur every 6 weeks for the first 12 months then every 12 weeks for the remainder of the study. The primary objective is to evaluate the effects of BMS-936558 on the frequency of circulating immune cell subsets, levels of soluble factors associated with immune responses, and tumor infiltrating lymphocyte populations (based on pre-treatment and week 5 paired biopsies). Secondary objectives are to assess the safety, tolerability, antitumor activity, and immunogenicity of BMS-936558. Exploratory objectives include the association of clinical activity and safety with selected biomarkers in peripheral blood and tumor microenvironment and the characterization of the pharmacokinetics of BMS-936558. As of February 1, 2012, 30 patients were enrolled.

e19570 Background: In comparative trials of P and F, bone and joint pain are evident and with similar incidences. Also, muscle pain is clinically noted. Pain severity may differ between P and F, especially when a short fixed-dose regimen of F is used. Methods: This is a prospective observational and ethics-approved study. It compares the incidence & severity of muscle and/or joint pain (MJP) in patients (pts) receiving P (6mg SC for 1 day) or fixed-dose F (300mcg SC for 7-8 days) initiated 24 hours after chemotherapy. Eligible were women with breast cancer receiving neo- or adjuvant chemotherapy, and P or F. Choice of P or F were at the oncologist’s discretion based on patient preference & insurance coverage. Pts were ineligible if they could not complete the pain diary, or had received P or F in the past 6 months. Efficacy of P and F was evaluated by comparing febrile neutropenia (FN) and neutropenia (N) requiring delay of the second cycle of chemotherapy. Patient & treatment characteristics were captured to assess for risk factors for developing MJP. A pain diary assessed MJP severity, its management and impact on everyday activities. It was completed starting the evening of chemotherapy for 14 consecutive days. Statistical analysis was performed with Stata 12, including multi-level longitudinal mixed models for MJP scores. Results: 140 pts were enrolled with mean age 52 yr and 58% receiving docetaxel-based chemotherapy. One-third received F and two-thirds received P. Both diary muscle and joint pain peaked in prevalence and severity on days 3 to 6. Over 50% of pts reported MJP at the peak. Pain that increased ≥3 points from baseline was reported by 48% of pts. Daily activities were affected in 48% of 1,960 reporting-days, with 26% reporting moderate or severe impairment. Despite similar incidences of pain, P was associated with lower mean muscle (p=0.0049) and joint (p=0.014) pain scores by regression analyses. FN and N were not different. Use of docetaxel was the sole baseline risk factor for developing MJP. Conclusions: Patients experience substantial MJP with impairment of daily activities but pts receiving pegfilgrastim experience less pain and less burden relating to pain.

e15006 Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD un...

4621 Background: Sunitinib is a standard tx for mRCC. The NLR, an index of systemic inflammation, is associated with recurrence of non mRCC and poor prognosis in several types of cancer. We set out...

4576 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of pr...

e15007 Background: Intracrine conversion of adrenal androgens to testosterone play an important role in CRPC progression. Treatments (tx) that block adrenal steroid synthesis have shown significant...

317 Background: The VEGFR inhibitor sunitinib is a standard tx for mRCC. ASIs include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). ASIs are used in the tx of hypertension (HTN), kidney disease, and heart failure. Preclinical and clinical studies in several cancer types have shown that they may inhibit tumor growth. Their effect on the outcome of sunitinib in mRCC is poorly defined. Aims: to study the effect of ASIs on the outcome sunitinib tx for mRCC. Methods: We performed a retrospective study of an unselected cohort of pts with mRCC, who were treated with 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest. Pts were divided into 2 groups: (1) ASIs users and (2) ASIs naive. The effect of ASIs use on objective response, time to progression (TTP), and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chisquare test and partial likelihood test from cox model. Results: Between 2004–2010, 124 pts with mRCC were treated with sunitinib. There were 44 ASIs users (group 1) and 80 nonusers (group 2). With regard to sunitinib tx initiation time, 39 users started ASIs before, 3 within 1 month, and 2 after 5 months. The groups were balanced regarding the following known clinical prognostic factors: past nephrectomy, RCC histology, time from diagnosis to tx, ≥ 2 metastatic sites, lung/liver/bone metastasis, ECOG performance status, Hb level, corrected ca > 10 mg/dL, platelets count, prior cytokines/ targeted tx, sunitinib induced HTN, % pts that had dose reduction/tx interruption, and mean dose/cycle. Objective response in group 1 vs. 2 was partial response (PR) 48% vs 38% (p=0.24), stable disease (SD) 38% both, and progressive disease (PD) 14% vs. 24% (p=0.19). Median TTP was 12 vs. 6 ms (HR 0.635 in ASIs users, p=0.034). Median OS was 25 vs. 22 ms (p=0.3). Conclusions: ASIs may improve the outcome of pts with mRCC that are treated with sunitinib. This should be investigated prospectively, and if validated, applied in clinical practice and clinical trials. No significant financial relationships to disclose.

4629 Background: We previously reported that VEGF SNP-634 is associated with development of sunitinib-induced HTN in mccRCC pts (J Clin Oncol 27:15s, 2009). We have now expanded this analysis to include a panel of established SNPs within VEGF [-2578 C/A (rs 699947), -1154 G/A (rs 1570360), 936 C/T (rs 3025039)] and VEGFR2 [889 G/A (rs 2305948), 1416 A/T (rs 1870377)]. We tested the hypothesis that VEGF and VEGFR2 SNPs differ for association with HTN and CO [tumor shrinkage (TS), progression-free survival (PFS) and overall survival (OS)] in mccRCC pts receiving sunitinib. Methods: mccRCC pts receiving sunitinib (50mg 4/2) with germline DNA were retrospectively identified. Genomic DNA was isolated from peripheral blood lymphocytes and amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data was analyzed using the Wilcoxon rank sum and Cochran-Armitage trend tests, and proportional hazards models. Results: Sixty-four pts were id...

5005 Background: VEGF SNPs (-634 C/C and -1498 T/T) have been associated with protection from grade III/IV HTN in breast cancer pts receiving bevacizumab plus paclitaxel (J Clin Oncol. 26:4672–4678). The aim of this study was to retrospectively evaluate the association among VEGF SNPs and the development of HTN in mRCC pts receiving sunitinib. Methods: mRCC patients receiving sunitinib (50mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. All BP measurements were recorded in clinic approximately every 4 weeks. Genomic DNA was isolated from peripheral blood lymphocytes. VEGF SNP's -634 C/G (5’UTR polymorphism, NCBI reference sequence #2010963), and -1498 C/T (promoter polymorphism NCBI reference sequence #833061) were amplified using primers designed to flanking sequences for the respective SNPs. Genotypes were assigned following sequence analysis. Data were analyzed using parametric and non-parametric methods. Results: Sixty-four patients were identified of which 63 had available SNP data; 78% were male; median age was 60 (range 35–80); 67% ECOG performance status of 0; 89% prior nephrectomy and 63% previously treated with cytokines (48%) and/or a TKI (24%). Median systolic and diastolic BPs at baseline were 139 mmHg (range, 93–190) and 80 mmHg (range, 47–103), respectively; 57% of patients were being treated with anti-hypertensive therapies at baseline. The distribution of pts for the VEGF-634 genotype was C/C (10%), C/G (33%) and G/G (57%). VEGF-634 C/C < C/G < G/G genotypes were associated with increasing frequency and duration of HTN (diastolic > 90 mmHg and/or systolic > 150 mmHg) during treatment with sunitinib (p = 0.03 and p = 0.007, respectively) and remained significant adjusting for baseline BP and use of anti-HTN meds (p = 0.05 and 0.02, respectively). Similar correlations were not found for VEGF-1498 genotypes. There was no association between VEGF SNPs and tumor volume reduction or PFS. Conclusions: VEGF SNP-634 G/G genotype is correlated with HTN during treatment with sunitinib in mRCC pts. [Table: see text]

Germ cell tumors (GCTs) account for 95% of testicular cancers. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past 2 decades. Testicular GCTs are classified into 2 broad groups--pure seminoma and nonseminoma--which are treated differently. Pure seminomas, unlike nonseminomas, are more likely to be localized to the testis at presentation. Nonseminoma is the more clinically aggressive tumor associated with elevated serum concentrations of alphafetoprotein (AFP). The diagnosis of a seminoma is restricted to pure seminoma histology and a normal serum concentration of AFP. When both seminoma and elements of a nonseminoma are present, management follows that for a nonseminoma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Testicular Cancer outline the diagnosis, workup, risk assessment, treatment, and follow-up schedules for patients with both pure seminoma and nonseminoma.

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Using the PHANGS-ALMA CO (2-1) survey, we characterize molecular gas properties on ${\sim}$100 pc scales across 102,778 independent sightlines in 70 nearby galaxies. This yields the best synthetic view of molecular gas properties on cloud scales across the local star-forming galaxy population obtained to date. Consistent with previous studies, we observe a wide range of molecular gas surface densities (3.4 dex), velocity dispersions (1.7 dex), and turbulent pressures (6.5 dex) across the galaxies in our sample. Under simplifying assumptions about sub-resolution gas structure, the inferred virial parameters suggest that the kinetic energy of the molecular gas typically exceeds its self-gravitational binding energy at ${\sim}$100 pc scales by a modest factor (1.3 on average). We find that the cloud-scale surface density, velocity dispersion, and turbulent pressure (1) increase towards the inner parts of galaxies, (2) are exceptionally high in the centers of barred galaxies (where the gas also appears less gravitationally bound), and (3) are moderately higher in spiral arms than in inter-arm regions. The galaxy-wide averages of these gas properties also correlate with the integrated stellar mass, star formation rate, and offset from the star-forming main sequence of the host galaxies. These correlations persist even when we exclude regions with extraordinary gas properties in galaxy centers, which contribute significantly to the inter-galaxy variations. Our results provide key empirical constraints on the physical link between molecular cloud populations and their galactic environment., 9 pages + appendices, ApJL in press. Data tables available at https://www.canfar.net/storage/list/phangs/RELEASES/Sun_etal_2020b