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An important hallmark of cancer is ‘metabolic reprogramming’ or the rewiring of cellular metabolism to support rapid cell proliferation [1–5]. Metabolic reprogramming through oncometabolite-mediated transformation or activation of oncogenes in renal cell carcinoma (RCC) globally impacts energy production as well as glucose and glutamine utilization in RCC cells, which can promote dependence on glutamine supply to support cell growth and proliferation [6, 7]. Novel inhibitors of glutaminase, a key enzyme in glutamine metabolism, target glutamine addiction as a viable treatment strategy in metastatic RCC (mRCC). Here, we review glutamine metabolic pathways and how changes in cellular glutamine utilization enable the progression of RCC. This overview provides scientific rationale for targeting this pathway in patients with mRCC. We will summarize the current understanding of cellular and molecular mechanisms underlying anti-tumor efficacy of glutaminase inhibitors in RCC, provide an overview of clinical efforts targeting glutaminase in mRCC, and review approaches for identifying biomarkers for patient stratification and detecting therapeutic response early on in patients treated with this novel class of anti-cancer drug. Ultimately, results of ongoing clinical trials will demonstrate whether glutaminase inhibition can be a worthy addition to the current armamentarium of drugs used for patients with mRCC.

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, &ldquo, clinical benefit&rdquo, was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

Significant developments in the global economy and information technology have been accompanied by a transformation in the nature and process of knowledge production and dissemination. Concepts such as the knowledge economy or creative economy have been formulated to accommodate the new and complex developments in knowledge, creativity, economy, and technology. While much of the current literature on the knowledge and creative economy substantially reflects the economic impact of knowledge and creativity, previous studies have rarely touched upon the role of translation in this development. By discussing the role of translation as a generative process in the creative economy and its implications for crossing boundaries in education, this paper argues that translation plays a significant role in the creation of a hybrid milieu. This dynamic cultural hybridity is stimulated by the circulation of knowledge and information via translation, but is also, per se, a driver inviting greater engagement of i...

Introduction: Transnasal endoscopy is commonly performed in an outpatient otolaryngology setting. Patients are typically administered a topical anesthetic and decongestant prior to this procedure to alleviate discomfort and improve visualization. There is no consensus on which topical anesthetic is most effective in optimizing patient experience during the procedure. Objective: To determine whether there is a difference in the efficacy between atomized 2% tetracaine and 4% lidocaine as a topical anesthetic prior to transnasal endoscopy. Study Design: Prospective, randomized, double-blind study. Methods: A total of 99 patients received oxymetazoline and were randomized to receive either 2% tetracaine or 4% lidocaine prior to transnasal endoscopy. Immediately following the procedure, participants completed a survey assessing level of discomfort and other adverse symptoms pertaining to the procedure using a 10-point visual analog scale (VAS). Results: There were no significant differences in VAS scores between the lidocaine and tetracaine groups. There were also no significant differences between genders in overall VAS scores and in the lidocaine and tetracaine subgroups. Older patients demonstrated significantly less discomfort or a sensation of bad taste overall. In contrast to patients receiving lidocaine, older patients receiving tetracaine experienced significantly less overall pain and discomfort, unpleasant taste, and dyspnea. Conclusion: In patients undergoing transnasal endoscopy, use of either 2% tetracaine or 4% lidocaine has similar effect. Tetracaine may be a better choice in older patients, however.

e16569Background: Multiple targeted therapies (TT) against the VEGFR, mTOR and PD-1 pathways exist to treat metastatic renal cell carcinoma (mRCC). Due to a lack of biomarkers, current practice rel...

e16072 Background: While targeted therapies have significantly changed clinical practice for metastatic renal cell carcinoma (RCC), the economic burden of these drugs is increasing without concomitant advances in strategies for choosing among such agents. We present a model of cost savings using a hypothetical biomarker panel of early response to guide selection of targeted and immune therapies in metastatic RCC patients. Methods: Using the Stanford RCC Outcomes database, we identified patients diagnosed with metastatic RCC who received any of the following: sunitinib, pazopanib, axitinib, sorafenib, cabozantinib, nivolumab, lenvatinib & everolimus, temsirolimus from 2003 through 2016 at Stanford Cancer Center. Primary outcomes included short-term and long-term costs of treatment according to standard-of-care imaging criteria. Drug costs were inferred from the 2017 Veterans Affairs Federal Supply Schedule pricing in USD. A hypothetical biomarker cost was set at $4,620—the current market price of an actively employed diagnostic test in breast cancer, OncotypeDX. These parameters were combined in a Markov model to simulate patient treatment courses and to assess the impact of an early response biomarker on drug expenditures. Results: 370 patients received a range of one to six lines of successive therapy. 170 (45.9%) were long-term patients with cumulative drugs costs totaling $31 million, or on average $185,362 per patient, and $104,521 per individual line of therapy received. 200 (54%) were short-term patients who received less than 3 months of targeted therapy. The costs of such potentially ineffective treatment totaled $4.1 million, or $15,455 per patient per individual line of therapy received. Application of an early biomarker panel at the outset would result in a potential cost savings of up to $6,215 per patient. Conclusions: Bothmetastatic RCC patients and payers suffer high costs from ineffective therapy. Our findings suggest an economic benefit for developing biomarker panels to predict early therapeutic response. Such biomarkers can result in immediate cost savings, and possibly improved quality-of-life for those liberated from unnecessary drug toxicity.

496 Background: We need biomarkers of response to guide treatment decisions in RCC. Our pilot study uses perfusion CT to assess early changes in tumor vascularity in response to targeted therapies. We will determine if perfusion CT measurements can help predict response to therapy after 1 week of treatment in patients with metastatic RCC. Methods: Nine patients with metastatic renal cell carcinoma treated with targeted therapy have been enrolled to date. CT perfusion measures were collected: (1) prior to treatment, (2) 7-10 days after start of treatment, and (3) 12 weeks after start of treatment. At each time point, 5 measures were analyzed: (1) blood volume (BV), (2) blood flow (BF), (3) mean transit time (MTT), (4) flow extraction product (FEP), and (5) tumor size. Clinical response was determined based on RECIST criteria. Univariate and multivariate logistic regression analyses were conducted to determine the association of the CT perfusion measures and clinical response. The relationship between clinical response and individual measure at each time point, change in each measure at each time point, and the rate of change over the measure across all time points (slope) were evaluated in each patient. Results: We found that two blood volume measurements are associated with outcome. 5/9 (56%) patients had stable disease and 4/9 (44%) had progressive disease. Decrease in blood volume from time prior to treatment to 7-10 days after start of treatment was significantly associated with decreased odds of having stable disease (OR 0.63 (0.4-0.99), p=0.04). When examining the rate of change, the slope of blood volume was significantly associated with decreased odds of having stable disease (OR 0.52 (0.27-1.01), p=0.05). Univariable logistic regression for each individual CT measure, FEP prior to treatment (OR 1.07 (0.99-1.15), p=0.08) and 12 weeks after treatment (OR 1.13 (0.99-1.29), p=0.06) were not significantly associated with stable disease. Conclusions: Changes in blood volume including absolute difference as well as rate of change of blood volume were statistically significantly different between patients with stable disease versus progressive disease. Clinical trial information: NCT01926990.

Introduction: CT-guided, frameless radiosurgery (SRS) is an alternative treatment to traditional catheter-angiography targeted, frame-based methods for intracranial arteriovenous malformations (AVMs). Despite the widespread use of frameless radiosurgery for treating intracranial tumors, its use for treating AVM is not well described. Methods: Patients who completed a course of single fraction SRS at The University of North Carolina or Georgetown University between 4/1/2005 – 4/1/2011 with single fraction SRS and received at least one follow-up imaging study were included. All patients received pre-treatment planning with CTA ± MRA and were treated on the CyberKnife (Accuray) radiosurgery system. Patients were evaluated for changes in clinical symptoms and radiographic changes evaluated with MRI/MRA and catheter-angiography. Results: 26 patients, 15 male and 11 female, were included in the present study at a median age of 41 years (IQR, 26-55 years). The Spetzler Martin grades of the AVMs included seven Grade I, twelve Grade II, six Grade III, and one Grade IV with fourteen (54%) of the patients having a pre-treatment hemorrhage. Median AVM nidal volume was 1.62cm3 (IQR, 0.57-8.26 cm3) and was treated with a median of 1900 cGy to the 80% isodose line. At median follow-up of 25 months (IQR, 19-36 months), 15 patients had a complete closure of their AVM, 6 patients had a partial closure, and 5 patients were stable. Time since treatment was a significant predictor of response, with patients experience complete closure having on average 11 months more follow-up than patients with partial or no closure (p = 0.03). One patient experienced a post-treatment hemorrage at 22 months. Conclusions: Frameless SRS can be targeted with non-invasive MRI/MRA and CTA imaging. Despite the difficulty of treating AVM without catheter angiography, early results with frameless, CT-guided SRS suggest that it can achieve similar results to frame-based methods at these time points.

Published data suggests that wedge resection for stage I non-small cell lung cancer (NSCLC) is associated with improved overall survival compared to stereotactic body radiation therapy. We report CyberKnife outcomes for high-risk surgical patients with biopsy-proven stage I NSCLC. PET/CT imaging was completed for staging. Three-to-five gold fiducial markers were implanted in or near tumors to serve as targeting references. Gross tumor volumes (GTVs) were contoured using lung windows; the margins were expanded by 5 mm to establish the planning treatment volume (PTV). Treatment plans were designed using a mean of 156 pencil beams. Doses delivered to the PTV ranged from 42 to 60 Gy in three fractions. The 30 Gy isodose contour extended at least 1 cm from the GTV to eradicate microscopic disease. Treatments were delivered using the CyberKnife system with tumor tracking. Examination and PET/CT imaging occurred at 3 month follow-up intervals. Forty patients (median age 76) with a median maximum tumor diameter of 2.6 cm (range, 1.4–5.0 cm) and a mean post-bronchodilator percent predicted forced expiratory volume in 1 s (FEV1) of 57% (range, 21–111%) were treated. A median dose of 48 Gy was delivered to the PTV over 3–13 days (median, 7 days). The 30 Gy isodose contour extended a mean 1.9 cm from the GTV. At a median 44 months (range, 12–72 months) follow-up, the 3 year Kaplan–Meier locoregional control and overall survival estimates compare favorably with contemporary wedge resection outcomes at 91 and 75%, respectively. CyberKnife is an effective treatment approach for stage I NSCLC that is similar to wedge resection, eradicating tumors with 1–2 cm margins in order to preserve lung function. Prospective randomized trials comparing CyberKnife with wedge resection are necessary to confirm equivalence.

Standard treatment for operable patients with single peripheral lung metastases is metastasectomy. We report mature CyberKnife outcomes for high-risk surgical patients with biopsy proven single peripheral lung metastases. Twenty-four patients (median age 73 years) with a mean maximum tumor diameter of 2.5 cm (range, 0.8–4.5 cm) were treated over a 6-year period extending from September 2004 to September 2010 and followed for a minimum of 1 year or until death. A mean dose of 52 Gy (range, 45–60 Gy) was delivered to the prescription isodose line in three fractions over a 3–11 day period (mean, 7 days). At a median follow-up of 20 months, the 2-year Kaplan–Meier local control and overall survival rates were 87 and 50%, respectively. CyberKnife with fiducial tracking is an effective treatment for high-risk surgical patients with single small peripheral lung metastases. Trials comparing CyberKnife with metastasectomy for operable patients are necessary to confirm equivalence.

Large fraction radiation therapy offers a shorter course of treatment and radiobiological advantages for prostate cancer treatment. The CyberKnife is an attractive technology for delivering large fraction doses based on the ability to deliver highly conformal radiation therapy to moving targets. In addition to intra-fractional translational motion (left-right, superior-inferior and anterior-posterior), prostate rotation (pitch, roll and yaw) can increase geographical miss risk. We describe our experience with six-dimensional (6D) intrafraction prostate motion correction using CyberKnife stereotactic body radiation therapy (SBRT). Eighty-eight patients were treated by SBRT alone or with supplemental external radiation therapy. Trans-perineal placement of four gold fiducials within the prostate accommodated X-ray guided prostate localization and beam adjustment. Fiducial separation and non-overlapping positioning permitted the orthogonal imaging required for 6D tracking. Fiducial placement accuracy was assessed using the CyberKnife fiducial extraction algorithm. Acute toxicities were assessed using Common Toxicity Criteria (CTC) v3. There were no Grade 3, or higher, complications and acute morbidity was minimal. Ninety-eight percent of patients completed treatment employing 6D prostate motion tracking with intrafractional beam correction. Suboptimal fiducial placement limited treatment to 3D tracking in 2 patients. Our experience may guide others in performing 6D correction of prostate motion with CyberKnife SBRT.

Background The CyberKnife is an appealing delivery system for hypofractionated stereotactic body radiation therapy (SBRT) because of its ability to deliver highly conformal radiation therapy to moving targets. This conformity is achieved via 100s of non-coplanar radiation beams, which could potentially increase transitory testicular irradiation and result in post-therapy hypogonadism. We report on our early experience with CyberKnife SBRT for low- to intermediate-risk prostate cancer patients and assess the rate of inducing biochemical and clinical hypogonadism. Methods Twenty-six patients were treated with hypofractionated SBRT to a dose of 36.25 Gy in 5 fractions. All patients had histologically confirmed low- to intermediate-risk prostate adenocarcinoma (clinical stage ≤ T2b, Gleason score ≤ 7, PSA ≤ 20 ng/ml). PSA and total testosterone levels were obtained pre-treatment, 1 month post-treatment and every 3 months thereafter, for 1 year. Biochemical hypogonadism was defined as a total serum testosterone level below 8 nmol/L. Urinary and gastrointestinal toxicity was assessed using Common Toxicity Criteria v3; quality of life was assessed using the American Urological Association Symptom Score, Sexual Health Inventory for Men and Expanded Prostate Cancer Index Composite questionnaires. Results All 26 patients completed the treatment with a median 15 months (range, 13-19 months) follow-up. Median pre-treatment PSA was 5.75 ng/ml (range, 2.3-10.3 ng/ml), and a decrease to a median of 0.7 ng/ml (range, 0.2-1.8 ng/ml) was observed by one year post-treatment. The median pre-treatment total serum testosterone level was 13.81 nmol/L (range, 5.55 - 39.87 nmol/L). Post-treatment testosterone levels slowly decreased with the median value at one year follow-up of 10.53 nmol/L, significantly lower than the pre-treatment value (p < 0.013). The median absolute fall was 3.28 nmol/L and the median percent fall was 23.75%. There was no increase in biochemical hypogonadism at one year post-treatment. Average EPIC sexual and hormonal scores were not significantly changed by one year post-treatment. Conclusions Hypofractionated SBRT offers the radiobiological benefit of a large fraction size and is well-tolerated by men with low- to intermediate-risk prostate cancer. Early results are encouraging with an excellent biochemical response. The rate of new biochemical and clinical hypogonadism was low one year after treatment.

We describe the first histopathologic analysis of prostatic tissue following hypofractionated robotic radiation therapy. A 66 year-old man presented with stage II, low risk adenocarcinoma of the prostate and underwent elective conformal hypofractionated radiation therapy. His pretreatment evaluation revealed T1c adenocarcinoma, Gleason's grade 3 + 3 = 6 and a prostate specific antigen (PSA) level of 4.87 ng/ml. Hypofractionated radiation therapy (37.5 Gy in five daily fractions of 7.5 Gy) was completed on an Internal Review Board approved protocol. One year later, he developed progressive urinary retention. Transurethral prostatic resection was performed to alleviate obstructive symptoms. Bilobar hypertrophy was observed without evidence of stricture. Histolopathologic analyses of resected prostate tissues revealed changes consistent with radiation treatment, including cellular changes, inflammation, glandular atrophy and hyperplasia. There was no evidence of residual cancer, fibrosis or necrosis. The patient's postoperative course was uneventful with post-treatment PSA of 0.5 ng/ml and residual grade 1 stress incontinence.

194 Background: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. While acute urinary symptoms are well recognized, late toxicities of SBRT have not been fully described. Here, we characterize the clinical features of late symptom flare and describe symptom management approaches. Methods: Two hudred sixteen patients with clinically localized prostate cancer were treated with SBRT between February 2008 and January 2011 at Georgetown University Hospital. Twenty-nine patients who experienced late-symptom flare were included in this retrospective analysis. Treatment was delivered using the CyberKnife (35 Gy to 36.25 Gy in five fractions). Prevalence of urinary toxicities was determined using CTCAE v.4. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite (EPIC) short form. Results: Median age was 66 with 55% being of African descent. Late grade 2 frequency/urgency peaked at 12 months (17.2%), then returned to baseline at 18 months. Late grade 2 retention peaked at 18 months (65.5%), then returned to baseline at 24 months. Late grade greater than or equal to 1 dysuria peaked at nine months (25.0%), then returned to baseline at 24 months. Alpha-antagonist usage peaked at 18 months (85%) then decreased at 24 months. At 12 months, 21% required anti-inflammatories and/or urethral analgesics. Median AUA score rose from a baseline of 6 to 15 at 12 months, then returned to baseline by 24 months. EPIC urinary function and bother scores dropped to a nadir at 9 to 12 months post-treatment, then returned to baseline at 24 months. Conclusions: Symptom flare is a late syndrome consisting of various degrees of urinary frequency/urgency, retention and dysuria. It occurs approximately one year following SBRT, resolves spontaneously, and urinary function returns to baseline by two years. Early identification and initiation of conservative symptomatic management may decrease the need for invasive interventions. Anticipatory counseling prior to treatment may limit bother due to these transient urinary symptoms.

e15134 Background: Clinical data suggest that fewer large fractions are radio-biologically superior to smaller fraction sizes in prostate cancer radiotherapy. The CyberKnife is the ideal delivery s...

Background Stereotactic body radiation therapy (SBRT) delivers fewer high-dose fractions of radiation which may be radiobiologically favorable to conventional low-dose fractions commonly used for prostate cancer radiotherapy. We report our early experience using SBRT for localized prostate cancer. Methods Patients treated with SBRT from June 2008 to May 2010 at Georgetown University Hospital for localized prostate carcinoma, with or without the use of androgen deprivation therapy (ADT), were included in this retrospective review of data that was prospectively collected in an institutional database. Treatment was delivered using the CyberKnife® with doses of 35 Gy or 36.25 Gy in 5 fractions. Biochemical control was assessed using the Phoenix definition. Toxicities were recorded and scored using the CTCAE v.3. Quality of life was assessed before and after treatment using the Short Form-12 Health Survey (SF-12), the American Urological Association Symptom Score (AUA) and Sexual Health Inventory for Men (SHIM) questionnaires. Late urinary symptom flare was defined as an AUA score ≥ 15 with an increase of ≥ 5 points above baseline six months after the completion of SBRT. Results One hundred patients (37 low-, 55 intermediate- and 8 high-risk according to the D’Amico classification) at a median age of 69 years (range, 48–90 years) received SBRT, with 11 patients receiving ADT. The median pre-treatment prostate-specific antigen (PSA) was 6.2 ng/ml (range, 1.9-31.6 ng/ml) and the median follow-up was 2.3 years (range, 1.4-3.5 years). At 2 years, median PSA decreased to 0.49 ng/ml (range, 0.1-1.9 ng/ml). Benign PSA bounce occurred in 31% of patients. There was one biochemical failure in a high-risk patient, yielding a two-year actuarial biochemical relapse free survival of 99%. The 2-year actuarial incidence rates of GI and GU toxicity ≥ grade 2 were 1% and 31%, respectively. A median baseline AUA symptom score of 8 significantly increased to 11 at 1 month (p = 0.001), however returned to baseline at 3 months (p = 0.60). Twenty one percent of patients experienced a late transient urinary symptom flare in the first two years following treatment. Of patients who were sexually potent prior to treatment, 79% maintained potency at 2 years post-treatment. Conclusions SBRT for clinically localized prostate cancer was well tolerated, with an early biochemical response similar to other radiation therapy treatments. Benign PSA bounces were common. Late GI and GU toxicity rates were comparable to conventionally fractionated radiation therapy and brachytherapy. Late urinary symptom flares were observed but the majority resolved with conservative management. A high percentage of men who were potent prior to treatment remained potent two years following treatment.