Citations

Purpose of review Adrenal masses are highly prevalent, found in 5% of the population. Differentiation of benign adrenocortical adenoma from adrenocortical carcinoma is currently hampered by the poor specificity and limited evidence base of imaging tests. This review summarizes the results of studies published to date on urine steroid metabolite profiling for distinguishing benign from malignant adrenal masses. Recent findings Three studies have described cohorts of at least 100 patients with adrenal tumors showing significant differences between urinary steroid metabolite excretions according to the nature of the underlying lesion, suggesting significant value of steroid metabolite profiling as a highly accurate diagnostic test. Summary Steroid profiling is emerging as a powerful novel diagnostic tool with a significant potential for improving the management for patients with adrenal tumors. Although the current studies use gas chromatography–mass spectrometry for proof of concept, widespread use of the method in routine clinical care will depend on transferring the approach to high-throughput tandem mass spectrometry platforms. The use of computational data analysis in conjunction with urine steroid metabolite profiling, that is, steroid metabolomics, adds accuracy and precision.

ObjectiveTo evaluate the use of monosyllabic word recognition versus sentence recognition to determine candidacy and long‐term benefit for cochlear implantation.Study DesignProspective multi‐center single‐subject design.MethodsA total of 21 adults aged 18 years and older with bilateral moderate to profound sensorineural hearing loss and low monosyllabic word scores received unilateral cochlear implantation. The consonant‐nucleus‐consonant (CNC) word test was the central measure of pre‐ and postoperative performance. Additional speech understanding tests included the Hearing in Noise Test sentences in quiet and AzBio sentences in +5 dB signal‐to‐noise ratio (SNR). Quality of life (QoL) was measured using the Abbreviated Profile of Hearing Aid Benefit and Health Utilities Index.ResultsPerformance on sentence recognition reached the ceiling of the test after only 3 months of implant use. In contrast, none of the participants in this study reached a score of 80% on CNC word recognition, even at the 12‐month postoperative test interval. Measures of QoL related to hearing were also significantly improved following implantation.ConclusionResults of this study demonstrate that monosyllabic words are appropriate for determining preoperative candidate and measuring long‐term postoperative speech recognition performance.Level of Evidence2c. Laryngoscope, 127:2368–2374, 2017

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

Abstract Background Multimodal analgesia is standard practice for total knee arthroplasty; however, the role of regional techniques in improved perioperative outcomes remains unknown. The authors hypothesized that peripheral nerve blockade would result in lower pain scores and opioid consumption than two competing periarticular injection solutions. Methods This three-arm, nonblinded trial randomized 165 adults undergoing unilateral primary total knee arthroplasty to receive (1) femoral catheter plus sciatic nerve blocks, (2) ropivacaine-based periarticular injection, or (3) liposomal bupivacaine-based periarticular injection. Primary outcome was maximal pain during postoperative day 1 (0 to 10, numerical pain rating scale) in intention-to-treat analysis. Additional outcomes included pain scores and opioid consumption for postoperative days 0 to 2 and 3 months. Results One hundred fifty-seven study patients received peripheral nerve block (n = 50), ropivacaine (n = 55), or liposomal bupivacaine (n = 52) and reported median maximal pain scores on postoperative day 1 of 3, 4, and 4.5 and on postoperative day 0 of 1, 4, and 5, respectively (average pain scores for postoperative day 0: 0.6, 1.7, and 2.4 and postoperative day 1: 2.5, 3.5, and 3.7). Postoperative day 1 median maximal pain scores were significantly lower for peripheral nerve blockade compared to liposomal bupivacaine-based periarticular injection ( P = 0.016; Hodges–Lehmann median difference [95% CI] = −1 [−2 to 0]). After postanesthesia care unit discharge, postoperative day 0 median maximal and average pain scores were significantly lower for peripheral nerve block compared to both periarticular injections (ropivacaine: maximal −2 [−3 to −1]; P < 0.001; average −0.8 [−1.3 to −0.2]; P = 0.003; and liposomal bupivacaine: maximal −3 [−4 to −2]; P < 0.001; average −1.4 [−2.0 to −0.8]; P < 0.001). Conclusions Ropivacaine-based periarticular injections provide pain control comparable on postoperative days 1 and 2 to a femoral catheter and single-injection sciatic nerve block. This study did not demonstrate an advantage of liposomal bupivacaine over ropivacaine in periarticular injections for total knee arthroplasty.

94 Background: Technetium (Tc99m) trofolastat (USANC) is a novel urea-based small molecule SPECT radiotracer with utility in imaging overexpression of PSMA in prostate cancer (PCa). Unlike earlier agents targeting PSMA, this ligand is rapidly internalized and retained in tumors. We conducted an open-label, multicenter phase 2 study in the US and Europe (NCT01667536). An interim analysis was performed at approximately 50% accrual. Methods: Patients (pts) with confirmed adenocarcinoma of the prostate scheduled for RP with EPLND at high risk for disease outside of the prostate gland were eligible. High risk pts were ≥cT3 or Kattan nomogram score ≥130. Within 30 days of screening, pts required a bone scan and pelvic MRI. After enrollment, pts received trofolastat followed by whole-body planar and SPECT/CT imaging 3 to 6 hrs later. Pts then underwent RP with EPLND within 21 days. SPECT/CT images were evaluated centrally by 3 readers blinded to clinical information and compared to on-site pathology assessments using a common scoring template. The primary endpoint was the ability of trofolastat to detect PCa within the gland. Secondary endpoints included detection of extent and location within the gland, pelvic lymph nodes and comparative performance against MRI. Results: 84 pts were enrolled to date from 16 centers. Interim data is available for 54 pts. A majority (≥2/3) of SPECT/CT readers correctly identified the presence or absence of primary PCa in 51/54 (94%, 85-98 95% CI) patients including 2 true-negative cases treated with neoadjuvant enzalutamide. Sensitivity and specificity were 94% (84-98 95% CI) and 100% (34-100 95% CI) respectively. Conclusions: Based on the interim data available, trofolastat has accurately detected primary prostate carcinoma within the gland with high sensitivity and specificity in high-risk pts prior to surgery. Updated results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this ongoing study will be presented. Clinical trial information: NCT01667536. [Table: see text]

93 Background: A key eligibility criterion in many active surveillance (AS) programs is that the biopsy exhibit only Gleason pattern 3 (G3) for a Gleason score of 6 or less. However, 25 to 35% of biopsy Gleason 6 is upgraded to Gleason 7 or higher in the prostatectomy (RP) specimen. Thus, there is a great need for biomarkers that, when measured on G3 tissue in a Gleason 6 biopsy, can predict the presence of unsampled higher grade tumor in the whole prostate. We evaluated PTEN loss by immunohistochemistry (IHC), and PTEN deletion, chromosome 8q (MYC) gain and 8p (LPL) loss by fluorescence in situ hybridization (FISH) for their ability to predict unsampled G4 tumor. Methods: A tissue microarray (TMA) was constructed of RP tissue from three groups of patients (n=50 per group) whose prostates exhibited only Gleason 3+3, only 3+4, or only 4+3 tumor, matched on age, year of RP, and race. In each patient, multiple cores sampled only from areas of G3 were evaluated for PTEN deletion by FISH, PTEN loss by IHC, and chromosome 8p/8q alterations by FISH. Biomarker results were compared between Gleason 6 versus 7 tumors using conditional logistic regression. Results: Patients underwent RP in 2001 to 2009, had median age 60, and median prostate-specific antigen 5.2; 63% of tumors were organ confined. In univariate analyses 8q gain (odds ratio OR=8.9, p<.0001), 8p loss (OR=6.9, p<.0001), PTEN loss by IHC (OR=5.7, p=.025), but not PTEN deletion by FISH (OR=1.5, p=.477) were significantly more common in G3 cores from Gleason 7 tumors than G3 cores from Gleason 6 tumors. In multivariable analyses, 8q gain (OR=6.2, p=.002) and 8p loss (OR=5.2, p=.0002) remained highly significant. At least one high risk biomarker (8q gain, 8p loss, PTEN loss, or PTEN deletion) was found in 35.7% of Gleason 3+3 versus 77.1% of Gleason 3+4 versus 91.3% of Gleason 4+3 tumors, p<.0001. Adjustment for confounding factors did not change the results. Conclusions: Chromosomal 8q gains (MYC), 8p loss (LPL), and PTEN loss measured in Gleason G3 TMA cores strongly differentiate whether the core comes from Gleason 6 or Gleason 7 tumor. If validated in biopsy Gleason 6 cores to predict prostatectomy Gleason 7 tumor these biomarkers could facilitate safe selection of men for active surveillance.

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]

516 Background: The impact of diabetes mellitus (DM) on outcomes in patients with renal cell carcinoma (RCC) is controversial. Herein, we evaluated the association of DM with survival among patients with RCC. Methods: We reviewed 2,589 patients treated with nephrectomy for sporadic, unilateral, M0 RCC between 1990 and 2008 and compared demographic and tumor characteristics in patients with and without DM (nonDM). Patients with DM (n=313) were matched 1:2 to nonDM patients according to date of surgery, age, smoking status, obesity, ECOG performance status (PS), CKD stage, histological subtype, and nuclear grade. Cancer-specific (CSS) and overall survival (OS) were compared by Kaplan-Meier analysis. The association of DM with outcomes was evaluated with Cox proportional hazards regression models. Results: A total of 313 (12%) patients had DM. DM patients were significantly older at RCC diagnosis, more likely to be obese, and had higher Charlson scores, CKD class, rates of smoking, and worse PS at surgery (p<0.001). Patients with DM were also more likely to have ccRCC (83% vs. 76%, p=0.02) and to undergo nephron-sparing surgery (42% vs. 35%, p=0.01), while other pathologic features were similar in DM and nonDM. Among the 939 matched cases and controls, 463 patients died within a median of 5.5 years after nephrectomy. Median follow-up for survivors was 8.6 years. Five-year CSS was not significantly different among DM patients 84% vs. nonDM patients 87% (p=0.11), although 5-year OS was significantly worse among DM patients (66% vs. 75%; p<0.001). Indeed, even after adjusting for Charlson score, DM patients were noted to have a significantly increased risk of all-cause mortality (HR 1.33; p=0.004). In a subanalysis of patients with clear cell RCC, DM patients were more likely to die from RCC compared with nonDM patients after adjusting for the SSIGN (Stage, Size, Grade, Necrosis) score (HR 1.44; p=0.034). Conclusions: In this surgical cohort, DM was independently associated with decreased CSS among patients with ccRCC and with decreased OS in all RCC subtypes. Further studies to determine the potential biologic mechanism for this interaction are warranted.

503 Background: We evaluated temporal patterns in the utilization of systemic therapy among patients undergoing cytoreductive nephrectomy (CN) for metastatic Renal Cell Carcinoma (mRCC) from a large national cancer registry and assessed patient characteristics associated with receipt of systemic treatment. Methods: We reviewed the National Cancer Database to identify patients with stage IV RCC who underwent CN between 1998-2010. Systemic therapy was defined as any treatment with immunotherapy and/or chemotherapy (including targeted agents). We evaluated the association between clinicopathologic features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations, and assessed the interaction of treatment with time, stratified as immunotherapy (1998-2004) versus targeted-therapy (2005-2010) eras. Results: Of 22,409 patients with mRCC undergoing CN, 8,830 (39%) received systemic therapy. Receipt of systemic therapy increased from 32% in 1998 to 49% in 2010 (p<0.001), largely due to increased utilization of chemotherapy (13.9% vs. 46.7%; p<0.001). Following adjustment, increasing patient age (51-60 years: OR 0.82 [CI 0.73-0.92]; 61-70 years: OR 0.67 [CI 0.59-0.76]; ≥71 years: OR 0.36 [CI 0.31-0.43]), as well as coverage with Medicaid (OR 0.61 [CI 0.5-0.74]), Medicare (OR 0.70 [CI 0.62-0.79]), or no insurance (OR 0.75 [CI 0.63-0.91]) were associated with decreased utilization of systemic therapy. Although use of systemic therapy in the elderly (≥71 years) and in patients with Medicare/Medicaid remained lower throughout the study period, each of these cohorts was significantly more likely to receive systemic treatment in the targeted versus immunotherapy era (all p values <0.05). Conclusions: Utilization of systemic therapy among patients undergoing CN has increased over time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology for lack of treatment is likely multifactorial, the potential health policy implications of continued disparities in care warrant further investigation.