bluuebunny/crossref_metadata_2025 huggingface dataset:
Results from a phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer (mBC).
Authors: Gupta Shilpa , Dhillon Jasreman , Magliocco Anthony Martin , Puskas John , Caceres Gisela , Masawi Fadzai , Doronin Yulia , Zhang Jingsong
Published: March 2019

471

Background: Novel targeted therapies are an unmet need in mBC. Androgen receptor (AR) is a rational target in BC and we conducted a phase 1/1b trial assessing safety and tolerability of AR antonist, enzalutamide (ENZ) in combination with gemcitabine and cisplatin (GC) in mBC. Methods: The dose escalation phase allowed patients with mBC regardless of the AR status (assessed on routine IHC) and dose expansion cohort allowed only AR+ pts. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 and 160 mg respectively with GC (G 1000 mg/m2 on days 1, 8 and C 70 mg/m2 on day 1 every 21 days). After 6 cycles of ENZ+GC, pts. continued maintenance ENZ until disease progression. Primary objective was safety and tolerability of ENZ and GC. Secondary objectives were PFS, OS and objective tumor response. Exploratory objectives included evaluation of AR expression in tumor tissues and correlation with outcomes and CTC evaluation at baseline and prior to cycle 3, including AR expression in CTCs and correlation with clinical outcomes. Key eligibility criteria included ECOG PS of 0-1, and no contraindications to ENZ and GC. Results: A total of 10 pts were enrolled between Nov. 2014 and Jan. 2017; 6 pts were enrolled on the dose escalation phase, there were no DLTs observed and ENZ dose of 160 mg was used for the dose expansion cohort, which enrolled 4 pts. The combination of ENZ and GC was well tolerated with expected toxicities, mainly from GC. Median age was 65.6 yrs, 9/10 pts were male; of the 8 evaluable pts, 1 had CR, 4 had PR, 2 had SD and 1 had PD; median OS was 10.59 mos and median PFS was 7.68 mos. CTCs were detectable in 9/10 pts and correlated with disease response. The pt with CR was a female pt with strongly AR + tumor (>90%) and continues to remain in CR 24 months from starting treatment. Exploratory analysis from CTCs and is ongoing. Conclusions: This is the 1st clinical trial to target AR signaling in mBC with ENZ and to evaluate safety of ENZ with GC. While there were limited number of pts enrolled, the results from this study provide early evidence that AR is a rational target in BC and anti-AR therapies can be safely combined with chemotherapy. Clinical trial information: NCT02300610.
Germline alterations in urothelial carcinoma (UC) patients with family history of UC.
Authors: Nassar Amin , Mouw Kent William , Esplin Edward D. , Yang Shan , Callis Tom , Nuzzo Pier Vitale , Chanza Nieves M. , Choueiri Toni K. , Kwiatkowski David J. , Sonpavde Guru
Published: March 2019

474

Background: UC is associated with germline alterations in a small minority of patients (pts). The prevalence of germline alterations in those with familial UC is unknown. We identified genomic alterations among familial UC pts to provide insights into pathogenesis and improve management. Methods: We analyzed deidentified data for UC pts with germline multigene panel testing (Invitae) who had a family history of UC, defined as a 1st-3rd degree relative with UC. Massively parallel sequencing used customized capture bait-sets to analyze exonic regions, flanking intronic sequences, and copy number variations (CNVs) for 1-126 genes. Pathogenic and likely pathogenic (P/LP) variants underwent orthogonal confirmation, per standard policy, including single nucleotide variants (SNVs)/small indels/CNVs. Patient characteristics were compared using the Fisher’s Exact and Wilcoxon-Rank Sum test. Results: 79 UC pts with a family history of UC were identified (67 bladder, 6 upper tract, 6 unknown). Six patients (8%) were excluded as the relation of the family member was unknown. 48/73 (66%) pts had first-degree relatives (fdr) with UC (4 upper tract, 39 bladder, 5 unknown) and 25 (34%) had second-degree (or higher) relatives (sdr) (2 upper tract, 22 bladder, 1 unknown). 56 germline alterations were found in 38 (52%) pts. 14 known pathogenic alterations occurred in 13 (18%) pts: SDHC (1), MITF (2), BRIP1 (1), BRCA2 (1), MSH2 (3), BRCA1 (1), CHEK2 (1), PTCH (1), MUTYH (2), BAP1 (1). 8/48 (17%) pts with fdr had pathogenic variants vs. 5/25 (20%) pts with sdr or more. There was no difference in the prevalence of pathogenic variants based on gender (p=0.37) or age (p=0.77). The limitations are modest sample size and differences in panels of genes. Conclusions: This is the first study to our knowledge to report germline alterations in UC pts with a family history of UC. Pathogenic germline alterations were seen in 18% of pts, which were enriched for DNA damage repair gene alterations, and could have important therapeutic implications. Further study of germline alterations using larger panels in pts with family history of UC may provide novel insights, since most pts did not have pathogenic alterations.
Validated five-factor prognostic model for survival of patients (pts) with metastatic urothelial carcinoma (mUC) receiving different post-platinum PD-L1 inhibitors.
Authors: Sonpavde Guru , Hennessy Daniel , Manitz Juliane , Niegisch Guenter , Powles Thomas , Rosenberg Jonathan E. , Bajorin Dean F. , Apolo Andrea B. , Pond Gregory Russell
Published: March 2019

476

Background: A prognostic model for overall survival (OS) of mUC was previously reported in the setting of post-platinum atezolizumab (Pond GR, GU ASCO 2018). This model was limited by employing only atezolizumab treated pts, small size of the validation dataset and unclear applicability to other PD-1/L1 inhibitors. Hence, we constructed a robust prognostic model utilizing the combined atezolizumab cohort as the discovery dataset and used a validation dataset comprised of post-platinum avelumab-treated pts. Methods: The discovery dataset consisted of pt level data from 2 phase I/II trials (IMvigor210 and PCD4989g) evaluating atezolizumab (n = 405). Pts enrolled on a phase I/II trial that received post-platinum avelumab (n = 242) comprised the validation dataset (EMR 100070-001). Cox regression analyses evaluated the association of candidate prognostic factors with OS. Factors were dichotomized and laboratory values were normalized by logarithmic transformation. Stepwise selection was employed to propose an optimal model using the discovery dataset. Discrimination (via c-statistic) and calibration were assessed in the avelumab dataset following the validation procedure by Royston and Altman (2013). Results: The 5 factors included in the optimal prognostic model in the discovery dataset were ECOG-PS (1 vs. 0; HR 1.80; 95% CI [1.36-2.36]), presence/absence of liver metastasis (HR 1.55; 95% CI [1.20-2.00]), number of platelets (HR 2.22; 95% CI [1.54-3.18]), neutrophil-lymphocyte ratio (NLR; HR 1.94; 95% CI [1.57-2.40]) and lactate dehydrogenase (LDH; HR 1.60; 95% CI [1.28-1.99]). The c-statistic for prediction of survival was 0.692 and 0.671 in the discovery and validation datasets, respectively. Acceptable or good calibration of expected 1-year survival was observed. Conclusions: A 5-factor externally validated prognostic model for OS is proposed employing a large dataset of 647 pts overall in the setting of post-platinum PD-L1 inhibitors for mUC. This model may assist in prognostic stratification and interpreting nonrandomized trials of post-platinum PD1/L1 inhibitors.
National trends and pathologic outcomes of neoadjuvant chemotherapy among patients with micropapillary variant urothelial carcinoma of the bladder.
Authors: Javier-Desloges Juan , Abello Alejandro , Syed Jamil , Leapman Michael
Published: March 2019

477

Background: Micropapillary variants of urothelial cell carcinoma (UCC) are associated with aggressive clinical behavior including an increased risk of regional and distant metastasis. Although neoadjuvant chemotherapy (NAC) improves survival for patients with UCC who achieve a complete pathologic response (pT0), less is known regarding the uptake of this practice in patients with micropapillary variant (MV) or its effect on pathologic response. Methods: We queried the National Cancer Database to identify all patients with a diagnosis of UCC including MV from 2004-2014. We restricted our analysis to patients who underwent radical cystectomy with or without NAC. We compared clinical, demographic, and pathologic characteristics and evaluated time trends associated with use of NAC. Following propensity score matching to balance covariates associated with the receipt of NAC, we used logistic regression models to study the association of NAC use and pT0 rate. Dual analyses were performed among patients with clinical stage II (cT2) disease, as well as the entire cohort (all stages). Results: We identified 102,266 patients, including 101,272 (99.03%) pure UCC and 994 (0.97%) MV. Patients with MV were younger (Median 70 years vs 73 years, p < 0.001), more commonly male (79.0 vs 73.6% p < 0.001), were more commonly treated in academic centers (66.43% vs 44.77%), there was no difference between urban/rural areas. Use of NAC among patients with cT2 increased in the entire cohort from 27% on 2004 to 49.7% in 2014 for UCC, and from 50% to 58% for MV. Among patients with cT2 disease, 38.4% of UCC received NAC and 49% MV received NAC (P < 0.001). Following propensity score matching, receipt of NAC was associated with pT0 for both histological diagnoses (OR 2.13 95% CI: 1.65-2.78 p < 0.001). This effect persisted on restriction to patients with cT2 (OR 3.32, 95% CI: 2.32-4.75, p < 0.001). Conclusions: There has been increased use of NAC among patients with micropapillary variant. Patients with cT2 micropapillary variant were equally like to be achieve a pathologic complete response to NAC as were patients without histologic variants of urothelial cell carcinoma.
The nonsurgical management of upper tract urothelial carcinoma: A role for active surveillance?
Authors: Syed Jamil , Nguyen Kevin , Javier-Desloges Juan , Leapman Michael , Raman Jay D. , Shuch Brian M.
Published: March 2019

485

Background: Approximately 7% of patients with localized upper tract urothelial cancer (UTUC) are treated without definitive therapy. Understanding outcomes and alternative therapy would aid in counseling older patients with co-morbidities. Methods: We utilized the National Cancer Database to identify patients with localized UTUC managed non-surgically between 2004 and 2013. Patient demographics, co-morbidity, tumor grade, and chemotherapy and radiation utilization were recorded. Survival analyses were performed with the Kaplan-Meier method and a cox proportional hazard regression model. Results: We identified 3,157 (10.9%) patients with localized UTUC who did not receive definitive surgery. Median age was 79 years, 55% were males, 79% had government health insurance, and 68% had a CDS of 0. Tumor grade was low (grade 1 or 2) in 632 (36.4%) and high (grade 3 or 4) in 1104 (63.6%). Median overall survival (OS) for the cohort was 2.2 years, significantly shorter for patients with greater co-morbidities. Chemotherapy or radiation was performed in 294 (9.3%) and 197 (6.3%) patients respectively. There were no OS differences for individuals receiving chemotherapy. Of patients who received radiation therapy, the median OS was 1.4 vs 2.0 years, (p<0.001) favoring no radiation. Those with high grade tumors had worse survival (1.9 vs 3.8 years (p<0.001). Significant predictors of shorter OS included older age, male gender, higher CDS, and government insurance. Conclusions: In this population-based cohort, 10.9% of patients with localized UTUC were managed non-surgically. Radiation and chemotherapy were not routinely utilized, and did not demonstrate improved survival. Median OS was significantly shorter for those with higher grade disease, increasing co-morbidity profile, male gender, and those with government insurance status.
Twenty-eight-day prophylaxis with apixaban after radical cystectomy: Early results in safety.
Authors: Anwar Taha , Raza Johar , Pokala Naveen , Hamilton Zachary , Murray Katie
Published: March 2019

488

Background: Venous thromboembolism (VTE) after oncologic surgery is a known risk and therefore guidelines recommend extended VTE prophylaxis up to 4 weeks for these populations. This prophylaxis is often costly and cumbersome to patients, as it requires self-injections with enoxaparin. The FDA has extended the indication for apixaban to include deep venous thrombosis (DVT) and pulmonary embolism (PE) prophylaxis in adults who have undergone hip or knee replacement surgery. The objective of this study was to identify safety concerns with using this prophylaxis for an extended time after radical cystectomy for bladder cancer. Methods: Patients from two institutions who underwent radical cystectomy for bladder cancer were retrospectively reviewed. Patients were included if they were discharged from the hospital with at least 28 days of prophylactic apixaban 2.5 mg BID. Descriptive statistics are used to show patient and outcome characteristics. Results: As of October 2018, 12 patients met inclusion criteria for this study. The median age was 69.5 years (interquartile range: 64.75 to 74 years) and 11 (91.7%) of the patients were male. 3 (25%), 1 (8.3%), 2 (16.7%), 1 (8.3%) and 5 (41.7%) of the patients were pathologic stage T0, Tis, T1, T2, T3/4, respectively, and 2 (16.7%) had node positive disease. Seven (58.3%) of the patients received neoadjuvant chemotherapy prior to radical cystectomy. No patients were identified with a symptomatic or asymptomatic VTE during pre-operative work up or during post-operative stay. No major bleeding events or complications related to the anticoagulant were identified in any patient, and no patient has developed a post-operative VTE including DVT or PE to date. Conclusions: Apixaban is approved for prophylaxis in preventing VTE after major surgery in other surgical specialties. This report shows that in the early stages of investigation of post-discharge use of apixaban, no increase in complications or readmissions have been identified in patients who have undergone radical cystectomy for bladder cancer. This safety, efficacy, and potential superiority needs further investigation.
Robot-assisted radical cystectomy (RARC) versus open radical cystectomy (ORC): Oncological outcomes in 469 patients with a mean follow-up of five years.
Authors: Faraj Kassem , Rose Kyle , Abdul-Muhsin Haidar , Navaratnam Anojan , Patton Michael , Cheney Scott , Tyson Mark D. , Castle Erik P.
Published: March 2019

492

Background: There is scant information about intermediate and long-term comparative outcomes between RARC and ORC, with the exception of a recent, small randomized-trial. We present our experience with RARC and ORC in managing bladder cancer patients who require cystectomy. Methods: A query of all patients who underwent radical cystectomy for a primary bladder tumor between 01/2007 and 6/2017 at our institution yield 469 patients. Data was collected on patient demographics, pre-operative information, operative details, pathology, and follow-up. Most RARCs were performed by a high-volume robotic surgeon who preferentially used the robotic approach at the start of all cases. Statistical analyses were generated using SPSS 22.0. Any open conversions were analyzed in the RARC cohort. Results: In 469 total patients, 197 (42.0%) and 272 (58.0%) underwent RARC and ORC, respectively. There were 163 (82.7%) and 224 (82.4%) males in each group and the mean ages (SD) were 71.5 (8.6) and 70.2 (10.5) years. Mean follow-up (SD) was 75 (37.7) and 61 (35.7) months, respectively. There were 130 (66.0%) and 172 (63.2%) patients who presented with T2 or greater disease (p=0.605). Soft-tissue margin rates were 4.1% for RARC and 6.7% for ORC patients (p=0.232). Neoadjuvant chemotherapy was used in 56.9% of RARC and 45.9% of ORC patients with ≥ cT2 disease (p=0.058). The 5-year overall survival was 60.0% vs 57.0% and the 10-year overall survival was 40.3% vs 44.8% for RARC vs. ORC patients, respectively (p=0.283). The 5-year recurrence-free survival was survival (RFS) was 71.7% vs 65.7% and the 10-year RFS was 70.5% vs 62.3% for the RARC vs. open groups, respectively (p=0.078). Aggressive histological variants, which were associated with greater likelihood for recurrence, were more common in the ORC group (13.7 vs. 22.4% p=0.013). Atypical recurrences (i.e. peritoneal, extrapelvic nodes) occurred in 6 (3.0%) and 14 (5.1%) RARC and ORC patients, respectively (p=0.266). Conclusions: In experienced hands, intermediate and long-term outcomes of RARC appear equivalent to ORC with regards to recurrence free survival, overall survival, and risk of atypical recurrences.
Development and validation of a DNA methylation panel for the prediction of outcome in node-positive penile squamous cell carcinoma after lymphadenectomy.
Authors: Zhu Yao , Gu Weijie , Wan Fangning , Wang Beihe , Wei Yu , Ye Dingwei
Published: March 2019

513

Background: Node-positive penile squamous cell carcinoma is lethal disease with heterogenous outcome after lymphadenectomy. Molecular prognostic factor are poorly tested in this population to individualize treatment. The aim of this study was to develop and validate the prognostic value of a DNA methylation panel in node-positive penile cancer after lymphadenectomy. Methods: Patients with node-positive penile squamous cell carcinoma, and received inguinal or ilioinguinal lymphadenectomy were eligible. The prognostic marker study had 3-stage design: first, discovery set of 23 frozen tissues was used to generate candidate CpG sites associated with overall survival; second, development set of 68 formalin-fixed and paraffin-embedded (FFPE) samples was used to construct a multivariable methylation panel for outcome stratification; third, validation set of 69 FFPE specimens from multi-center database was used to independently validate the performance of the prognostic marker. The study was approved by local ethnic committee. The primary endpoint was overall survival. The prognostic value of the DNA methylation panel value was evaluated by hazard ratio (HR), concordance index (C-index) and clinical benefit. Results: At discovery stage, 11 CpG sites were significantly associated with overall survival. In development set, we constructed a 3-CpGs-based prognostic panel for survival prediction. The HR of the panel (dichotomized using median cutoff) was 6.5 in multivariate analyses (p < 0.001). Addition of methylation panel significantly improved the C-index of N stage from 0.64 to 0.75 (incremental C = 0.11, p < 0.001). In the validation set, the methylation panel showed a HR of 7.8 in multivariate analyses. Addition of the molecular marker significantly improved the C-index of N stage from 0.69 to 0.78 (incremental C = 0.09, p < 0.001). The main limitation was retrospective design. Conclusions: We developed and validated a methylation prognostic panel for node-positive penile cancer. The prognostic maker showed remarkable improvement in risk stratification, and need further evaluation in prospective setting.
A phase II study of ribociclib in men with unresectable, incurable teratoma with recent progression.
Authors: Castellano Daniel E. , Quinn David I. , Feldman Darren R. , Fizazi Karim , Garcia del Muro Xavier , Gietema Jourik A. , Lauer Richard C. , Ising Mary Elizabeth , Aregay Mehreteab , Crystal Adam Samuel , Vaughn David J.
Published: March 2019

517

Background: Most patients with teratoma are managed by surgery and no standard medical therapy exists for progressive and/or unresectable teratoma. Teratomas have functional expression of retinoblastoma protein and clinical activity was observed with CDK4/6 inhibition (Vaughn DJ, et al. Cancer. 2015). Here, we report results with the CDK4/6 inhibitor ribociclib (RIBO) for unresectable teratoma. Methods: This multicenter, double-blind study enrolled patients (pts) ≥ 15 years old with unresectable, progressive teratoma without malignant transformation, ECOG PS 0-1, and ≥ 1 line of prior chemotherapy. Pts were randomized (2:1) to receive RIBO (600 mg/day, 3 weeks on/1 week off) or placebo (PBO). Crossover to RIBO was permitted following progressive disease (PD) on PBO. The primary endpoint was progression-free survival (PFS). Secondary endpoints included additional efficacy measures, safety, and tolerability. Results: The trial was closed prematurely in the setting of slow accrual. Ten pts were randomized (8 to RIBO, 2 to PBO). Median age was 33 years (range, 21-53). All pts received study treatment, and both pts in the PBO arm crossed over to RIBO following PD. Median exposure was 385 days for RIBO and 166 days for PBO. The PFS rates at 24 months were 71% and 0% in the RIBO and PBO arms, respectively. All 8 pts in the RIBO arm had stable disease (SD) as best response at first evaluation. In the PBO arm, 1 pt had best response of PD and the other SD with durations of treatment of 78 and 254 days, respectively. After crossover, both pts received RIBO, with a best response of SD, and durations of treatment of 943 and 133 days, respectively; the former entered a rollover protocol and the latter discontinued treatment due to an adverse event. The most common reason for discontinuation in both groups was PD. Grade ≥ 3 adverse events in the RIBO group included neutropenia and non-cardiac chest pain in 2 pts, and headache, decreased appetite, asthenia, fatigue, vomiting, and increased blood creatinine in 1 pt each; all but non-cardiac chest pain were suspected to be drug related. Conclusions: In this rare clinical setting, with a limited small sample size, RIBO prolonged PFS as compared to PBO and no new safety signals emerged. Clinical trial information: NCT02300987.
Persistence of platinum in semen of cisplatin-treated survivors of advanced testicular cancer.
Authors: Malone Eoghan Ruadh , Lewin Jeremy Howard , Lau Susan , Hamilton Robert James , Hansen Aaron Richard , Jarvi Keith , Zhang Wenjiang , Chen Eric Xueyu , Bedard Philippe L.
Published: March 2019

519

Background: Even in patients (pts) with widely metastatic germ cell tumors cure rates are high with cisplatin based chemotherapy. Survivors of testicular cancer often have impaired gonadal function possibly related to chemotherapy. Most pts develop temporary azoospermia with recovery in about 50% after 2 years and 80% after 5 years. Platinum persists in blood in these pts, however, it is not known whether platinum also persists in semen. Methods: Pts who completed cisplatin > 3 months previously were enrolled. Age, total cisplatin dose and date of completion of treatment were collected. A semen sample was collected from each patient for analysis to assess semen quality. A blood sample was collected to assess FSH/LH/testosterone/creatinine. Serum and semen platinum levels were measured using HPLC-tandem mass spectrometry. Results: Between 11/2017 and 09/2018, 9 pts (median age 32 years; range: 18-52) were enrolled to the study, all were treated with standard Bleomycin, Etoposide, Cisplatin regimen. Blood samples were collected from 7 pts, and semen samples from 4 pts. Median total cisplatin dose given was 658 mg (range: 570-780). Median serum platinum concentration was 0.395 ng/mL (range: 0.10-0.94) at a median of 10 months (range 4.5-13) post completion of treatment. Median semen platinum concentration was 1.06 ng/mL (range: 0.25-1.47) at a median of 10 months (range: 6-14) post completion of treatment. Semen platinum levels were associated with total cisplatin dose administered (Pearson correlation, r = 0.645) and time from completion of treatment (Pearson correlation, r = 0.386). In all 4 pts with matched samples, the semen platinum level was higher than the serum platinum level. Semen analysis showed 2 pts were azoospermic post treatment, 1 of these was also azoospermic prior to treatment; 1 pt had normal semen analysis post treatment and 1 had a low sperm count post treatment. Conclusions: This is the first study demonstrating that platinum persists in semen > 6 months post completion of cisplatin-containing chemotherapy. Platinum levels are higher in semen than in blood following treatment. Our preliminary findings may have important implications for reproductive health of survivors of advanced testicular cancer.
Validation of plasma miR-371a-3p expression in patients with metastatic and early stage germ cell tumor.
Authors: Nappi Lucia , Thi Marisa , Lum Amy , Huntsman David , Eigl Bernhard J. , Chi Kim N. , Martin Christopher , O Neil Brock , Maughan Benjamin Louis , So Alan , Black Peter C. , Gleave Martin , Wyatt Alexander William , Lavoie Jean-Michel , Khalaf Daniel , Daneshmand Siamak , Hamilton Robert James , Leao Ricardo Romao Nazario , Nichols Craig R. , Kollmannsberger Christian K.
Published: March 2019

526

Background: Identification of relapsing/residual viable germ cell malignancy (GCM) is often challenging in patients with CSI on surveillance or with residual post-chemotherapy disease. The presence of a biomarker for GCM would overcome the uncertainty of the current methods and improve the quality of care of those patients. Methods: A 2-cohorts pilot study involving patients with clearcut evidence of GCM (clinical stage IS, metastatic and GCM prior orchiectomy) for the development cohort and patients with CSI with or without signs of tumor relapse and patients with metastatic GCM post-chemotherapy for the validation cohort. Blood samples collected in Streck tubes were obtained prior to chemotherapy for the development cohort and post-orchiectomy, at the time of suspicious relapse or post-chemotherapy in the validation cohort. Plasma miR-371a-3p (miR371) was analyzed by RT-PCR. Positive predictive value (PPV), sensitivity, specificity, negative predictive values (NPV) and AUC of the ROC for miR371 and standard diagnostic tools (CT scan, AFP, BHCG and LDH) were calculated correlating qualitative miR371 expression to the presence of viable GCM. Results: 132 patients were enrolled into the development (33 pts) and validation (99 pts) cohorts. Within the development cohort 31/33 pts were miR371 positive, 2/33 pts were negative. 31 true positives were found among the 31 miR371 positive patients for a PPV of 100% (31/31). Two true negatives were found among the 2 patients who had no miR371 expression identified (teratoma, lymphoma). The validation cohort was chosen to evaluate the methodology among patients with predicted lower volumes or no clinically apparent disease. 13/99 patients within the validation cohort were miR371 positive and all 13 had subsequent confirmation of viable GCM. For the overall study of 132 pts, PPV was 100% (46/46), NPV 98%, sensitivity 96% and specificity 100%, the AUC of the ROC was 0.96. Conclusions: Detectable circulating miR-371a-3p levels predict viable GCM and may represent a strategy for biological rather than radiographic assessment for surveillance of early stage and for post-treatment patients. Larger studies to validate these and like results have been planned.
The features and management of late relapse of non-seminomatous germ cell tumors: The Royal Marsden Experience.
Authors: Huddart Robert A , Mayer Erik , Jay Alexander , Pearce Adam , Reid Alison Helen , Nicol David
Published: March 2019

529

Background: Late relapses (LR) of non-seminomatous germ cell tumours (NSGCT), defined as those occurring after a disease free interval of 2 years, are increasingly recognised. We reviewed the features of LR in NSGCT within a tertiary referral testicular cancer service. Methods: 3,064 patients (pts) were referred to the testis multi-disciplinary team (January 2005 to Dec 2017). Pts who experienced a LR where initial pathology demonstrated NSGCT were identified. Data of their original and late presentation and management was reviewed from patient electronic records. Results: Of the 3,064 pts, 101 (3.3%) had a LR, with 43 pts (43%) relapsing after 10 years. 36 were symptomatic and 39 had raised markers (AFP 29, HCG 9, both 1). Table 1 shows stage at initial presentation and time to relapse. As regards treatment before late relapse, 13 CS1 patients had received prior chemotherapy (Cht) (8 as adjuvant and 5 Cht for early relapse). 59/60 CS2/3 patients received Cht as primary treatment and 41 had a post chemotherapy retroperitoneal lymph node dissection(PC-RPLND (bilateral template in 12). 20 of these 41 men who had a PC-RPLND experienced a LR in the retroperitoneum (6 after bilateral template) Patient management at relapse is summarised in table.Time to recurrence was longer in CS2/3 patients (p<0.001). 84 surgical procedures were [performed in 82 patients; histology was TD in 43, Yolk sac 14, De-differentiated in 7 and viable GCT in 12, benign 8. To date 22 patients have died, 13 of these patients relapsed at multiple sites. Conclusions: LR of NSGCT frequently occurs after an extended interval and typically occurs earlier in CS1 disease compared to higher stages. Aggressive surgery +/- chemotherapy can cure most patients. [Table: see text]
Performance of a validated urine exosome gene expression test (EPI) in men within the USPSTF suggested age-group of 55 to 69 years at initial biopsy with a PSA 2-10 ng/mL.
Authors: Donovan Michael J. , Noerholm Mikkel , Torkler Phillipp , Skog Johan , Margolis Eric , Brown Gordon Andrew , McKiernan James M.
Published: March 2019

53

Background: Prostate-specific antigen (PSA) plays a key-role in prostate cancer (PCa) risk stratification but leads to over-diagnosis of low grade PCa. Recently, the USPSTF recommended that the decision to undergo PSA-based screening for men aged 55 to 69 years should be an individual one. We have developed and validated a non-invasive diagnostic test (ExoDx Prostate(IntelliScore), EPI) as a decision aid to guide the initial prostate biopsy decision process for men in the PSA gray zone of 2-10 ng/mL. The EPI test is a urine exosome gene expression assay to discriminate high-grade (GG 2) from low-grade (GG 1) and benign disease, thereby reducing the number of unnecessary biopsies. Methods: Patient data from two clinical trials were merged and constrained by age (55-69) according to the USPSTF suggested age-group resulting in a cohort of 701 patients with PSA 2-10 ng/mL, scheduled for initial prostate needle biopsy. EPI test results as well as PCPT2.0 risk calculator, ERSPC risk calculator and PSA results are compared with biopsy outcomes. Performances are reported using the area under the receiver operating characteristic curve (AUC), Negative predictive value (NPV), Positive predictive value (PPV), Sensitivity, and Specificity for discriminating ≥GG2 from GG1 and benign disease. Results: EPI showed a superior AUC of 0.70 compared to PSA (AUC: 0.57), PCPT2.0 (AUC: 0.60) and ERSPC (AUC: 0.58) (all p-values < 0.001) for discriminating ≥GG2 PCa from benign and GG1. The previously validated EPI cut-point of 15.6 would avoid 22% of all prostate biopsies and 29% of unnecessary biopsies, with an NPV of 93% and miss only 5.4% of ≥GG2, respectively. Conclusions: EPI is a non-invasive, easy to use urine exosome RNA expression assay to discriminate high-grade (GG2) from low-grade (GG1) PCa and benign disease. EPI significantly outperformed the other standard of care parameters tested and applying the EPI test for risk stratification of patients in the USPSTF suggested age group, should reduce the number of unnecessary biopsies.
Clinical features and outcomes of secondary somatic malignancy (SSM) associated with primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT).
Authors: Dean Lucas W. , Wong Nathan Colin , Dason Shawn , Isharwal Sumit , Donoghue Mark , Jia Liwei , Tap William D. , Joseph Gabriella , Funt Samuel Aaron , McHugh Deaglan Joseph , Al-Ahmadie Hikmat , Reuter Victor E. , Sheinfeld Joel , Bajorin Dean F. , Motzer Robert J. , Bosl George J. , Bains Manjit S. , Jones David Randolph , Solit David B. , Feldman Darren R.
Published: March 2019

531

Background: The incidence of secondary somatic malignancy (SSM) arising from teratoma is increased in 2 settings; late relapse and primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT). Here, we report the clinical features and outcomes of patients with SSM in the setting of PM-NSGCT. Methods: Between 1985 and 2018, 29 patients with PM-NSGCT and SSM who had sufficient clinical follow-up to evaluate outcome were identified. Clinical and pathologic parameters were reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) from time of SSM diagnosis and the log rank test to compare estimates. Results: Median age was 28 years (range 18-59) and all patients were male. Most presented with local symptoms (n=24, 83%), elevated tumor markers (n=26, 90%), and disease isolated to the mediastinum (n=25, 86%). A total of 39 SSM histologies were present in the 29 cases, with 8 (28%) having 2 (n=6) or 3 (n=2) SSM histologies; 25 (86%) also had viable non-teratomatous GCT in the mediastinal mass. Sarcoma was found in all 29 cases including rhabdomyosarcoma (n=15), angiosarcoma (n=6), sarcoma NOS (n=5), spindle cell (n=4), PNET (n=3), and other (n=3). Non-sarcoma histologies (n=1 each) included AML, SCC, and neuroblastoma. Most patients received GCT-directed chemotherapy followed by an attempt at surgical resection (90%). With a median follow-up of 2 years for survivors, median OS was 1.8 years (95% CI 0-3.9 years), with 18 patients succumbing to disease. Complete surgical resection was achieved in 23 men (79%) and was associated with superior OS (3.1 vs. 0.3 years, p=0.005). At relapse or progression, 11 received SSM histology-directed and 7 GCT-directed chemotherapy with no difference in OS (1.3 vs. 1.2 years, p=0.993). 7 patients developed SSM in the form of leukemia, a finding associated with significantly inferior OS (0.3 vs. 3.0 years, p=0.009). Conclusions: Sarcoma is the predominant SSM histology associated with PM-NSGCT and portends a poor prognosis even with initially localized disease. Complete resection following chemotherapy is critical to achieving long-term survival whereas SSM in the form of leukemia portends especially poor outcome.
Clinical features and outcomes of tumor lysis syndrome in patients with genitourinary cancers.
Authors: Wang Jue , Leung Bryan
Published: March 2019

533

Background: Genitourinary (GU) cancers account about 20% of all human cancer in the United States. Tumor lysis syndrome (TLS) is an oncologic emergency with few treatment options. While TLS has been extensively documented in patients with hematological malignancies, it is rarely described in patients with GU cancers. The objective of this study was to investigate the clinical characteristics and outcomes of TLS, a rare but life-threatening complication in GU cancers. Methods: Systematic review of the literature and pooled analysis of published cases of TLS in GU cancers. Results: A total of 180 patients with TLS in solid tumor were included in our study. The median age was 57 years (8-94). Male: female ratio was 1.7. The most common sites were gastrointestinal (29%); followed by genitourinary (22%); lung (16%); melanoma (11%), breast cancer (8.3%). Liver metastasis was documented in 70% of study subjects. TLS occurred as a consequence of cancer therapy in 68% of subjects; and spontaneously in 32% of subjects. Older age and liver metastasis predict high mortality. The clinical features, treatment and outcomes of TLS in 40 cases of GU cancers including testicular germ cell tumor (TGCT) (n=14), renal cell carcinoma (n=10), prostate cancer (n=15), penile cancer (n=1) and urothelial carcinoma (n=3) were compared. The mortality rate of TLS were 50% in TGCT, 70% in renal cell carcinoma, 64% in prostate cancer 67% in urothelial carcinoma. Conclusions: TLS in GU cancers is associated with very high mortality. TLS should be considered on the differential diagnosis, when evaluating renal failure and electrolyte derangement in patients with metastatic GU cancers with liver metastases. The clinical features and outcomes of TLS in genitourinary cancers. [Table: see text]
Survival rates after retroperitoneal lymph node dissection (RPLND) for testicular seminoma.
Authors: Tabakin Alexandra , Kim Sinae , Polotti Charles , Shinder Brian , Rivera-Nunez Zorimar , Sterling Joshua , Farber Nicholas , Radadia Kushan Dilip , Kim Isaac Yi , Singer Eric A. , Jang Thomas
Published: March 2019

534

Background: RPLND as first-line treatment for testicular seminoma is less well defined than for testicular nonseminomas. Furthermore, RPLND performed in the post-chemotherapy (PC) setting for seminoma patients with a PET avid residual mass > 3 cm can be technically challenging. We describe utilization of RPLND in the primary and PC settings and report on overall survival rates following surgery for these men. Methods: Using 2004-2014 data from the National Cancer Database, we identified 62,727 men with 1° testicular cancer, of which 31,068 men were diagnosed as having seminoma. After excluding men with benign, non-germ cell, and nonseminoma histologies, those who did not undergo RPLND, and those whose clinical stage (CS) or survival data were unavailable, 412 men comprised our final cohort. Men were further stratified according to whether they had 1° RPLND vs PC-RPLND, with 1° RPLND defined as RPLND performed for CS IA-IIB without prior chemotherapy, and PC-RPLND classified as RPLND performed for CS IIA-IIIC after chemotherapy. Descriptive statistics were used to summarize clinical and demographic factors. The Kaplan-Meier method was used to determine overall survival. Results: From 2004-2014, 412 men with testicular seminoma underwent RPLND, of which 89% and 11% were in the 1° and PC settings, respectively. There were no significant differences in clinical or demographic characteristics when comparing men in these 2 groups. The majority of men with testicular seminoma undergoing PC-RPLND were treated at an academic center (63.8%) or comprehensive community cancer program (21.3%). The median follow-up was 4.1 years. Of 372 patients with available survival data, five-year overall survival was 94.2% and 89.0% in the 1° RPLND and PC- RPLND groups, respectively. Conclusions: Though RPLND is rarely used as 1° therapy in testicular seminoma, overall survival rates appear to be excellent, as they do for men with testicular seminoma after PC-RPLND. Ongoing trials evaluating the use of RPLND for early metastatic, low-volume disease will clarify its role in the management of testicular seminoma.
Intraoperative and early postoperative outcomes in post-chemotherapy retroperitoneal lymphadenectomy using validated grading classifications.
Authors: Umbreit Eric , McIntosh Andrew G. , Suk-ouichai Chalariat , Segarra Luis , Holland Levi , Fellman Bryan M. , Tu Shi-Ming , Pettaway Curtis Alvin , Pisters Louis L. , Ward John Francis , Wood Christopher G. , Karam Jose A.
Published: March 2019

535

Background: Post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an integral treatment modality in the management of advanced germ cell tumors. We sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAE) and early postoperative complications. Methods: After IRB approval, we analyzed perioperative outcomes of 453 patients (pts) who underwent PC-RPLND between 2000 and June 2018. iAE and early postoperative complications (within 90 days) were graded using Kaafarani and Clavien-Dindo classification, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications. Results: Of the 453 pts, 287 (63%) were clinical stage III and had a median post-chemotherapy retroperitoneal mass size of 4.1 cm (IQR 2.4-7.4 cm). There were 132 iAE, which occurred in 115 (25%) pts. Early postoperative complications occurred in 255 (56%) pts. Major iAE (grade ≥ 3) was observed in 15 (3%) pts and major postoperative complications (grade ≥ 3) were noted in 83 (18%) pts. The most common iAE was vascular injury (112 of 132 events, 85%), which occurred in 92 (20%) pts. The most common postoperative complication was ileus, occurring in 121 (27%) pts. Residual retroperitoneal mass size (OR = 1.14; 95% CI: 1.09–1.20, p<0.001), non-pulmonary metastases (OR = 3.18; 95% CI: 1.68–6.00, p<0.001), previous laparotomy (OR = 1.92; 95% CI: 1.01–3.66, p=0.047), previous RPLND (OR = 1.14; 95% CI: 1.01–5.59, p=0.046), and adjuvant surgical procedures (OR = 13.54; 95% CI: 7.01–26.14, p<0.001) increased the risk of iAE and postoperative complications. Postoperative complications were more likely for patients that experienced an iAE (OR = 2.50; 95% CI: 1.58–3.97, p<0.001). Conclusions: This is the first analysis of PC-RPLND defining morbidity using validated classifications of severity for iAE and postoperative complications. Larger retroperitoneal mass, non-pulmonary metastases, previous surgery and adjuvant surgical procedures increased the risk of perioperative complications. iAE increased the risk of postoperative complications.
Role of robot assisted retroperitoneal lymph node dissection in metastatic malignant mesothelioma of the tunica vaginalis: Case series.
Authors: Faraj Kassem , Abdul-Muhsin Haidar , Navaratnam Anojan , Rose Kyle , Ho Thai Huu , Bryce Alan Haruo , Singh Parminder , Cheney Scott , Tyson Mark D. , Castle Erik P.
Published: March 2019

536

Background: The management of malignant mesothelioma of the tunica vaginalis of the testes (MMTVT) is not clearly defined, though retroperitoneal lymph node dissection has been reported as a diagnostic and potentially therapeutic option. Herein we present our experience with robot assisted retroperitoneal lymph node dissection (RARPLND) in a series of patients with MMTVT. Methods: The Mayo Clinic cancer registry was queried from 1972-present for all patients who had a diagnosis of MMTVT. Six patients were identified, five of whom were treated with RPLND, where four underwent RARPLND. Data was collected on pertinent demographic, preoperative, perioperative, postoperative outcomes and follow-up oncological data. Results: In five patients who underwent RPLND, the median age was 50 years (IQR 34-51), median BMI was 26.9 (IQR 26.4-30.6). Four patients originally presented with right sided symptomatic hydroceles, while one presented with right sided chronic epididymitis. Orchiectomy (one simple, two inguinal radical) was performed in three patients and hydrocelectomy in the other two patients prior to presentation. Preoperative cross-sectional imaging, including PET-CT scan in three patients, was negative for lymphadenopathy or metastasis. RARPLND was performed in 4/5 (80%) cases and concomitant hemiscrotectomy in 4/5 (80%) cases. Full bilateral template was performed in three patients and right modified template was performed in the remaining two. Median lymph node yield was 29 (IQR 22-32) and median blood loss was 275 cc (IQR 200-300). Positive retroperitoneal lymph nodes were found in 3/5 (60%) cases. Final margins of hemiscrotectomy were negative in all four cases. All patients who underwent RARPLND were discharged home on postoperative day one. One patient received four cycles of adjuvant Cisplatin and Pemetrexed. Mean follow-up was 27 months (range 2-47). No patients recurred. Conclusions: MMTVT is a very rare malignancy with high potential for retroperitoneal lymph node dissemination. Regardless of the approach, RPLND may provide both a diagnostic and therapeutic benefit, with the robotic approach affording a potentially expedited recovery.
Programmed death-ligand 1 (PD-L1) expression in pheochromocytoma.
Authors: Hashimoto Yasuhiro , Yamamoto Hayato , Hatakeyama Shingo , Yoneyama Takahiro , Ohyama Chikara
Published: March 2019

537

Background: Programmed cell death ligand-1 (PD-L1) is a key target molecule of immunotherapy that is frequently overexpressed in several neoplasms. But there were few reports about PD-L1 expression of pheochromocytoma. In the present study, we examined PD-L1 expression in pheochromocytoma. Methods: PD-L1 mRNA expression was compared across 184 pheochromocytoma, 492 prostate cancer cases and 404 bladder cancer cases based on The Cancer Genome Atlas (TCGA). Furthermore, we enrolled 32 pheochromocytoma patients treated with surgery at our hospital between June 2005 and February 2016. We conducted an immunohistochemistry (IHC) of PD-L1 using the SP142 assay. PD-L1 expression was scored at three diagnostic levels (0/1/2). Results: Comparison of PD-L1 mRNA expression based on the TCGA revealed that PD-L1 expression was significantly higher in pheochromocytoma than in bladder cancer and in prostate cancer (p < 0.001). In the SP 142 assay of our 32 pheochromocytoma, the prevalence of positive PD-L1 expression (IHC score 1 or 2 (1/2)) in tumor-infiltrating immune cells (TICs) was 8 patients (25%). The prevalence of positive PD-L1 expression in tumor cells (TCs) was 9 patients (28.1%). Tumor diameter of PD-L1 (+) in TICs patients was 3.36±0.35 cm and that of PD-L1 (-) in TCs patients was 5.37±0.50cm, there was statistically significance between two groups. (unpaired t test: p=0.044) In our cohort, there were two malignant pheochromocytoma. But there were not PD-L1 positive cases in malignant pheochromocytoma. Conclusions: PD-L1 expression is relatively high in pheochromocytoma compared to bladder cancer and prostate cancer based on TCGA. In the SP142 assay of our 32 pheochromocytoma cases, tumor diameter of PD-L1 (-) in TICs cases was larger than that of PD-L1 (+) cases. In our cohort, there were not PD-L1 (+) cases in malignant pheochromocytoma. These findings suggest that PD-L1 expression of pheochromocytoma was comparatively common and PD-L1 positive expression of pheochromocytoma may not be associated with tumor aggressiveness.
Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study.
Authors: Powles Thomas , Plimack Elizabeth R. , Stus Viktor , Gafanov Rustem Airatovich , Hawkins Robert E. , Nosov Dmitry , Pouliot Frederic , Alekseev Boris Yakovlevich , Soulieres Denis , Melichar Bohuslav , Vynnychenko Ihor , Kryzhanivska Anna , Bondarenko Igor , Azevedo Sergio Jobim , Borchiellini Delphine , Shou Qiong , Perini Rodolfo F. , Chen Mei , Atkins Michael B. , Rini Brian I.
Published: March 2019

543

Background: A phase 1b study of pembro (anti–PD-1) plus axi (VEGFR-TKI) showed promising antitumor activity and manageable safety in patients (pts) with previously untreated mRCC. The global, open-label, phase 3 KEYNOTE-426 study assessed the efficacy and safety of pembro + axi vs sunitinib as first-line therapy for mRCC (NCT02853331). Methods: Eligible pts with clear-cell mRCC, no previous systemic therapy for mRCC, and KPS ≥70% were randomized 1:1 to pembro 200 mg IV Q3W for a maximum of 35 cycles plus axi 5 mg orally BID or sunitinib 50 mg orally QD (4-wk on/2-wk off schedule). Treatment was given until PD, intolerable toxicity, or pt/investigator decision. Randomization was stratified by IMDC risk group and geographic region. Primary endpoints were OS and PFS (RECIST v1.1 by blinded, independent central review [BICR]). ORR was the key secondary endpoint. At the protocol-specified first interim analysis, the superiority thresholds were P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR (if OS and PFS were significant). Results: 861 pts were randomized: 432 to pembro + axi, 429 to sunitinib. After a 12.8-mo median follow-up, 59.0% of pts in the pembro + axi arm and 43.1% in the sunitinib arm remained on treatment. Pembro + axi significantly improved OS (HR 0.53 [95% CI 0.38-0.74]; P < 0.0001; 12-mo rate 89.9% vs 78.3%), PFS (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001; median 15.1 vs 11.1 mo), and ORR (59.3% vs 35.7%; P < 0.0001). Duration of response was prolonged with pembro + axi (median not reached vs 15.2 mo). The pembro + axi benefit was observed in all subgroups tested, including all IMDC risk and PD-L1 expression subgroups. Treatment-related AEs were grade 3-5 in 62.9% of pts in the pembro + axi arm vs 58.1% in the sunitinib arm and led to regimen discontinuation in 6.3% vs 10.1%. Conclusions: Pembrolizumab + axitinib provided superior OS, PFS, and ORR compared with sunitinib and had manageable safety in pts with previously untreated, advanced or metastatic clear-cell RCC. These data suggest that pembrolizumab + axitinib should be a new standard of care for this population. Clinical trial information: NCT02853331.