bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.
Authors: Ghinea Nicolae
Published: February 2018

341

Background: Perineural invasion (PNI) is generally accepted as a major route of cancer dissemination encountered in malignancies associated with highly enervated organs. However, the effect of cancer cells on the blood vessels nourishing the nerves (i.e., vasa nervorum) remains unknown. Methods: We used immunohistochemistry involving three specific antibodies that recognize different endothelial markers (CD34, VEGF-R2 and FSHR), and standard histochemical methods (HES, PAS, TRICHROM) to detect changes in the vasa nervorum of nerves invaded by cancer cells in tissue samples from 85 patients diagnosed with locally advanced prostate cancer (LAPC). Genes known to be implicated in the process of angiogenesis and vascular remodeling have been also explored. NanoString nCounter Analysis covering 86 target genes was used for comparison of gene expression levels between LAPC (6 frozen samples) and normal prostate (NP; 2 frozen samples). Results: The percentage of the area occupied by CD34-positive vasa nervorum endothelial cells associated to nerves with PNI was significantly higher than that in nerves without PNI (6.93 ± 1.08 versus 1.76 ± 0.32; p = 0.003), suggesting a process of angiogenesis. In 18/85 (21%) of patients diagnosed with LAPC the vasa nervorum arterioles had a thick (25 ± 5 µm) tunica media consisting of collagen fibers. More than 75% of CD34-positive vasa nervorum of nerves with or without PNI expressed FSHR. In contrast, none of vasa nervorum expressed detectable VEGF-R2. A panel of 19 genes was found to be significantly (p < 0.05), differentially expressed between LAPC and NP. Six of them (ANGPT1, ITGB3, PGGFB, VEGFC, FSHR, and SDC1) have previously been associated with tumor progression, angiogenesis, and metastasis. Other three genes (SELE, SELP, and ESAM) are known to be responsible for the accumulation of blood leukocytes at sites of inflammation by mediating the adhesion of cells to the vascular lining. Conclusions: Perineural invasion of cancer cells caused angiogenesis and vascular remodeling of vasa nervorum in locally advanced prostate cancer.
Primary resistance in docetaxel and androgen deprivation therapy in metastatic castrate sensitive prostate cancer patients.
Authors: Pouptsis Athanasios , Germanou Styliani , Waldron Nick , Young Thomas , Khan Madeha , Hughes Simon , Josephs Debra Hannah , Rudman Sarah Maria , Enting Deborah , Chowdhury Simon
Published: February 2018

342

Background: Docetaxel chemotherapy combined with androgen deprivation therapy (ADT) has become the new standard of care in patients with metastatic castrate sensitive prostate cancer as it has shown significant benefit in terms of overall survival (OS) and response rates (Sweeney 2015, James 2016). However a subgroup of patients still experience early progression. Methods: We searched the hospital database for patients treated with docetaxel in the castrate sensitive setting. Eligible patients included those with newly diagnosed metastatic prostate adenocarcinoma and also patients with relapsed metastatic disease post radical radiotherapy or radical prostatectomy. Patients starting chemotherapy > 12 weeks after commencing ADT were excluded. Results: We identified 72 patients treated with docetaxel and ADT between August 2014 and September 2017. The median age was 66 years (49-84 years). Of the 72 patients, 63 (88%) had bone metastases, 5 (7%) had visceral metastases and 45 (63%) had pelvic lymph node disease. Seven patients (9.7%) had relapsed metastatic disease post radical treatment. All patients had ≤6 cycles of docetaxel. Median time from diagnosis of metastatic disease to commencing castrate resistant treatment was 13 months (2-41 months). Median duration of follow-up was 16 months (5-39 months). Six patients (8%) had biochemical, radiological or clinical progression during, or at completion of docetaxel chemotherapy. One patient terminated treatment before completion of six cycles due to disease progression. The median presenting PSA in this group was 49.5 ug/L (9.04-2290 ug/L) and 2 patients had visceral disease. Of these 6 patients, 2 have died, and the median OS for the group was 11.5 months (8-22 months). Five patients were subsequently treated with enzalutamide and 1 with abiraterone. Conclusions: Despite the improvement in OS and response rates with the use of early docetaxel, a clinically significant number of patients developed disease progression during treatment, and these patients have a particularly poor prognosis. These patients should be the focus of future clinical trials.
Clinical experience with PSMA-Actinium-225 (Ac-225) radioligand therapy (RLT) in end-stage metastatic castration-resistant prostate cancer (mCRPC) patients.
Authors: van der Doelen Maarten Johannes , Mehra Niven , Smits Minke , van Oort Inge M. , Janssen Marcel J.R. , Haberkorn Uwe , Kratochwil Clemens , Gerritsen Winald
Published: February 2018

344

Background: Prostate-specific membrane antigen (PSMA) is an ideal target for RLT in mCRPC patients (pts). Alpha-emitting radioisotope Actinium-225 (Ac-225) may be more efficacious than beta-emitting Lutetium-177, due to higher rates of double-strand DNA breaks in prostate cancer cells, with less tissue penetration and minimal bystander effects in PSMA-negative cells. Limited data is available on the clinical efficacy and side effects of PSMA-Ac-225 RLT in mCRPC pts. Here we describe our clinical experience so far. Methods: Between February 2016 and October 2017, 11 pts underwent PSMA-Ac-225 RLT in Heidelberg, Germany. Prostate-specific antigen (PSA) responses were measured every two weeks. Pts underwent PSMA PET/CT prior to and after RLT. Consenting pts had tissue and blood collected for translational biomarker studies, including targeted-next generation sequencing and whole genome sequencing to discover biomarkers and mechanisms of RLT resistance. In addition, pts received structured questionnaires on quality of life and xerostomia evaluation. Results: All pts were heavily pre-treated, with a median of four therapies prior to PSMA-Ac-225 RLT. Pts underwent a median of three RLT cycles (range 1-4 cycles) of median 8 MBq (range 6-10 MBq). Five pts (45%) had died at time of analysis. Median overall survival since start of RLT was 12.6 months (95% CI 5.0-20.1). Median baseline PSA was 878 µg/L (range 6-2249). Eight of eleven pts had > 50% PSA response, with median change in PSA reduction of 87%. Six pts were evaluable according to PCWG3 criteria with 5/6 (83%) pts showing partial responses, and one patient with stable disease following RLT. No grade 3-4 hematologic toxicity occurred. Grade 2-3 xerostomia was mentioned by all pts. Pts with features of neuro-endocrine prostate cancer (NEPC) showed less response to RLT, with blood-based NEPC biomarkers increasing during RLT. Conclusions: PSMA-Ac-225 RLT resulted in remarkable clinical, biochemical and radiological responses in end-stage mCRPC pts, and may be considered a promising therapy for mCRPC pts.
Are prostate cancer treatments correlated to sleep distress?
Authors: Mitteldorf Darryl , Nelms Jerrod
Published: February 2018

347

Background: Sleep distress associated with prostate cancer due to emotional issues like anxiety is well documented. But there have been no investigations focused on sleep distress correlated to specific types of prostate cancer treatments. Methods: During a ten day period in July, 2016, 963 men diagnosed with prostate cancer completed an online survey containing demographic and treatment history questions, the Pittsburg Sleep Quality Index (PSQI) and a current state of health self-assessment. The subjects were randomly chosen from the Malecare prostate cancer support network in the United States and completed the survey. 27% of survey subjects reported being initially diagnosed with Gleason 8 or higher. 42% reported using either androgen deprivation therapy, Zofigo, Xtandi or Xofigo within three months of our survey. Only 5% had been continually on active surveillance. We compiled the PSQI Component score and correlated the scores to a specific prostate cancer treatments, adjudicating for pre-existing conditions such as emotional disorders or apnea. We stratified for race, age, sexual orientation and if the subject had a sleep partner. Results: The PSQI handout says that a total score of 5 or greater indicates sleep distress worthy of consultation with a healthcare provider. Our investigation also considered a “4” to indicate poor sleep quality among participants. Only 398 (41.33%) of our participants scored less than 5 on the PSQI, while only 232 (24.09%) scored less than 4. From these statistics, we showed that over 75% of our study sample suffered sleep distress. However, our analysis failed to disclose significant correlations between specific types of prostate cancer treatments and extent of sleep distress. We did not see correlations regarding subject’s age, race, sleep co-habitation, time from diagnosis to survey and other treatment and demographic stratifications. Conclusions: Sleep distress is well established and broadly experienced by prostate cancer patients. Our study showed there is no advantage to any specific prostate cancer treatment in terms of sleep distress. We also found that severity and instances of sleep distress are distributed without significance across age, race, sexual orientation and time to treatment after diagnosis.
Disseminated intravascular coagulation secondary to advanced prostate cancer: Clinical characteristics, management, and prognosis.
Authors: Ni Benny , Wang Jue
Published: February 2018

355

Background: Although disseminated intravascular coagulation (DIC) is a recognized complication of prostate cancer, little is known about the clinical features and optimal management of these patients. Although anecdotal case studies indicating that the prognosis of prostate cancer associated with DIC might improve with chemotherapy, the clinical data from single case report are far from sufficient for establishment of a standardized treatment strategy. The main objective of this study was to determine the clinical features, treatment and prognosis clinical outcome of patients with prostate cancer complicated by DIC. Methods: We conducted a pooled analysis of 85 prostate cancer patients diagnosed with DIC, two treated in our institution and 83 patients from published literature between January 1976 and June 2017. Results: Eighty-five patients were included in final analysis. The median age was 68 years (range, 44 to 92 years). The majority of patients (98%) has adenocarcinoma. Two (2%) patients with small cell carcinoma. The median of PSA was 614 ng/ml (range: 0.8 – 8138). A Gleason score of 8 or higher was found in 67% of patients. Distant metastasis was reported in 98% of patients. At diagnosis of DIC, the median platelet count was 75 *109 /L (range: 3-205). Regarding the presenting symptoms of DIC, subcutaneous bleeding was reported in 64% of cases; hematuria in 27%. Invasive procedure including prostate biopsy might have been the provoking events of DIC in 25% of the cases. Seventy-one patients received cancer directed therapy including various androgen deprivation, chemotherapy, and novel androgen signaling inhibitor, whereas 13 patients received only best supportive care (BSC). The median overall survival (OS) of the entire cohort of patients was 10 months (95% confidence interval [CI], 5.3-14.7). Significantly prolonged OS was observed in the cancer therapy group, with a median survival of 12 months compared to 2 weeks in the BSC group (p < 0.001, log-rank test). Conclusions: Our analysis showed that patients with prostate cancer complicated by DIC had very poor prognosis, and active cancer therapy might improve OS of these patients.
Treatment outcome of everolimus against neuroendocrine prostate cancer (NEPC).
Authors: Shimomura Tatsuya , Kurauchi Takashi , Sakanaka Keigo , Egawa Shin
Published: February 2018

365

Background: Neuroendocrine prostate cancer (NEPC) is a lethal disease subset with median overall survival of less than 1 year from time of detection. The treatment strategy against NEPC is not yet established. Some clinical trials are ongoing now. Recently, clinical trial (RADIIANT4) showed that treatment with everolimus was associated with significant improvement in survival in patients with progressive lung or gastrointestinal neuroendocrine tumors. And FDA approved new indication for everolimus for progressive, nonfunctional GI and lung neuroendocrine tumors last year. In this study we tried to introduce everolimus against pathologically proven NEPC and investigated the clinical outcomes of this agent. Methods: Total of seven cases were included in this study. All cases were proven the existence of neuroendocrine prostate cancer pathologically. Everolimus (10mg/d) were introduced into all cases. We investigated the neuroendocrine tumor markers (neuron-specific enolase: NSE, and pro-gastrin-releasing peptide: pro GRP), radiologic examination and survival. Results: The median follow up period was 6 months. At least one of the tumor markers increased above normal limit in all cases. NSE increased in four cases, pro GRP increased in five cases and both markers increased in two cases. Tumor markers decreased in five of seven (71.4%) cases (NSE: 2 of 4 cases, pro GRP: 4 of 5 cases) after introduction of everolimus. Median decreasing rate were 67.1% in NSE and 65.5% in pro GRP. Two of seven (28.6%) cases progressed in radiologic examination and died from prostate cancer. One case was very advanced disease and everolimus was introduced after failure of systemic chemotherapy (CDDP + etoposide). Another case was advanced disease with bone marrow carcinomatosis. In terms of adverse event, 4 cases had stomatitis and one case had hyperglycemia. Conclusions: In this study, evelolimus showed efficacy against NEPC. It decreased tumor markers and stabilized the tumor status. Although this study was retrospective and number of cases was limited, there is a possibility that evelolimus would be a one of the treatment options against NEPC.
Prognostic and predictive role of CTCs and AR-V7+ CTCs expression in metastatic catrate resistant prostate cancer (mCRPC): A feasibility study.
Authors: Maruzzo Marco , Rossi Elisabetta , Basso Umberto , Facchinetti Antonella , Anile Giuseppe , Pierantoni Francesco , Galuppo Sara , Evangelista Laura , Pizzirani Enrico , Zamarchi Rita , Zagonel Vittorina
Published: February 2018

367

Background: Circulating tumor cells (CTC) counts ≥ 5/7.5 mL predict shorter survival in patients (pts) with mCRPC. Moreover, the presence of androgen receptor splice variant-7 mRNA (AR-V7) in CTCs is thought to play a relevant role in the development of primary or acquired resistance to enzalutamide (E) or abiraterone (A). We developed a new immunofluorescence-based assay for AR-V7+ CTCs and tested its association with PFS and OS. Methods: We performed a single-centre observational prospective trial enrolling pts with mCRPC candidate to receive E or A. CTC samples have been collected at baseline, after 1 month (mo) and every 3 mos thereafter until progression or at 12 mos without progression. CTCs have been enumerated with CellSearch System. We integrated the standard assay with a mAb able to recognize the AR-V7 protein. Slides from samples underwent automated immunofluorescent staining and AR-V7+ CTCs were enumerated. Results: Since Sep 2016, 31 pts have been enrolled (Table). We compared CTC counts between standard and the integrated assay and found no differences in the mean total CTC number ± (Wilcoxon Signed Rank test, p= 0.31). 16 out of 28 evaluable pts (57%) had ≥ 1 CTCs at baseline, 9 pts (32%) had ≥ 5 CTCs/7.5 ml, 4 pts (14.3%) were AR-V7+ before any exposure to A or E. After a median follow-up time of 8.1 mos, 6 pts have progressed and 4 died. No association has been found between CTCs ≥ 5/7.5 mL and survival. The presence of at least 1 AR-V7+ CTC at baseline did not correlate with PSA response, but had a weak association with shorter PFS (log-rank test, p = 0.055) and a significant impact (p = 0.02) on OS. Conclusions: We developed a new integrated assay for AR-V7+ CTCs, based on an automated platform that permits serial sampling with low inter- / intra-test variability. The clinical utility in anticipating the resistance to E or A is under study. [Table: see text]
Germline pathologic mutations and cancer family history in prostate cancer patients.
Authors: Moses Marcus Marie , Ledet Elisa , Ernst Emma M. , Cotogno Patrick , Schiff Joshua , Lewis Brian E. , Sartor A. Oliver
Published: February 2018

378

Background: Prostate cancer (PCa) patients (pts) with metastases and/or strong family history (FH) of cancer (Ca) are at higher risk of a germline mutation. The identification of alterations in PCa pts may be important for risk stratification as well as personalizing treatment options. The goal of this study was characterization of FH and pathogenic variants (PV) detected in PCa pts, with both localized and metastatic disease. Methods: 300 PCa pts from Tulane Cancer Center underwent germline testing. 265 Caucasian (C) and 35 African-Americans (AA) were tested and met the NCCN criteria for testing and/or had distant metastases (mets). Germline genetic testing was done via commercial panels (30-80 genes) (Invitae. San Francisco, Ca). PCa pts had extensive FH screening. Clinical annotation included age at diagnosis (dx), race, and presence of mets at any time. Chi square tests were used to compare clinical correlates and PVs. Results: Of the 300 pts tested, 182 pts (60.6%) had mets and 118 (39.4%) did not. 41 pts (13.6%) had ≥ 1 germline pathogenic variant (PV) and 161 pts (53.6%) had ≥ 1 germline variant of uncertain significance (VUS). PVs were detected in BRCA2 (n = 10), MUTYH (n = 8), CHEK2 (n = 6), BRCA1 (n = 4), ATM (n = 4), TP53 (n = 3), PMS2 (n = 2), BLM (n = 2), MITF (n = 2), NBN (n = 1), and RAD51D (n = 1). MUTYH and MITF are not known to be linked to prostate cancer. There was no significant relationships in FH PCa and FH non-PCa in regard to likelihood of a PV (p = .86 and p = .18). Of the 300 pts tested, 136 pts (45.3%) had PCa FH, 131 pts (43.6%) had breast Ca FH, 61 pts (20.3%) had lung Ca FH, 61 pts (20.3%) had colon Ca FH, 37 pts (12.3%) had pancreatic Ca FH, and 32 pts (10.6%) had ovarian Ca FH. 45.6% of C men (n = 121) and 42.8% of AA men (n = 15) had PCa FH. Pts with a non-PCa FH (n = 255) were 1.37 times more likely to develop mets (p = .01168). The median age of dx were 61 for PV pts, 62 for VUS pts, and 61 for negative pts (non-significant). 21/182 pts with mets (11.5%) had a PV; 8/182 (4.4%) pts with mets had a BRCA2 PV. Conclusions: In metastatic patients, FH of prostate cancer alone cannot predict those with PV. The most common Cas observed in these pts were breast, lung, colon and pancreatic. A larger cohort is needed to fully characterize and understand the co-segregation of PCa with other Cas.
An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi , Snyder Lawrence B , Willard Ryan R , Vitale Nicholas , Raina Kanak , Pizzano Jennifer , Gordon Deborah A , Bookbinder Mark , Macaluso Jennifer , Dong Hanqing , Liu Zheng , Ferraro Caterina , Wang Gan , Wang Jing , Crews Craig M , Houston John , Crew Andrew P , Taylor Ian
Published: February 2018

381

Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC that leads to ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, DMPK, toxicology and preclinical efficacy studies. Results: This AR PROTAC completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. The AR PROTAC degrades all clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, the AR PROTAC demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.
Interim analysis of a prospective randomized trial of dietary carbohydrate restriction for men with a rising PSA after failed primary treatment: Carbohydrate and Prostate Study 2 (CAPS2).
Authors: Freedland Stephen J. , Allen Jenifer , Armstrong Andrew J. , Moul Judd W. , Sandler Howard M. , Levin Dana , Howard Lauren E. , Lin Pao-hwa
Published: February 2018

382

Background: Nearly one third of men treated with curative intent for localized prostate cancer (PC) will develop a rising PSA. The rate of PSA rise (PSA doubling time aka PSASDT) is a predictor metastases and PC death. In laboratory mice, an extreme low carbohydrate diet slows PC growth. We tested whether this diet could slow PSADT in men with recurrent PC. Methods: We are conducting a 6-month multi-center randomized phase II trial of dietary carbohydrate restriction vs. no diet intervention control. Men had to have a BMI ≥24 kg/m2, received radical prostatectomy or definitive local radiation for PC, had a PSA 0.4-20.0 ng/ml (3-20 if prior radiation therapy) within the past 3 months, and current PSADT 3-36 months. The intervention arm was instructed to eat < 20 grams/carbs/day with no other limits. The control arm was told to make no diet. In this interim analysis, we present the efficacy of the dietary intervention with regards to weight loss. Arms were compared using rank-sum. Total anticipated enrollment is 60. The primary outcome is differences in PSADT between arms. Secondary outcomes include weight loss, and dietary make-up. Results: To date, 28 patients (14 in each study arm) have completed the study. Characteristics were well-balanced at baseline. At the 6-month dietary assessment, calorie consumption was similar between the two study arms (p = 0.090) among the 16 patients (7 low-carb, 9 control) with diet information. Subjects in the low-carb arm ate fewer carbs (29 vs. 188 g, p = 0.008) and more protein (125 vs. 73 g, p = 0.044) but similar amounts of fat (75 vs. 67 g, p = 0.672) vs. subjects in the control arm. Six months on the low carb diet resulted in greater weight loss (median: 31.7 vs. 0.8 lbs, p < 0.001), lower BMI (24.4 vs. 29.6 kg/m2, p < 0.001), and smaller waist circumference (95.7 vs. 108.9 cm, p = 0.002). Conclusions: In this interim analysis of an on-going dietary study for men with a rising PSA after definitive local treatment, an extreme low carbohydrate diet results in dramatic weight loss in 6 months. Whether this weight loss slows PC growth is an on-going question. Clinical trial information: NCT01763944.
Results of POUT: A phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC).
Authors: Birtle Alison Jane , Chester John David , Jones Robert Jones , Johnson Mark , Hill Michaela , Bryan Richard T , Catto James , Donovan Jenny , French Ann , Harris Chris , Keeley Francis , Kockelbergh Roger , Powles Thomas , Todd Rachel , Tregellas Lucy , Wilson Caroline , Winterbottom Andrew , Lewis Rebecca , Hall Emma ,   On Behalf of the POUT Investigators
Published: February 2018

407

Background: The role of post nephro-ureterectomy (NU) treatment for UTUC is unclear. POUT (CRUK/11/027; NCT01993979) addresses whether adjuvant chemotherapy improves disease free survival (DFS) for pts with histologically confirmed pT2-T4 N0-3 M0 UTUC. Methods: Pts (max n = 345) ≤90 days post NU were randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly cross sectional imaging and cystoscopy for the first 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. The trial was powered to detect a hazard ratio (HR) of 0.65 (i.e. improvement in 3 year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p < 0.001) early stopping rules for efficacy & inefficacy. Secondary endpoints included metastasis-free survival (PFS), overall survival (OS), toxicity & quality of life. Results: Between May 2012 & Sept 2017, 248 pts were recruited (123 surveillance; 125 chemotherapy) at 57 UK centres. In Oct 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected thus far (data snapshot 05/09/2017) met the early stopping rule for efficacy. At the time of interim analysis, median follow-up was 17.6 months (IQR 7.5-33.6). Pts had median age 69 years (range 36-88), 30% pT2, 65% pT3; 91% pN0;. Grade ≥3 toxicities were reported in 60% chemotherapy pts & 24% surveillance pts. 47/123 (surveillance) & 29/125 (chemotherapy) DFS events were reported; unadjusted HR = 0.47 (95% CI: 0.29, 0.74) in favour of chemotherapy (log-rank p = 0.0009). Two year DFS was 51% for surveillance (95% CI: 39, 61) and 70% for chemotherapy (95% CI: 58, 79). PFS favoured chemotherapy: HR = 0.49 (95% CI: 0.30, 0.79, p = 0.003). Conclusions: Adjuvant chemotherapy improved PFS in UTUC. POUT is the largest randomised trial in this pt population; the trial was terminated early because of efficacy favouring the chemotherapy arm. Whilst follow up for OS continues, this should be considered a new standard of care in these patients. Clinical trial information: ISRCTN98387754.
Selective bladder preservation with twice-daily radiation plus 5-flourouracil/cisplatin (FCT) or daily radiation plus gemcitabine (GD) for patients with muscle invasive bladder cancer: Primary results of NRG/RTOG 0712—A randomized phase 2 multicenter trial.
Authors: Coen John J , Zhang Peixin , Saylor Philip James , Lee Cheryl T. , Wu Chin-Lee , Parker William , Lautenschlaeger Tim , Zietman Anthony L. , Efstathiou Jason A. , Jani Ashesh B. , Kucuk Omer , Souhami Luis , Rodgers Joseph P , Sandler Howard M. , Shipley William U.
Published: February 2018

408

Background: To assess GD or FCT as the chemoradiation (CRT) component of a bladder sparing regimen. Methods: Patients with T2-4a bladder cancer were randomized. Patients had a maximal transurethral resection and induction CRT to 40 Gy followed by cystoscopic assessment. Patients with a complete response (CR) received consolidation CRT to 64 Gy. Others were offered cystectomy and no further CRT. Adjuvant gemcitabine/cisplatin chemotherapy was subsequently administered. The primary endpoint was the rate of distant metastasis at 3 years (DM3). Toxicity and other efficacy related endpoints including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3) were also assessed. Using the Clopper-Pearson method, the study required 32 patients per arm, with a benchmark DM3 of 25% and a 1-sided significance level of 0.1. If both arms meet this benchmark, toxicity will be used to select a regimen for future study. This study was not designed to compare arms. Results: From 12/2008 to 4/2014, 70 patients were enrolled; 66 were eligible for analysis (33 per arm). Median follow-up was 4.3 years. DM3 was 22% and 16% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. CR rates were 88% and 78%, respectively. Of 33 patients in the FCT group, 32 (97%) completed induction, 27 (93%) completed induction and consolidation, and 18 (55%) completed the entire protocol. Of 33 patients in the GD group, these figures were 31 (94%), 23 (92%), and 16 (49%), respectively. Of 33 patients in the FCT group, 21 (64%) had grade 3-4 toxicity during protocol treatment with 18 (55%), 2 (6%) and 2 (6%) experiencing hematologic, GI and GU toxicity, respectively. For 33 patients in the GD group, these figures were 18 (55%) overall and 14 (43%), 3 (9%) and 2 (6%), respectively. Conclusions: Both regimens are promising, given DM3 rates < 25%. As there was less toxicity in the GD arm, it would be reasonable to consider a gemcitabine based option as well as a cisplatin based regimen for future trials. Daily radiation may be as effective as twice-daily radiation, which may broaden appeal. Clinical trial information: NCT00777491.
New 6-factor prognostic model for patients (pts) with advanced urothelial carcinoma (UC) receiving post-platinum atezolizumab.
Authors: Pond Gregory Russell , Niegisch Guenter , Rosenberg Jonathan E. , Dreicer Robert , Powles Thomas , Necchi Andrea , Wei Xiao X. , Grivas Petros , Balar Arjun Vasant , Galsky Matt D. , Srinivas Sandy , Choueiri Toni K. , Bellmunt Joaquim , Bajorin Dean F. , Sonpavde Guru
Published: February 2018

413

Background: Prognostic factors for overall survival (OS) have been identified in pts receiving post-platinum chemotherapy for advanced UC, but it is unknown whether these factors and/or others optimally predict OS for pts treated with PD1/PD-L1 inhibitor therapy. Methods: Pt level data from two UC salvage trials evaluating atezolizumab were used: IMvigor210 (n = 310) for training and PCD4989g (n = 95) for validation. Univariable and multivariable Cox regression analyses were performed to evaluate the association of the prognostic factors recognized in the chemotherapy setting (ECOG performance status [ECOG-PS], liver metastasis (LM), anemia, treatment-free interval, albumin), neutrophil-lymphocyte ratio (NLR), eosinophil count, platelet count (PLT), site of primary/metastases, stage at diagnosis, smoking, LDH, prior therapies and immune cell PD-L1 status by IHC with OS. Clinical factors were dichotomous and lab values normalized by logarithmic transformation as needed. Stepwise selection was employed to propose an optimal model using the training dataset; pts were then categorized by number of risk factors. Concordance, discrimination (c-statistic) and calibration were assessed in the validation dataset using bootstrap analyses. Results: The factors included in the optimal prognostic model for OS were: ECOG-PS 1 vs. 0 (HR 1.64 [95% CI: 1.20, 2.24], p = 0.002), LM (1.45 [1.08, 1.94], p = 0.014), PLT (1.73 [1.14, 2.61], p = 0.010), NLR (1.84 [1.45, 2.34], p < 0.001), LDH (1.54 [1.19, 1.99], p = < 0.001) and anemia (HR = 1.60 [1.17, 2.21] p = 0.004). The c-statistic was 0.690 (95% CI = 0.649-0.715) and 0.759 (0.694-0.795) in the training and validation datasets, respectively. 1-year OS of pts in the training and the validation cohorts were similar. PD-L1 score was statistically significant when adjusted for the optimal model, but did not improve clinical interpretability (c-statistic = 0.698). Conclusions: A new validated 6-factor prognostic model for OS including ECOG-PS, LM, PLT, NLR, LDH and anemia is proposed in the setting of post-platinum atezolizumab for advanced UC. Applicability of the model to other PD1/PD-L1 inhibitors and PD-L1 IHC assays warrant investigation.
A comparison of nephrotoxicity between patients with a solitary-functioning kidney and those with bilateral-functioning kidneys in cisplatin-based chemotherapy for advanced urothelial carcinoma: A Japanese retrospective multi-institutional study.
Authors: Inoue Takamitsu , Miyazaki Jun , Ichioka Daishi , Narita Shintaro , Kageyama Susumu , Sugimoto Mikio , Mitsuzuka Koji , Kinoshita Hidefumi , Kikuchi Eiji , Matsui Yoshiyuki , Fujie Keiko , Habuchi Tomonori , Nishiyama Hiroyuki
Published: February 2018

420

Background: To compare the prevalence of nephrotoxicity between patients with a solitary-functioning kidney versus those with bilateral-functioning kidneys during the administration of cisplatin-based chemotherapy for advanced urothelial carcinoma. Methods: We retrospectively analyzed 244 advanced urothelial carcinoma patients treated with cisplatin-based chemotherapy between 2004 and 2010 at 17 institutes in Japan. The urinary tract function status was determined based on the data of nephroureterectomy, hydronephrosis, and relief of upper urinary tract obstruction. A total of 244 patients were divided into four groups according to their urinary tract functioning status and eGFR results, including bilateral-functioning kidneys with pretreatment eGFR≥60 mL/min/1.73 m2 group (n = 83, 34.0%); a solitary-functioning kidney with pretreatment eGFR≥60 mL/min/1.73 m2 group (n = 36, 14.8%); bilateral-functioning kidneys with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 45, 18.4%); and a solitary-functioning kidney with pretreatment eGFR < 60 mL/min/1.73 m2 group (n = 80, 32.8%). Results: The prevalence of nephrotoxicity with impaired eGFR of > 10% and 30% from baseline in the post-third-course of chemotherapy was significantly higher in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney, among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.023 and p = 0.026). During all courses of chemotherapy, the prevalence of nephrotoxicity with impaired eGFR of > 20% from baseline were significantly higher in patients with bilateral-functioning kidneys than those with a solitary-functioning kidney among patients with pretreatment eGFR < 60 mL/min/1.73 m2 (p = 0.034), whereas no significant difference was observed among patients with pretreatment eGFR ≥60 mL/min/1.73 m2. Conclusions: The results suggest that cisplatin-based chemotherapy may have more nephrotoxicity in patients with bilateral-functioning kidneys than in those with a solitary-functioning kidney.
Immune-related adverse events (irAE) in GU cancer patients receiving immune checkpoint inhibitors.
Authors: Zang Peter , Drakaki Alexandra , Faiena Izak , Chan Betty , Tsao-Wei Denice , Groshen Susan G. , Quinn David I. , Dorff Tanya B.
Published: February 2018

422

Background: Immune checkpoint inhibitors (ICI), particularly PD-1 and PD-L1 antibodies, prolong survival in advanced renal cell (RCC) and urothelial cancer (UC) patients. However, they can cause a variety of serious irAE. We assessed frequency and onset of irAE at experienced centers, and evaluated whether baseline characteristics were associated with irAE. Methods: Pharmacy and clinic schedules identified RCC and UC patients treated with ICI at USC Norris (n = 51) and UCLA (n = 26) from 2014-2016. Prior radiation was defined as completion within 3 months before ICI. Fisher’s exact 2-tailed test was used to evaluate for associations of variables with irAE. Results: 77 patients median age 69 years (49-93) received ICI, 31 with RCC and 46 with UC; 36 received atezolizumab, 29 nivolumab, 9 pembrolizumab, 2 durvalumab, and 1 avelumab. 25 (32.5%) had irAE including pneumonitis (4%), myositis (3%), neurologic event (1%), hepatitis (8%), colitis (1%), rash (8%), endocrinopathy (6%), or hematologic event (1%). 11 (14%) required steroids, 3 (4%) required more intense immunosuppression (infliximab), 1 died of complications from irAE (pneumonitis). 5 were rechallenged with ICI after irAE resolution. Median time to onset of irAEs was 15 weeks; earliest onset of irAE (non-dermatologic) was 3 days after 1st dose, latest onset was 112 weeks. Associations of irAE with variables are listed in the table. Conclusions: irAE were more common in our experience than in published datasets, especially endocrine events, and could occur after the first dose. There was an association between irAE and allergy to antibiotics as well as external beam radiation therapy (EBRT) within 3 months before ICI therapy. [Table: see text]
Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) in patients (pts) with impaired renal function.
Authors: Koshkin Vadim S. , Barata Pedro C. , Zahoor Haris , Rybicki Lisa A. , Almassi Nima , Redden Alicia M , Fergany Amr Farouk , Kaouk Jihad , Haber Georges-Pascal , Stephenson Andrew J. , Martin Allison , Allman Kimberly D , Beach Jennifer , Ornstein Moshe Chaim , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I. , Grivas Petros
Published: February 2018

446

Background: Cisplatin-based NAC followed by radical cystectomy is the standard of care in MIBC but many pts are cisplatin-unfit. Data in pts with low glomerular filtration rate (GFR) who receive cisplatin-based NAC is limited. Methods: A retrospective analysis of pts who received cisplatin-based NAC at Cleveland Clinic (2005-2016) was conducted. Pts with pre-NAC GFR < 60 ml/min by either CG or MDRD formula (low GFR; N = 30) were compared to pts with GFR ≥60 (normal GFR; N = 94) in terms of NAC tolerability and outcomes including pathologic complete (pCR, pT0N0) and partial response (pPR, < pT2N0). A secondary analysis compared 3 groups of pts: GFR < 50ml/min (N = 10), GFR 50-59 ml/min (N = 20), and GFR ≥60 (N = 94). Results: Low GFR pts were older (median age 71 vs 65, p < 0.001) and had higher rates of hydronephrosis (33% vs 15%, p = 0.03). ECOG PS, other demographic and TURBT features (stage, LVI, CIS) did not differ significantly. Low GFR pts were more likely to receive gemcitabine/cisplatin (83% vs 71%, p = 0.04) and get split-dose cisplatin (38% vs 16%, p = 0.02). Split-dose cisplatin use in low GFR pts did not impact NAC tolerability or outcomes. NAC cycles completed (median 3 per group) were comparable, and most low GFR pts (70%) completed intended NAC regimen. Low GFR pts were more likely to have early NAC discontinuation (30% vs 13%, p = 0.03) and NAC modification (delay, dose reduction, discontinuation) (66% vs 40%, p = 0.02). No differences were seen in cystectomy completion rate (93% per group), time to cystectomy, length of stay, surgical complications, and GFR change from baseline. Combined pCR/pPR was higher in normal GFR group (54% vs 25%, p = 0.01). Among pts with very low GFR ( < 50 ml/min), 60% completed intended NAC regimen and 70% had NAC modification. Rates of pCR and pPR were low: 0% and 12%, respectively. Conclusions: Low GFR pts were older, had more NAC discontinuations/modifications and lower pCR/pPR rate, but most completed planned NAC cycles. Relative to normal GFR pts, low GFR pts were not prevented or delayed in getting cystectomy, and had comparable impact of NAC on GFR. For carefully selected pts with GFR < 60 ml/min, cisplatin-based NAC is a treatment option, consistent with prior data.
Nomogram-based risk prediction of local and distant relapse after radical cystectomy, and role of perioperative chemotherapy, in patients with muscle-invasive bladder cancer (MIBC): A multicenter study.
Authors: Necchi Andrea , Pond Gregory Russell , Plimack Elizabeth R. , Niegisch Guenter , Yu Evan Y. , Pal Sumanta K. , Bamias Aristotelis , Agarwal Neeraj , Alva Ajjai Shivaram , Srinivas Sandy , Crabb Simon J. , Vaishampayan Ulka N. , Bowles Daniel W. , Berthold Dominik R. , Theodore Christine , Sridhar Srikala S. , Powles Thomas , Rosenberg Jonathan E. , Bellmunt Joaquim , Galsky Matt D. ,   Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)
Published: February 2018

448

Background: Neoadjuvant and adjuvant chemotherapy improve relapse-free survival (RFS) and overall survival of patients (pts) with MIBC. Limited information is available regarding risk prediction of local (RL) vs. distant relapse (RD), including role of perioperative chemotherapy (POC), added to radical cystectomy (Cy). Methods: Data from 1,559 pts, treated at 29 centers from the U.S., Europe, Israel, and Canada, were collected. Pts received Cy for MIBC from 02/90 to 12/13. Of these pts, 782 (50.2%) received POC and Cy, 777 (49.8%) Cy alone. RL and RD were defined as follows: pelvic lymph-nodes/soft tissue only and any extra-pelvic recurrences, respectively. Cumulative incidence methods were used to estimate time-to-(TT) RL/RD, which accounts for the competing risk of other types of relapse. Univariable and multivariable (MVA) Cox regression analyses were performed from the complete-case dataset (n = 1,082). Risk groups were defined according to the number of adverse factors, with corresponding nomogram-based RL and RD risk estimation. All tests were two-sided and statistical significance was defined as a p-value of 0.05 or less. Results: A total of 830 pts (55%) developed a relapse, 447 in the Cy group and 383 in the Cy+POC group. On MVA, POC administration was associated with longer TTRL (p < 0.001) and TTRD (p < 0.001). Other factors associated with RL: histology (non-UC, odds ratio [OR] = 1.47, 95%CI: 1.07-2.01, p = 0.022), pT-stage (p < 0.001), pN-stage (p = 0.038), surgical margins (p < 0.001). For RD: Charlson score (p = 0.006), pT-stage (p < 0.001), pN-stage (p < 0.001). The c-index of the model for RL was 0.685 (95% bootstrapped CI: 0.664-0.718), and for RD was 0.684 (0.655-0.721). Three risk group categories were obtained for both endpoints (0, 1-2, and > 2 risk factors). Results were confirmed after applying 90-day or 180-day landmark analyses, pending external validation. Conclusions: In the largest study that separately analyzed RL and RD risk, we were able to provide risk tools that may be used to optimize locoregional treatments and compare POC benchmark with new drugs in the perioperative setting.
Immunological correlates of response to immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts).
Authors: Tzeng Alice , Diaz-Montero C. Marcela , Rayman Patricia A. , Kim Jin Sub , Pavicic Paul G , Finke James , Barata Pedro C. , Lamenza Marcelo , Devonshire Sarah , Schach Kim , Emamekhoo Hamid , Ernstoff Marc S. , Hoimes Christopher J. , Rini Brian I. , Garcia Jorge A. , Gilligan Timothy D. , Ornstein Moshe Chaim , Grivas Petros
Published: February 2018

454

Background: Identification of biomarkers predictive of response to ICI could help guide treatment (tx) decisions. We assessed the correlation between PD1/PDL1 expression in key immunomodulatory subsets (myeloid-derived suppressor cells [MDSC]; CD8+ T cells) and tx response in mUC pts treated with ICI. Methods: Serial peripheral blood samples were collected from mUC pts treated with ICI. Flow cytometry was used to quantify PD1/PDL1 expression in MDSC (CD33+HLADR−) and CD8+ T cells (CD8+CD4−) from live peripheral blood mononuclear cells. MDSC were subdivided into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14− CD15+), and immature (I)-MDSC (CD14− CD15−). Mixed-model regression and Wilcoxon rank-sum tests were performed to assess post-ICI changes in immune marker expression and identify correlations between PD1/PDL1 expression and best overall response (BOR) to ICI. Results: Of 36 ICI-treated pts with ≥2 blood samples, 24 received anti-PDL1 (22 atezolizumab/2 avelumab; [A]) and 12 received anti-PD1 (pembrolizumab [P]). 78% were men, median age 69 (46–81), 28% never smokers, 19% had prior intravesical BCG, 39% prior neoadjuvant chemotherapy, and 64% prior cystectomy. BOR to ICI included 3 PR/14 SD/7 PD (A) and 1 CR/2 PR/6 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC (mean change −5.26/dose; p = 0.009), while those of P correlated with decreased %PD1+ M- and I- MDSC (mean change −1.55 and −1.14/dose; p = 0.04 and 0.02, respectively). Though pre-tx %PD1+ CD8+ T cells did not predict BOR, greater PD1 expression by CD8+ T cells within 12 weeks after ICI initiation correlated with BOR (Table). Conclusions: ICI tx correlated with distinct changes in PD1/PDL1 expression by specific peripheral immune cell subsets. Responders to ICI had higher % of PD1+ CD8+ T cells after ICI than non-responders, though pre-tx % were comparable between groups. Further validation of these and other potential blood/tissue biomarkers is ongoing. [Table: see text]
Antitumor effect of cationic liposome incorporating keto-mycolic acid from Mycobacterium bovis bacillus Calmette-Guérin in mouse model.
Authors: Yoshino Takayuki , Miyazaki Jun , Kojima Takahiro , Kandori Shuya , Akaza Hideyuki , Yano Ikuya , Nishiyama Hiroyuki
Published: February 2018

461

Background: Intravesical instillation of live bacillus Calmette-Guérin (BCG) is an established immunotherapy for non-muscle invasive bladder cancer. However, development of non-infectious agents has been expected, because there are several problems due to instillation of live bacteria. BCG cell wall skeleton is known to stimulate host immune system, but the mechanism is still unknown. Mycolic acid (MA), which consist of three subclasses (α, keto, methoxy), is the most abundant lipid component of BCG cell wall and is expected to be one of essential active components. Objective: In order to identify active component from BCG cell wall and develop non-infectious BCG-derived immunotherapy, anti-tumor activities of cationic liposomes incorporating each subclass of MA were assessed using mouse syngeneic graft model. Methods: Heat killed packed cells of M. bovis BCG Tokyo 172 were fully hydrolyzed and MA was obtained. MA was separated to three subclasses by thin layer chromatography. Cationic and hydrophilic liposomes incorporating each subclass of MA were prepared. C57BL/6 mice were subcutaneously inoculated with a mixture of　MB49 cells and PBS or liposome with/without MA followed by additional injection of PBS or liposome. Tumor growth was monitored. Infiltration of CD4/8 lymphocytes was examined by immunostaining. Results: Cationic liposomes were internalized into cytoplasm of MB49 cells, a mouse bladder cancer cell line. Cell proliferation was not affected by liposome incorporating MA. Tumor growth was significantly suppressed in mice treated with keto MA-liposome (vs PBS, p = 0.007), but not in mice treated withα-or methoxy-MA liposomes. Number of infiltrating CD8 lymphocytes was higher in tumor treated with keto MA-liposome than control. Antitumor effect of keto MA-liposome disappeared in nude mouse, while the effect existed in beige mouse with NK activity deficiency (vs PBS, p = 0.045). Conclusions: Keto MA-liposome showed the strongest antitumor effects in mouse model among three subclasses. T cell immunity may contribute to those effects.