bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of immunization with the ii-key modified HER2/neu(776-790) (AE37) peptide vaccine on pre-existent immunity to PSA in HLA-A24+ prostate cancer patients: Association with increased AE37-specific immunologic responses.
Authors: Perez Sonia A. , Anastasopoulou Eleftheria , Pappou Efi , Pistamaltzian Nikolaos Fragkiskos , von Hofe Eric , Papamichail Michael , Baxevanis Constantin N. 
Published: March 2020

e15125 Background: In solid tumors such as prostate cancer, novel biomarkers are needed for assessing immunological responses and clinical efficacy. By using dextramers specific for PSA we have retrospectively analyzed CD8+ T cell frequencies in patients with HER-2/neu+ prostate cancer who had received the AE37 vaccine in a phase I study (Perez SA et al Clin. Cancer Res. 2010, 16:3495). AE37 binds to numerous MHC alleles (Perez SA et al Clin. Cancer Res. 2010, 16:3495) (Salazar LG, Clin Cancer Res. 2003, 9:5559) encouraging its use as a therapeutic vaccine for general HER-2/neu+ cancer patients. Methods: CD8+ Dextramer+ T cells were measured, retrospectively, in the blood (which was stored in N2 liquid) of HLA-A24+ (n= 12) and HLA-A2+ (n=12) patients. Blood lymphocytes collected before, during and 6-months post vaccination were all analyzed with the same method involving direct labeling with HLA A24/PSA(153-161)-FITC and PerCP-conjugated anti-CD8 monoclonal antibody. Results: 8 of 12 HLA-A24+ patients had preexistent immunity to PSA as evidenced by the increased percentages of CD8+ HLA-A24/PSA(153-161)+ T cells in pre-vaccination samples. All of these patients had shown increased in vitro (IFNγ-based ELISPOT assay) and in vivo (DTH) immunological responses to the AE37 vaccine in the phase I study (Perez SA et al Clin. Cancer Res. 2010, 16:3495). Importantly, this preexistent immunity was significantly boosted in 5 patients during vaccinations with AE37, was slightly increased in 2 others, whereas in one patient no changes were observed during vaccinations. Conclusions: These results suggest that HLA-A24 expression along with preexistent immunity to PSA(153-164) may represent biomarkers based on which HER-2/neu+ patients can be selected most likely to benefit from vaccination with AE37. A phase II trial is warranted for validating these results. Given the promiscuity of AE37, it would be intriguing to examine if preexistent immunity to other prostate antigens restricted by various MHC alleles exist and to demonstrate an increase in preexistent immunity in association with a positive immunologic response to vaccination with AE37.
Prostate cancer inhibitory activity of a novel dual inhibitor, EL102, in combination with docetaxel, and its effects on MDR1-mediated drug resistance in vitro.
Authors: Glynn Sharon A. , Toner Aidan , Lewis Joe , Sullivan Frank , Breen Laura , Clynes Martin , Giles Francis J. 
Published: March 2020

e15126 Background: EL102 is a dual-action drug promoting apoptosis and inhibiting angiogenesis. It exerts its action though the inhibition of Hif1a induced hypoxic signalling and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity in normoxia and hypoxia indicating it may be equally active in these different tumor compartments. We tested its ability to circumvent chemotherapeutic drug resistance. Methods: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and motility in vitro, calculating IC50s for CWR22, 22Rv2, PC3 and DU145 prostate cancer cell lines, comparing sensitivity between androgen dependent, androgen independent and metastatic prostate cancer. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine CWR22 xenografts. The ability to overcome MDR1 and BCRP mediated drug resistance was also tested using DLKP drug resistant variants which exhibit 200 fold resistance to doxorubicin, docetaxel, paclitaxel and vincristine. Results: We found that prostate cancer cell lines are sensitive to EL102 with IC50s in the region of 10-50nM. Of particular interest was the identical sensitivity of the androgen independent 22Rv1 and its androgen dependent parent CWR22, suggesting ability to overcome hormone refractory prostate cancer. Additionally we demonstrate dose response for inhibition of cell motility in metastatic DU145. In CWR22 murine mouse models treatment with EL102 resulted in decreased tumor volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumor growth than EL102 or docetaxel alone. The lung cancer cell line DLKP, its drug resistant variants DLKPA (MDR1 overexpressing) and DLKPMitox (BCRP overexpressing) were equally sensitive to EL102 indicating that EL102 is not a substrate for MDR1 or BCRP. Conclusions: EL102 is a potential therapeutic for the treatment of prostate cancer, in particular in combination with docetaxel, and exhbibits the potential to overcome drug resistane. Future studies will include the efficacy of this drug in prostate cancer metastatic mouse models.
Increased cardiovascular risks associated with primary androgen deprivation therapy versus radical prostatectomy among patients with localized prostate cancer.
Authors: Liu Jinan , Shi Lizheng , Sartor A. Oliver , Culbertson Richard 
Published: March 2020

e15130 Background: We examined whether primary androgen deprivation therapy (PADT), as compared to radical prostatectomy (RP), was associated with cardiovascular disease and death. Methods: Male patients with localized prostate cancer were identified in the SEER-Medicare (01/1998-12/2007). PADT patients were matched to the RP patients via propensity score. Cardiovascular risks ((i.e., ischemic heart disease (IHD), congestive heart failure (CHF), or cerebrovascular disease) were examined by Cox (PH) model; cardiovascular death by Fine & Gray competing risk. Important independent variables were controlled for. Results: The baseline variables were comparable. For the sample without cardiovascular disease (CVD) history, significantly increased risks for IHD, CHF, and aggregate risk of CVD were found in PADT group (all p-values <0.05), and the risks for cerebrovascular disease and cardiovascular death were also increased but not significantly (both p-values>0.05); for the sample with CVD history, all the risks aforementioned were significantly increased in PADT group (all p-values <0.05). Conclusions: In this retrospective study, PADT was associated with increased cardiovascular disease and death when compared with RP, especially in the sample with history of CVD. [Table: see text] [Table: see text]
Efficacy of low-dose ketoconazole in the treatment of castration-resistant prostate cancer (CRPC): A single-institution experience.
Authors: Ortega Cinzia , Ruatta Fiorella , Prati Veronica , Ballatore Valentina , Capaldi Antonio , Garibaldi Elisabetta , Gabriele Pietro , Muto Giovanni , Aglietta Massimo 
Published: March 2020

e15133 Background: The management of rising PSA in CRPC remains controversial. Secondary hormonal manipulations are commonly used before starting chemotherapy. Ketoconazole, an antimycotic that affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This retrospective study describes our experience with low doses of ketoconazole and prednisone treatment for CRPC. Methods: From 4/2007 to 12/2011, 65 patients with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally bid with orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Performance status of all patients was ECOG0. Overall, 34/65 (52.3%) patients had only bone metastases, 12/65 (18.5%) had nodal metastases, 17/65 (26.2%) both and only 2/65 (3.1%) had bone plus lung mets. All patients had low tumor burden and PSADT >6 months. Thirty-six out of 53 patients with bone mets received concomitant zoledronic acid. PSA response was defined as a >50% fall in PSA from baseline and PSA nadir was calculated. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Patients were monitored clinically and with serial PSA measurements every 1-month. Results: Median age was 74.05 (range: 52.8-84.4) years; median baseline PSA was 29.95 (range: 1.18-1348.8) ng/ml; median duration of the treatment was 5.87 (range: 0.57-52.4) months. All pts were evaluable for PSA response. At a median F.U.of 15.4 mos. 19/65 patients (29.2%) showed a decrease in PSA >50%, with a median TTP of 17.23 mos for responders. Overall TTP was 5.86 mos and it was not affected by metastatic sites (p= 0.71).Toxicity was mild and no patients discontinued therapy because of side-effects. Five out of 65 patients had G2 (CTC.AE 4) nausea and moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Our data confirm that low-dose ketoconazole is an effective and well-tolerated treatment in patients with CRPC and should be considered in the subset of patients with low-volume disease and a rising PSA level despite maximal androgen blockade.
Clinical experience with oral vinorelbine (NVBO) plus prednisone as first- or second-line chemotherapy of metastatic hormone-refractory prostate cancer (HRPC).
Authors: Cervera Grau Jose Manuel , Beltran Miguel , Garcia Carbonero Iciar , Girones Regina , Gonzalez del Alba Aranzazu , Calderero Veronica , Gonzalvez Maria Luisa , Domenech Montserrat , Diaz Nieves , Jimenez Paula , Juan Vidal Oscar , Saenz Alberto , Perez Francisco Javier 
Published: March 2020

e15144 Background: IV NVB plus hydrocortisone (HC) compared with HC alone resulted in improved clinical benefit, progression-free survival (PFS) and PSA response rate in HRPC. The oral formulation of NVB avoids the side effects associated with the IV injection, may reduce administration and toxicity-related costs and is easy to administer. Due to these advantages, single agent NVBO treatment could be considered as an optimal option for patients (p) with HRPC previously treated with a taxane or as first-line treatment when a taxane is not indicated. We retrospectively evaluated efficacy and toxicity or NVBO administered as single agent as first or second-line chemotherapy of metastatic HRPC. Methods: Retrospectively data was collected from p with metastatic HRPC treated with NVBO 80 mg/m2 on days 1 and 8, with a prior test of myelosensitivity at 60 mg/m2 for the 1st cycle (cy), plus prednisone 10 mg/day. Patients had received either a taxane as 1st-line treatment or had a documented contraindication to receiving docetaxel. 1 cy was equivalent to a 3-week period. Results: Data on 67 p treated in 13 Spanish centres were included. Median age 73 years (range 54-86). ECOG PS 0, 16.4%; 1, 56.7%; 2, 11.9%. Median PSA 88.9 ng/mL. Prior chemotherapy, 58.2%. Median number of cy was 4 (range 1-6). 56.9% of p could escalate NVBO to 80 mg/m2. 265 cy were performed, 9.1% were delayed and 2.3% had a dose reduction. Grade 3-4 events were infrequent and mainly hematological: neutropenia (6% of p), anemia (4.5%), pain (3%), infection (1.5%), asthenia (3%), respiratory (1.5%), cystitis (1.5%), rectal bleeding (1.5%), febrile syndrome (1.5%), renal (1.5%). No febrile neutropenia was reported. PSA response rate 16.1%, PSA stable was reported in 41.9%. 39 p were evaluable for measurable disease; among them, PR 17.9%, SD 48.7%. Median follow-up, 7.1 months. Median overall survival, 11 months [95% CI: 7.3-14.7]. Median PFS, 2.9 months [95% CI: 2.2-3.6]. Conclusions: NVBO is a safe and active regimen in previous chemotherapy treated HRPC. For those p who cannot receive a taxane as first-line therapy, NVBO can also be considered as an effective first-line treatment.
Correlation of biologic recurrence after radical prostatectomy and a positive surgical margin with the predominant Gleason pattern on the specimen.
Authors: Neuzillet Yann , Pichon Audrey , Lebret Thierry , Raynaud Jean-Pierre , Botto Henry 
Published: March 2020

e15145 Background: The risk of biological recurrence following radical prostatectomy depends, among other factors, on surgical margins status. This study compared the prognosis of prostate cancer patients with positive surgical margins according to the predominant Gleason pattern (PrdGP). Methods: Prospective study of 247 consecutive prostate cancer patients, who underwent radical prostatectomy (RP) from 3/2007 to 12/2009, and were followed up in our institution. Pathological stage and Gleason score were determined in RP specimens by a pathological reference. Biological recurrence was defined as two consecutive values of PSA > 0.2 ng/mL. The median overall follow-up was 33 months (2 to 54 months). Biological recurrence-free survival was estimated and compared using Kaplan-Meier plots and Log rank test. A multivariate logistic regression model was done with PrdGP4, and two other predictive variables (pT≥3a, preoperative PSA level) entered as statistically significant independent predictors of biological recurrence. Results: Forty-eight patients (19.4%) had a positive surgical margins, 26 patients have PrdGP3 (54%) and 22 have PrdGP4 (46%). Whereas 7 biological recurrences were observed in PrdGP4 patients, none occurred in PrdGP3 patients. Biological recurrence-free survivals were significantly different (Log rank p=0.001). In multivariate analysis, PrdGP4 was a predictor of biological recurrence (p<0.0001, OR= 9.023, 95% CI [3.161–25.757]). Conclusions: This study demonstrates that biological recurrence after positive surgical margin are correlated with the predominant Gleason pattern assessed on radical prostatectomy specimen which s more easily evaluable than accurate margins features. Adjuvant treatment, specifically external beam radiotherapy, should be indicated in accordance to this result. [Table: see text]
The relations between age and androgen deprivation therapy use among men receiving radiation therapy for prostate cancer in the Medicare population.
Authors: Quon Jennifer L. , Yu James B. , Soulos Pamela R. , Gross Cary P. 
Published: March 2020

e15150 Background: For older men with prostate cancer who are undergoing radiotherapy, the benefit of neoadjuvant and concurrent androgen deprivation therapy (ncADT) varies according to tumor characteristics and life expectancy (LE). National Comprehensive Cancer Network (NCCN) guidelines recommend ncADT for men with high-risk cancer characteristics, but not for men with low-risk cancer, or for men with LE < 5 years. Although older patients with shorter LE have the lowest likelihood of benefit, it is unclear whether ncADT is used less frequently in this group. Methods: We used the Surveillance, Epidemiology, and End Results-Medicare database to assess patterns of ncADT use among men diagnosed with prostate cancer during 2004 through 2007 who received external beam radiation. Men were stratified according to NCCN guidelines into low- (T1-T2a/N0/M0 and Gleason 2-6 and PSA< 10 ng/mL), intermediate- (T2b-T2c or Gleason 7 or PSA 10-20 ng/mL), and high- (Gleason >7 or PSA> 20 ng/mL) risk groups. Men were further stratified according to LE, which was calculated based on age and comorbid illness. We used logistic regression to identify patient and clinical factors associated with ncADT use within each risk group. Results: There were 11,080 men in the sample (mean age= 74.2 years; 83.5% white). The use of ncADT was highest in the high-risk group (80.7%). However, a considerable number of men in the intermediate- (54.1%) and low-risk (27.8%) groups also received ncADT. Compared to men with longer LE, men with LE < 5 years had higher rates of ncADT use in all risk groups. For instance, in the low-risk group 32.7% men with LE < 5 years received ncADT compared to 26.5% men with LE ≥ 10 years. Similarly, within each risk group, advancing age was associated with a higher likelihood of receiving ncADT (OR for men aged 80-84 compared to 67-69 = 1.93(95% CI 1.37-2.70); 1.51(95% CI 1.22-1.87); and 1.71, (95% CI 1.14-2.57) for high-, intermediate-, and low-risk groups, respectively). Conclusions: The use of ncADT in actual practice is not consistent with guideline recommendations and is used more frequently among men who are older, have a shorter LE, and are less likely to benefit from therapy.
A phase I trial of AEZS-108 in castration- and taxane-resistant prostate cancer.
Authors: Liu Stephen V. , Schally Andrew V , Dorff Tanya B. , Tsao-Wei Denice , Groshen Susan G. , Hawes Debra , Xiong Shigang , Quinn David I. , Tai Yu-Chong , Block Norman L. , Engel Juergen , Pinski Jacek K. 
Published: March 2020

e15153 Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH), which is highly expressed on prostate cancer cells. AEZS-108 is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of LHRH receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide enumeration of CTCs and results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs. Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Due to potential cardiotoxicity, patients with an ejection fraction < 50% or prior exposure to doxorubicin or mitoxantrone were excluded. Pituitary function was closely monitored. Patients received AEZS-108 every 21 days for up to 6 cycles until progression or unacceptable toxicity. The primary endpoint was safety. Results: Enrollment began in November 2010 and is ongoing. Currently, 13 patients have been enrolled. The first two planned dose levels had no dose-limiting toxicities observed. Two patients on the third dose level experienced a dose limiting toxicity. The second dose level has been reopened for expansion. There have been no cardiac or pituitary toxicities. At the time of submission, a decrease in PSA was noted in 6 of the 13 patients. Final results detailing safety, response and the suggested dose for the phase II portion will be reported. All correlative studies will also be reported. Conclusions: In general, AEZS-108 has been well tolerated. The phase II portion of the study will begin once the MTD is established.
Alterations of natural killer cell receptors as biomarkers associated with the severity of the disease in prostate cancer.
Authors: Pasero Christine , Gravis Gwenaelle , Rocchi Palma , Just-Landi Sylvaine , Livrati Philippe , Thomassin Jeanne , Brunelle Serge , Salem Naji , Walz Jochen , Olive Daniel 
Published: March 2020

e15155 Background: Recently, therapeutic vaccines and monoclonal antibody-based therapies have been investigated as promising new treatments against prostate cancer (PC). Natural killer (NK) cells which have anti-tumoral activity thus represent promising candidates for immunotherapy. Our group have reported major impairments of NK in acute myeloid leukemia and recently in metastatic breast cancer. The aim of this work was to evaluate the phenotype and function of NK cells in patients with localized and metastatic PC to determine their role in disease progression. Methods: Activating and inhibitory receptors were analyzed in peripheral NK cells from 14 patients with localized PC, 33 with metastatic disease and 30 healthy donors. NK function was evaluated by measuring CD107 degranulation. Results: The ratio mean fluorescence intensity RMFI (MFI receptor/MFI control isotype) of the activating receptor NKp30 was significantly lower in patients (7.30 +/- 0.68, p=0.0059) than in HD (10.99 +/- 1.34), whereas NKp46 was lower in the metastatic patients only (11.76 +/- 1.18) compared to the localized cases (21.86 +/- 4.25) and HD (19.13 +/- 2.39). The RMFI of 2B4 (47.14 +/- 7.99), the percentage of positive cells for the inhibitory receptor ILT2 (49.34 +/- 3.90, p=0.0003) and the maturation marker CD57 (41.13 +/- 4.69, p=0.0014) were significantly upregulated in patients compared with HD (2B4 23.09 +/- 4.74, ILT2 20.65 +/- 3.09, CD57 21.36 +/- 3.07), with a more pronounced increase in the metastatic groups. The RMFI of other receptors such as NKG2D or CD94 does not differ. NK cells from patients were significantly less effective (17.90% +/- 1.48, p<0.0001) than NK from HD (30.31% +/- 2.70) to degranulate against the K562 target or prostate tumor cell lines. Conclusions: We observed an altered phenotype of NK cells in PC, correlated with decreased NK cell function, with alterations more pronounced during metastatic progression. Prostate tumor cells could have the ability to impair NK cell visibility through the modulation of their receptors and consequently decrease their cytotoxic function. This highlights the possibility of restoring NK cells cytotoxicity as a future therapy against PC.
Treatment patterns in men with castration-resistant prostate cancer receiving docetaxel.
Authors: Davis Keith L. , Gutierrez Benjamin , Zyczynski Teresa Maria , Kaye James A. 
Published: March 2020

e15165 Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the US since 2004 (TAX 327), yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the US were reviewed: 48 from oncology (N=344) and 8 from urology (N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising PSA, progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other drugs. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons for docetaxel delay and sub-maximal exposure in some CRPC patients.