bluuebunny/crossref_metadata_2025_split huggingface dataset:
CK- and small nuclear size circulating tumor cell (CTCs) phenotypes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ferraldeschi Roberta , McDaniel Andrew , Krupa Rachel , Louw Jessica , Tucker Eric , Bales Natalee , Marrinucci Dena , Riisnaes Ruth , Mateo Joaquin , Dittamore Ryan , De Bono Johann Sebastian , Tomlins Scott A. , Attard Gerhardt 
Published: February 2017

209 Background: Circulating tumor cell (CTCs) are traditionally defined as EpCAM/CK+ cells, CD45-, and morphologically distinct. However, recent evidence suggests that other populations of CTC candidates exist including cells that are EpCAM/CK- or smaller in size than traditional CTCs. CTC positive selection techniques that isolate CTCs based on size, density, or EpCam positivity may miss subpopulations. We aimed to molecularly characterize novel CTC candidates utilizing the Epic Sciences platform, which performs no physical selection. Methods: Blood from 10 healthy volunteers (HV) and 39 patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) were collected and shipped to Epic Sciences, where all nucleated cells were plated onto glass slides and subjected to immunofluorescence (IF) staining and CTC identification by fluorescent scanners and algorithms. Traditional CTCs were identified as CK+CD45- cells with intact DAPI nuclei and after pathologist review of their morphology. Candidate CK- CTC populations were identified as CK-CD45- that were morphologically malignant. Small nuclear size candidate CTCs were identified as CK+CD45- cells with diameters similar to or smaller than that of a typical white blood cells (WBCs). All candidate CTC were evaluated with prostate cancer relevant biomarkers, including androgen receptor (AR) by IF and PTEN loss and ERG rearrangements by FISH. Results: Thrity eight out of 39 pts had one or more traditional CTCs/mL and 36 out of 39 pts had one or more CK- CTCs/mL of blood. Eight out of 39 samples had more than 10 CK- CTCs/mL. Fifteen out of 39 samples had evidence of small nuclear size CTCs at varying incidences and sizes of cells. We observed PCa biomarkers including high AR expression, PTEN deletion, and ERG rearrangements in both CK- and small nuclear size CTCs. These features were not observed in over 1,000 WBCs evaluated and HV. Conclusions: Candidate CTC that are CK-CD45- and/or with a small nucleus are identified on the Epic Sciences platform in blood from mCRPC pts. Studies are ongoing to determine their clinical relevance.
Physician referral patterns among men with advanced prostate cancer.
Authors: Yong Candice , Onukwugha Ebere , Mullins C. Daniel , Abdulhalim Abdulla M. , Qian Yi , Arellano Jorge , Balakumaran Arun , Liede Alexander , Hussain Arif 
Published: February 2017

211 Background: Among men diagnosed with localized prostate cancer (PC), the type of specialist visited has been shown to influence the type of treatment regimen prescribed. There is limited data on referral patterns among men diagnosed with advanced PC. The objective of this study was to characterize referral patterns across physician types who treat men with stage IV nonmetastatic (M0) and metastatic (M1) PC. Methods: Using the linked US SEER (Surveillance, Epidemiology, and End Results) and Medicare database, we identified men aged 66 or older who were diagnosed with incident stage IV M0 or M1 PC between 2000 and 2007. We evaluated patterns of the first and second type of physicians visited after diagnosis of PC for men with visits to the following physician types: urologist, medical oncologist (medonc), radiation oncologist (radonc), or primary care physician (PCP). Results were stratified by M0 and M1 disease. Results: We identified 9,826 men with stage IV PC (median age=77 years). Of these 9,826 men, 8,736 (89%) visited at least two physician types (93% among men with M0 and 87% among men with M1). Across the physician types of interest, 94% of men initially visited a urologist (52%) or PCP (42%). Among men who visited a urologist first, most were referred to a PCP, while smaller percentages were referred to a medonc or radonc (Table). Among men who saw a PCP first, most were referred to a urologist next; smaller proportions were referred to a medonc or radonc. Men with M1 PC had more referrals to medonc and fewer referrals to radonc than men with M0 PC. Conclusions: In this analysis of nearly 10,000 men aged 66 or older with stage IV PC in the US, most men initially visited a urologist or PCP regardless of whether or not they had distant metastasis. Based on the patterns observed, the most frequent referral pattern occurred between urologists and PCPs. More referrals to a medonc were evident if the men had M1 disease. [Table: see text]
Pain palliation as an oncology label indication: Lessons learned in custirsen phase III development.
Authors: Beer Tomasz M. , Hotte Sebastien J. , De Bono Johann Sebastian , Beuzeboc Philippe , Gabrail Nashat Y. , Cain Daniel , Jacobs Cindy , Fizazi Karim 
Published: February 2017

222 Background: Durable pain palliation (dPP) in metastatic castrate-resistant prostate cancer (mCRPC) is a measure of clinical benefit suitable for a label indication. A randomized, double-blind, placebo-controlled, phase III study developed with FDA under a Special Protocol Assessment (SPA) compared custirsen/taxane (cust/tax) to placebo/taxane (plac/tax) as second-line chemotherapy for patients (pts) with mCRPC with disease progression during or after first-line docetaxel. Primary efficacy was 12-week or more dPP. Other endpoints included overall survival (OS), serious adverse events (AEs), and ≥Gr 3 AEs. Methods: Patients were randomized (1:1) to second-line taxane (docetaxel retreatment or cabazitaxel; based on prior docetaxel response, progression) + 640 mg custirsen or placebo. Eligible pts had to have baseline stable pain on consistent opioid-analgesic regimen. With a one-sided alpha of 0.025, power of 90%, and estimated difference in proportion of 25% vs. 10% dPP, the trial required 292 pts. Results: Trial was activated at a total of 62 sites and was stopped after 20 months (mo) with only 35 pts screened/14 pts enrolled. Requirements for baseline stable pain/analgesic use proved too restrictive to complete enrollment. Demographics were comparable. Prior response to first-line docetaxel occurred in 93% pts. Disease progression after first-line docetaxel based on bone scan (n=10) or prostate-specific antigen (n=4); median time from end of first-line to progression one mo. Treatment of a median thre cycles plac/tax arm compared to six cycles cust/tax arm. Three pts achieved dPP (n=1 [14%] plac/tax; n=2 [29%] cust/tax). Median OS (95% CI) was 7.8 (3.2, 11.5) mo plac/tax vs. 11.8 (9.8, 15.7) mo cust/tax. AEs greater than or equal to Gr 3 reported for two pts or more included: back pain (0 plac/tax; 2 cust/tax), hyperesthesia (0,2), asthenia (2,1). Serious AEs reported for nine subjects (4,5). Only serious AE reported in more than 1 pt was hyperesthesia, leading to study discontinuation (0, 2). Conclusions: Enrollment was not feasible due to restrictive trial criteria of stable baseline pain/consistent analgesia, which were too difficult to achieve. Thus, a survival based study has been launched and is recruiting, with monitoring of pain/analgesic use. Pragmatic criteria for oncology pain studies are needed. Clinical trial information: NCT01083615.
Dehydroepiandrosterone metabolism in fresh human prostate: A feasibility study.
Authors: Ercole Cesar E. , Chang Kai-Hsiung , AboAli Ghada , Magi-Galluzzi Cristina , Stephenson Andrew J. , Klein Eric A. , Sharifi Nima 
Published: February 2017

225 Background: Understanding adrenal androgen metabolism in the prostate provides the opportunity to better define mechanisms of resistance for patients with prostate cancer. This is especially important with men who have a recurrence after their initial treatment (e.g., surgery or radiation) and are subsequently treated with androgen deprivation therapy by chemical or surgical castration. Unfortunately, these patients tend to progress to castrate resistant prostate cancer. With the contribution of adrenal androgens in mind, we sought to determine the feasibility of characterizing the metabolites of dehydroepiandrosterone (DHEA) in the human prostate. Methods: With institutional review board approval, tissue procurement occurred via the Department of Pathology at the Cleveland Clinic. We obtained prostate tissue from patients immediately after radical prostatectomy. The tissue was processed in culture withserum free medium in triplicate and was treated with tritiated-DHEA ([3H]-DHEA; 100 nM, 300,000–600,000cpm; PerkinElmer). Media was collected at specific time intervals (6, 24, 48, and 72 hours). Once all the time points were collected, they were treated with a β-glucuronidase and steroids were extracted. These samples were processed and analyzed with high-performance liquid chromatography (HPLC) and a radioactivity detector for comparison with known standards (DHEA, androstenedione, 5α-androstanedione, testosterone, and dihydrotestosterone). Results: Evaluation of the HPLC tracings showed metabolism of [3H]-DHEA to downstream androgen products and correlated with standard peaks. These tracings were reproducible and consistent with each sample’s triplicate and from specimen to specimen. Conclusions: It is feasible to consistently determine the products of DHEA metabolism in fresh prostate tissues. By obtaining a better understanding of how androgen metabolites are formed we can dissect how response and resistance to hormonal therapy are regulated.
Primary care physician (PCP) referral patterns for prostate cancer (PC) patients: Web-based survey.
Authors: Sunkara Rajitha , Lele Uday , Soyano Aixa , Kozyreva Olga 
Published: February 2017

228 Background: Prostate cancer (PC) is the most common cancer and second most common cause of cancer related death in men. The therapeutic options for PC patients are rapidly expanding making treatment decisions more complex. For patients with high-risk PC, significant body of evidence demonstrates that multidisciplinary approach improves outcome. PCP has a major role in early detection, provision of counseling, appropriate referral and management of metabolic side effects (SE) of androgen deprivation therapy (ADT). We conducted a survey among PCP’s to understand their referral patterns. Methods: We emailed a 10 question web based survey to around 300 practicing PCP’s in the Boston area. Of them, 56 responded. We analyzed the responses using independent t test for demographics and ANOVA for years of experience of the individual physician. Additional multivariate analysis was done using all independent variables together. Results: 30.3% of the physicians never feel the need to refer a newly diagnosed prostate cancer patient to a medical oncologist (MO). 60.8% of the PCP’s anticipate that urologist should refer the patients to a MO. Only 9% of PCP’s feel responsible for managing the SE of ADT. 46.4% anticipate urologist and 44.6 % anticipate oncologist to manage the SE of ADT. Female physicians appear to be more comfortable in providing counseling to the newly diagnosed PC patients than the male physicians (P=0.001). Male physicians and US medical graduates tend to refer to the MO most often than the female physicians and foreign medical graduates (P=0.013 and p=0.015 respectively). On multivariate analysis US medical graduates with higher years of experience are more comfortable providing the counseling and discussion of newer treatment options for a newly diagnosed PC (p=0.011 and 0.016 respectively). Overall 44.6% are not aware of newer treatment options for castration resistant PC. Conclusions: In the era of expanding armamentarium of treatments for PC, our results indicate the need to increase the awareness of PCP’s regarding the available treatments and emphasize the importance of multidisciplinary approach to better serve the PC patients with appropriate and timely referrals.
Familial clustering of prostate cancer (Pca) cases in a nonselected south European population (sEp).
Authors: Gil-Bazo Ignacio , Castanon Eduardo , Fusco Juan Pablo , Martin Patricia , Zubiri Leire , Ceniceros Lucia , Legaspi Jairo , Gil-Aldea Isabel 
Published: February 2017

233 Background: Universal Pca screening programs (SP) are controversial. The selection of high-risk subjects might improve the efficiency of early SP. A positive family history (FH) of Pca increases its relative risk and also increases with multiple affected relatives. Pca FH is associated with earlier onset and aggressive behavior. Therefore, in this subpopulation SP would have clear advantages. This is the first study to investigate the incidence of familial Pca conducted in a sEp. Methods: Overall, 365 cancer patients (pts) of Spanish (n=342) or Portuguese (n=23) origin diagnosed at a single institution were included in the analysis. A non-selected cohort of 182 (173 with known FH) consecutive males (cases) diagnosed with Pca was studied for FH of any type of cancer including Pca. Another cohort of 183 (174 with known FH) males (controls) with similar demographic characteristics and diagnosed with other cancer types different from Pca was also studied for FH of cancer. We investigated whether Pca pts in a sEp show a higher incidence of familial Pca aggregation than subjects affected by other solid tumors. Results: Among Pca pts with a positive FH for Pca, 30.2% showed their father as the only Pca relative, 22.6% one or more brothers, 15% one or more uncles, 13.3% their father and one or more brothers, 9.4% their grandfather and 9.5% showed other combinations. Regarding the number of relatives affected, in our Pca cohort 1 relative was the most frequent finding with 41/53 pts (77.1%), 2 in 4 cases (7.6%), 3 in 3 subjects (5.8%) and 4 or more relatives in 5 cases (9.5%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (64.7% vs 67.8%; p=0.664). However, in our cohort of Pca cases, 53/173 pts (30.6%) had a FH of Pca in first or second degree whereas, among cancer control pts only 18/174 pts (10.34%) showed a Pca FH (p=0.001). Conclusions: We present the first estimation of Pca FH in a non-selected sEp with Pca. 30% of Pca cases showed a positive FH for Pca, being that incidence significantly higher (threefold) compared to cancer pts from a different origin. Therefore, the usefulness of directed SP for subjects with positive FH of Pca should be prospectively evaluated.
Phase I clinical study of cabazitaxel plus prednisolone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a Japanese population.
Authors: Takahashi Shunji , Mukai Hirofumi , Uemura Hirotsugu , Uemura Hiroji , Kosaka Takeo , Nishiyama Hiroyuki , Suzuki Kazuhiro , Kakehi Yoshiyuki , Okihara Koji , Namiki Shunichi , Ogawa Osamu , Kato Masashi , Nakai Yasutomo , Ohno Keiji ,   TED11576 Investigators
Published: February 2017

237 Background: Cabazitaxel (CBZ), a novel taxoid agent, promotes tubulin assembly and stabilizes microtubules, as docetaxel (DTX). CBZ had antitumor activity in DTX-resistant tumor models in vitro. We assessed dose-limiting toxicities (DLTs), safety and efficacy of CBZ in patients (pts) with mCRPC with prior DTX treatment. Methods: This was an open-label, dose escalation study of CBZ every 3 weeks, with daily prednisolone. Two CBZ dose levels (20 or 25 mg/m2) were set in the dose escalation cohort to determine the maximum tolerated dose (MTD). Pts in the expansion cohort received the MTD. DLTs were evaluated at cycle 1 and were defined as follows: Grade (Gr) 4 neutropenia > 7 days, Gr 4 thrombocytopenia, Gr 4 febrile neutropenia (FN), or Gr 3/4 non-hematological toxicities. Gr 3/4 neutropenia was prospectively studied based on occurrence of Gr 3/4 neutropenia during prior DTX treatment. Results: A total of 48 pts received CBZ (median age 66.1 years; ECOG PS: 0, 34 pts; 1, 14 pts; median cumulative DTX dose 753 mg/m2). None of the evaluable pts in the dose escalation cohort experienced a DLT. All pts had at least one Gr 3/4 adverse event (AE). Frequent Gr 3/4 AEs at 25 mg/m2 were neutropenia (44 pts, 100%) and FN (24 pts, 54.5%). G-CSF prophylaxis was not allowed at cycle 1 and was only used in 10% of cycles from cycle 2 onward. Neutropenia occurrence during prior DTX treatment did not affect neutropenia or FN incidence during CBZ treatment. No pt discontinued CBZ due to neutropenia or FN and no toxic death was reported. In total, 12/41 pts (29.3%) had a PSA response, and 2/12 evaluable pts had a partial response as the best overall response. Conclusions: The safety profile of CBZ in Japanese pts was generally consistent with that reported in previous studies. The cumulative dose of prior DTX was higher and use of G-CSF prophylaxis less frequent than in previous studies, which may have contributed to the increased incidence of neutropenia and FN in Japanese pts. The majority of neutropenia and FN events were manageable and did not lead to treatment discontinuation. In terms of safety and efficacy, CBZ has a favourable risk–benefit profile in Japanese pts with mCRPC following prior DTX therapy. Clinical trial information: NCT01324583.
Regional analysis of a cohort compassionate-use program (CUP) and early access program (EAP) with cabazitaxel (Cbz) plus prednisone (P; Cbz + P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (D).
Authors: Malik Zafar , di Lorenzo Giuseppe , Bracarda Sergio , Ardavanis Alexandros , Basaran Mert , Parente Phillip , de Schultz Wito , Saad Fred , van Oort Inge , Gerritsen Winald R. , Antón Aparicio Luis M. , Matus Geoffrey , Hitier Simon , Heidenreich Axel , Bahl Amit 
Published: February 2017

242 Background: Cbz is an established second-line treatment for pts with mCRPC, having demonstrated an overall survival benefit (with P) vs mitoxantrone with P in the Phase III TROPIC trial. The global CUP (CABAZ_C_05005) and EAP (NCT01254279) (both funded by Sanofi) aimed to provide access to Cbz + P before commercial availability and to document safety in a real-world population. We present a regional analysis of interim data from the CUP and EAP. Methods: Expected total enrolment is 1,450 pts. Pts received Cbz 25 mg/m2 IV Q3W + P 10 mg QD until disease progression (PD), death, unacceptable toxicity or physician/pt decision. Granulocyte colony-stimulating factor (G-CSF) was administered per ASCO guidelines. The cut-off date for this analysis was 30 May 2012. Results: Globally, 1,301 pts have been included from eight regions (Eastern Europe [EE], Western Europe [WE], Northern Europe [NE] and Southern Europe [SE]; Asia [As]; Canada [Ca]; Latin America [LA]; and Australia [Aus]). Key data by region are shown in the Table. Median age varied from 65 years (Ca) to 70 years (Aus, LA, SE). In pts who progressed after last D line, time from last D dose to last PD ranged from 2.3 months (EE, LA) to 6.6 months (Ca). G-CSF use (therapeutic or prophylactic) at Cycle 1 varied widely between regions, from 23% (WE) to 79% (As). Between 11% (LA) and 30% (NE) of patients received ≥10 cycles of Cbz. Conclusions: In this extensive, real-world CUP/EAP cohort of mCRPC pts, substantial regional variation was observed for baseline and on-treatment parameters, including time from last D dose to last PD and G-CSF use. The low proportion of patients receiving ≥10 cycles in LA, Ca and WE may result from a limit of 10 cycles of therapy in some centers. Clinical trial information: NCT01254279. [Table: see text]
Immune impact induced by PSA-tricom, a therapeutic vaccine for prostate cancer.
Authors: Madan Ravi Amrit , Tsang Kwong Yok , Jochems Caroline , Marte Jennifer L. , Tucker Jo A , Hodge James W. , Singh Harpreet , Surolia Ira , O'Sullivan Coyne Geraldine Helen , Liewehr David J. , Steinberg Seth M. , Heery Christopher Ryan , Schlom Jeffrey , Gulley James L. 
Published: February 2017

245 Background: PSA-TRICOM is a vector-based therapeutic cancer vaccine designed to generate a targeted anti-tumor immune response against prostate-specific antigen (PSA)–expressing tumor cells. Early clinical trials have evaluated the immunologic impact of this vaccine and demonstrated promising clinical activity. PSA-TRICOM is being evaluated in a phase III trial in metastatic castration resistant prostate cancer (mCRPC). Methods: We recently conducted a broad overview of both published and new data which analyzed the immune responses to PSA-TRICOM. Immune responses included ELISPOT for antigen-specific immune response and flow-cytometry analysis of peripheral immune cells. Results: 104 patients (pts) with prostate cancer were tested for T-cell responses and 59 out of 104 (57%) demonstrated a greater than or equal to 2-fold increase in PSA-specific T cells 4 weeks after vaccine. The responders had a median 5-fold increase relative to pre-vaccine levels. For most pts PSA-specific immune responses (likely memory cells) seen 28 days following the most recent vaccine are quantitatively similar to levels of circulating influenza-specific T cells in the same pts. In addition, 19 out of 28 pts (68%) evaluated demonstrated immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). Since PSA-TRICOM is designed to generate a cellular (TH1 immune response), it is not surprising that 2 out of 349 pts (<1.0%) demonstrated evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. Conclusions: PSA-TRICOM has demonstrated the ability to generate immune responses. Despite these findings, it is important to note that systemic immune response to PSA may underestimate the true therapeutic immune response since it does not measure cells that trafficked to tumor or antigen spreading. Furthermore, while the entire PSA gene is the vaccine, only one epitope of PSA is specifically evaluated in the T-cell responses. Further immune analysis continues in an ongoing phase III of PSA-TRICOM in mCRPC (NCT01322490), accruing worldwide, and two trials combining PSA-TRICOM with enzalutamide (biochemical recurrence/ NCT01875250 and mCRPC/ NCT01867333) currently accruing at NCI. Clinical trial information: multiple trials.