bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial results of patients with early-stage prostate cancer on active holistic surveillance.
Authors: Katz Aaron , Fontes Andrew S , Kosinski Kaitlin E. 
Published: February 2017

19 Background: There is currently no consensus on how active surveillance should be utilized in order to optimize the benefit of patients with prostate cancer (PCa) to prevent overtreatment. Our institution’s protocol, known as Active Holistic Surveillance (AHS) integrates MRI screening in the place of serial biopsies. Nutritional supplements and lifestyle changes are also suggested in order to provide a holistic way to reduce progression. We look to compare definitive treatment rates of our cohort on AHS to other publications in the literature. Methods: A retrospective chart review was conducted on 200 patients placed on active surveillance for low and low-intermediate risk PCa under D’Amico criteria from February 2002 to July 2015. Enrollment criteria was defined by clinical stage (T1c), PSA under 20 ng/mL, diagnosis of a Gleason 6 or Gleason 7 with a tumor volume of >50%, and a PSA doubling time of greater than 1 year. The main objective of the study was to evaluate the rate of patients discontinuing AHS to receive definitive therapy and reasons for leaving our AHS protocol. Results: 200 patients (age 44-84 years) have a median follow-up of 40 months (range 4-161). A total of 24 out of 200 patients (12%) moved on to definitive treatment. For patients on AHS before 2010 until 2012, the rates of definitive treatment were 0%. In 2013, 8 patients (4%) received definitive treatment. In 2014, 12 patients (6%) received definitive treatment. In 2015, 4 patients (2%) received definitive treatment to date.The average treatment rate per year is 4%. Reasons for 24 patients discontinuing AHS included biopsy progression (16.67%), MRI progression (29.17%), MRI progression with biopsy confirmation (29.17%), patient preference (20.83%), and 1 patient was deceased due to an unrelated illness (4.17%). Conclusions: Low rates of discontinuation compared to other publications in the literature demonstrate that AHS can be a successful protocol for low-risk and low-intermediate risk PCa patients, and that a holistic approach can be beneficial to active surveillance patients.
Integration of bone scan (BS) and computerized tomography (CT) findings as an endpoint to assess bone metastasis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Parker Scott J. , Pond Gregory Russell , Sonpavde Guru , Alex Anitha , Heilbrun Marta Elise , Agarwal Neeraj 
Published: February 2017

191 Background: Progression of bone metastasis in mCRPC is assessed solely by BS findings and correlates modestly with overall survival (OS). Given the lack of reliability of BS findings and the ready availability of routinely performed CT scans, which commonly identify bone metastases, we aimed to better assess progression in bone by integrating BS and CT findings and to explore their association with OS. Methods: Data were obtained from patients treated at the University of Utah receiving docetaxel-based chemotherapy (D) or post-docetaxel therapy with orteronel (O). Patients with both baseline and on-therapy CT and BS within 90 days were eligible for analysis. CT and BS underwent central radiology review for bone lesions by a single radiologist. Progressive disease (PD) was defined as ≥ 1 new lesion. Survival was measured from start of therapy. Cox proportional hazards regression was used to explore potential prognosticators of overall survival (OS). Statistical significance was defined as 2-sided p < 0.05. Therapy was a stratification factor. Results: Twenty-eight patients were evaluable including 18 patients receiving D, and 10 receiving O post-docetaxel. The mean age of these patients was 71.4 years and median (95% CI) overall survival was 18.4 (9.7-35.4) months. Four patients had PD on both BS and CT, while 2 (7%) had PD on CT but not BS and 3 had PD on BS but not CT. Patients with PD on BS or CT had worse OS (HR = 2.68, 95% CI = 1.04-6.90, p = 0.041) than those with no PD on either CT or BS. Looking at individual lesions, 4 (14%) patients had new lesions identified on CT which was not observed using BS, and they were associated with worse OS (HR = 3.72, 1.01-13.66, p = 0.048). Conversely, no significant difference in OS was observed for 4 patients with lesions identified on BS which were not observed using CT (HR = 2.67, 0.58-12.32, p = 0.21). Conclusions: This hypothesis-generating study suggests that CT can complement and enhance the ability of BS to capture PD and predict OS. Integration of BS findings using Prostate Cancer Working Group (PCWG)-3 guidelines to define PD and CT bone findings should be investigated in a larger study as an intermediate endpoint.
Analysis of the PROCEED registry by baseline prostate-specific antigen (PSA) quartiles: Preliminary analysis of real-world sipuleucel-T (sip-T) use.
Authors: Higano Celestia S. , Armstrong Andrew J. , Cooperberg Matthew R. , Concepcion Raoul S. , Tutrone Ronald F. , Olsson Carl A. , Pieczonka Christopher Michael , Shore Neal D. , Chang Nancy N. , LIll Jennifer Susan , Sartor A. Oliver 
Published: February 2017

193 Background: Sip-T is an FDA-approved, autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Post-hoc analysis of the phase 3 IMPACT study revealed that compared with the highest baseline PSA quartile, patients (pts) in the lowest quartile treated with sip-T had a larger overall survival (OS) benefit, suggesting sip-T is most beneficial if administered earlier in the treatment of mCRPC (Schellhammer et al., Urology. 2013.). This analysis evaluated pt characteristics by PSA quartiles in PROCEED (NCT01306890). Methods: Pts enrolled in PROCEED with baseline PSA and ≥ 1 sip-T infusion were included in this analysis. PSA values were divided into quartiles, and trends in baseline pt characteristics were evaluated as well as time to first anticancer intervention (tACI) with approved mCRPC therapies (docetaxel [D], cabazitaxel, abiraterone [abi], or enzalutamide [enz]) following sip-T treatment. Radium-223 was approved too late in the conduct of PROCEED to be included in the tACI analysis. Results: PSA quartiles from 1880 eligible PROCEED pts were lower than those of IMPACT (Table). Pts in the highest PROCEED quartile were older, more likely to have ECOG performance status ≥ 1, > 10 bone metastases, visceral metastases, and higher ALP and LDH, and lower hemoglobin compared with the lowest PROCEED quartile. More African American men and greater prior systemic therapy use were observed in the highest PSA quartile. Following sip-T, the median tACI (11.0, 8.2, 7.6, and 6.6 mos) was inversely proportional to PSA quartile. Conclusions: Lower baseline PSA values in PROCEED relative to IMPACT suggest that in a real-world setting, clinicians are using sip-T earlier in the treatment of mCRPC. Pts in the lowest PSA quartile had the best prognostic features and longest tACI. Additional patient follow-up is ongoing to evaluate OS and survival by quartile from PROCEED. Clinical trial information: NCT01306890. [Table: see text]
Effect of a new type androgen receptor antagonist, TAS3681, on ligand-independent AR activation through its AR downregulation activity.
Authors: Kajiwara Daisuke , Minamiguchi Kazuhisa , Seki Masanao , Mizutani Hiroya , Aoyagi Hiroki , Okajima Shigeo , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: February 2017

199 Background: Two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis, represent important advances in the management of castration-resistant prostate cancer (CRPC). However, eventually almost all of patients acquire resistance to these drugs by a variety of mechanisms. Ligand independent AR activation such as induction of AR splice variants and AR overexpression are major issues of current CRPC progression. In the present study, we report the biological characterization of TAS3681, which is a new AR antagonist with AR downregulation activity, and propose this concept as a potential new approach for the treatment of CRPC. Methods: For assay of AR transactivation, prostate cancer (PCa) cells were transiently transfected with androgen-responsive reporter gene construct. The transfected cells were treated with growth factor and cytokine in steroid-depleted media, and luciferase activity was measured. To evaluate the effect of TAS3681 on AR and c-Myc protein expression, PCa cells were treated with TAS3681 in steroid-depleted media. AR and c-Myc protein levels were determined by western blot. Real-time PCR was used to analyze the mRNA levels of c-Myc and c-Myc target gene. Chromatin immunoprecipitation was performed to determine the enrichment of AR at the element. Results: TAS3681 dose-dependently reduced AR protein levels in PCa cells. In contrast to enzalutamide, TAS3681 suppressed androgen-independent AR transactivation by growth factor and cytokine. In PCa cells which express full-length AR and splice variant AR-v7, TAS3681 suppressed AR-v7 target gene expression through downregulation of AR-v7. Moreover, TAS3681 reduced expression of c-Myc, critical driver of androgen-independent mechanisms of PCa progression, via AR downregulation activity. In addition, real-time PCR assay showed the transcriptional suppression of c-Myc and its target gene by TAS3681. Conclusions: TAS3681 exhibits suppressive effects on ligand-independent AR activation via AR decreasing activity. These finding suggest that TAS3681 could be a candidate of breakthrough therapy for resistance to current AR pathway target drugs.
A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.
Authors: Dhawan Mallika Sachdev , Lee Mina , Bryce Alan H. , Weinberg Vivian K. , Ryan Charles J. , Derleth Christina Louise , Harzstark Andrea Lynne , Small Eric Jay , Aggarwal Rahul Raj 
Published: February 2017

202 Background: Cabazitaxel and prednisone (Cbz/pred) extend survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m2 (N = 12), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.
An analysis of sodium 18f-fluoride PET/CT and prostate specific antigen (PSA) changes in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Strauss Julius , Ahlman Mark , Karzai Fatima , Heery Christopher Ryan , Cordes Lisa M , McMahon Sheri , Couvillon Anna , Rauckhorst Myrna , Thomas Chrisa , Theoret Marc Robert , Marte Jennifer L. , Millo Corina , Lindenberg Maria Liza , Turkbey Ismail B. , Choyke Peter L. , Figg William Douglas , Schlom Jeffrey , Dahut William L. , Gulley James L. , Madan Ravi Amrit 
Published: February 2017

203 Background: Recently there has been growing evidence that 18F-Fluoride PET/CT has increased sensitivity relative to technetium-99m diphosphonate (Tc-99m MDP) bone scan for evaluating metastatic bone disease. This analysis studied changes in 18F-Fluoride PET/CT and evaluated associations with PSA changes for mCRPC patients (pts) on enzalutamide (enz). Methods: As part of a randomized phase II study evaluating enz with or without vaccine therapy, men with mCRPC electively underwent 18F-Fluoride PET/CT at 3 month (mos) intervals [NCT01867333]. At these points serum PSA was collected. Data was taken on max SUV and volume of presumed cancerous lesions and a variable, ΣSUV*Volume, was calculated which was defined as the sum of the products of SUV max and volume of cancerous lesions. Results: At the time of our analysis, 19 pts had PSA and PET/CT data for at least 2 time points within 1 year of initiating therapy. The median baseline PSA was 19.6 ng/ml (0.76-587). All pts had predominantly bone disease with 10 having small volume lymphadenopathy. Only 1/19 pts progressed by PSA Working Group criteria. An analysis found that 18/19 pts (95%) had an association between changes in PSA and ΣSUV*Volume. Of these 18 pts, 13 had a major ( > 50%) and 1 had a minor ( > 30%) PSA response and all 14 had an accompanying decrease in ΣSUV*Volume. For 11/14 pts with PSA responses, the change in ΣSUV*Volume paralleled the change in PSA at all time points, while for 3 pts an associated change between ΣSUV*Volume and PSA was delayed by 3 mos. 4/14 pts had short term responses lasting only 3 mos followed by PSA increases. For these 4 pts the changes in ΣSUV*Volume paralleled PSA changes, decreasing at 3 mos and increasing thereafter. Finally 4/18 patients had no PSA response to therapy. All 4 pts had increases in ΣSUV*Volume which paralleled rising PSA values. Conclusions: Preliminary data from a small cohort suggests that findings on 18F-Fluoride PET/CT are associated with PSA changes. This represents a substantial difference from standard Tc-99m MDP and further suggests that 18F-Fluoride PET/CT may provide a more sensitive analysis of bone disease. Additional data from this and other studies are required.
Regulation of steroid-5-alpha-reductase 2 (SRD5A2) in human prostate by epigenetic modifications.
Authors: Olumi Aria F. , Ge Rongbin , Wang Zongwei , Wu Shulin , Tabetabaei Shahin , Wu Chin-Lee 
Published: February 2017

204 Background: 5-alpha reductase type 2 (SRD5A2), an enzyme that is critical for prostatic development and growth. We have found that many aging prostate tissues do not express the enzyme. We previously showed that expression of SRD5A2 is not static and epigenetic modulations by DNA methyltransferase and pro-inflammatory cytokines play important roles in silencing of SRD5A2. Here we wished to define the methylation pattern and identify specific CpG dinucleotides that are methylated in the SRD5A2promoter region. Methods: Ninety six prostate samples from patients were obtained by transurethral resection of prostate (TURP). Methylation of SRD5A2 promoter was assessed using Methylated CpG Island Recovery Assay (MIRA). Bisulfide conversion of Genomic DNA was performed using Epimark bisulfide conversion kit. Primers for bisulfide sequencing were designed using MethPrimer software and bisulfide sequencing was performed using 3730XL DNA Sequencers. Binding of histone demethylase to promoter DNA was analyzed by ChiP assay. Results: We randomly selected 3 TURP samples with methylated SRD5A2 promoters and 3 TURP samples with un-methylated SRD5A2 promoters, and then bisulfide conversion and sequencing were performed to verify the methylation pattern of CpG dinucleotides on SRD5A2 promoter. We found that bisulfide sequencing analysis of SRD5A2 promoter was consistent with MIRA analysis. To further analyze the mediators of SRD5A2 promoter region, we show that TNF-alpha up-regulates expression of Snail protein, which is a central regulator of both DNA methylation and histone methylation, and increases the binding of H3K9me to SRD5A2promoter region, but not H3K27me or H4K20me. Conclusions: Methylation of SRD5A2 promoter, which is regulated by DNMT1, proinflammatory cytokines and the histone methylase, H3K9me, accounts for suppression of SRD5A2 in many adult human prostate tissues. Bisulfide conversion and sequencing confirm and focus the specified CpG dinucleotides that are methylated enabling us to evaluate mechanisms and patterns of SRD5A2 promoter methylation in order to study the functional significance of SRD5A2 methylation. Grant support: NIH/R01 DK091353.
Fractionated dose radiolabeled anti−prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu−J591) for progressive metastatic castration−resistant prostate cancer (mCRPC).
Authors: Batra Jaspreet S. , Karir Beerinder S. , Pinto-Chengot Kavya , Jhanwar Yuliya , Vallabhajosula Shankar , Christos Paul J. , Hodes Gillian , Lam Linda , Molina Ana M. , Beltran Himisha , Nanus David M. , Goldsmith Stanley J. , Bander Neil Harrison , Tagawa Scott T. 
Published: February 2017

205 Background: Phase I and II single dose 177Lu−J591 studies have been published. Based on the theoretical advantages of dose fractionation on safety and efficacy, we initiated a phase I dose−escalation study of fractionated−dose 177Lu−J591. Methods: Men with progressive mCRPC with normal neutrophil and platelet counts were enrolled. The initial portion was 3+3 dose−escalation, with 6 cohorts of 3−6 patients receiving 2 doses 177Lu−J591, 2 weeks apart starting with 20 mCi/m2, escalating to 45 mCi/m2. After determining maximum tolerated dose (MTD), patients enrolled in 2 expansion cohorts at recommended phase II doses (RP2D). Planar imaging of 177Lu−J591 at 6−8 days following the initial dose was performed. Pre− and post−treatment PSA was measured for all patients and the highest dose−level cohorts had CTC counts (CellSearch) measured before and after treatment. Results: 48 patients enrolled with median age 74 (55−95) ), median baseline PSA 45.38 (1.93−766.5), 37.5% with prior chemo. The RP2D’s of fractionated 177Lu−J591 were 40 mCi/m2 or 45 mCi/m2 x2 with option for GCSF. Overall PSA decline ≥ 50% in 9 (18.8%), ≥ 30% in 14 (29.2%) and any PSA decline in 26 (54.2%); at RP2D doses (n = 32), 8 (25%) with ≥ 50%, 12 (37.5%) with ≥ 30%, and 20 (62.5%) with any PSA decline. Of 25 with available CTC counts, 14 declined, 8 remained stably favorable, and 3 increased. Of 12 with unfavorable baseline CTC counts, 8 (66.7%) became favorable at follow up, 2 decreased by 30% and 88% but remained ≥ 5, and 2 increased; 1 converted from < 5 to ≥ 5. Thirty-five (72.9%) had grade 3/4 hematological toxicities; 19 (59.4%) with Gr 4 heme toxicity in RP2D cohorts, with 15 (16.9%) receiving at least 1 platelet transfusion, 6 receiving GCSF, and 0 with febrile neutropenia. Overall 4 had Gr 1 transaminitis and 14 (29.2%) had grade 1 infusion reactions (without pre−medication). Accurate targeting of 177Lu−J591 at known sites of disease seen in 84.4%. Conclusions: Fractionated 177Lu−J591 is well tolerated with predictable, reversible myelosuppression, achieving a higher cumulative dose than possible with a single dose. Both PSA and CTC count control was achieved. Clinical trial information: NCT00538668.
A phase II study of cabozantinib in metastatic castration-resistant prostate cancer (mCRPC) with visceral metastases (VM) with very small nuclear circulating tumor cell (vsnCTC) association studies.
Authors: Huynh Richard , Chen Jie-Fu , Tighiouart Mourad , Sievert Margarit , Oppenheim Amy , Moldawer Nancy P. , Knudsen Beatrice , Freeman Michael , Bhowmick Neil , Rogatko Andre , Tseng Hsian-Rong , Chung Leland WK , Scher Kevin , Figlin Robert A. , Posadas Edwin M. 
Published: February 2017

208 Background: Cabozantinib is a multi-targeted tyrosine kinase inhibitor (TKI) that has recognized clinical activity in mCRPC. While phase 3 studies did not show a significant improvement in overall survival (OS), patients with VM had improved OS compared to those with only osseous metastases in subgroup analysis. Our group has also identified a subgroup of CTCs strongly associated with the presence of VM (Chen, Cancer 2015). We hypothesized that cabozantinib would yield clinical benefit and changes in vsnCTC counts would reflect disease behavior. Methods: This study was designed as an open label study of cabozantinib 60 mg daily, for mCRPC patients with visceral disease. The primary endpoint is clinical benefit rate (radiographic stable disease + partial response (PR) by RECIST 1.1) at 12 weeks (CBR12). Serum PSA concentrations were not used as a primary endpoint. CTCs were enumerated by NanoVelcro CTC Assay and characterized using published methods. Results: Thirteen patients have completed at least 8 weeks of treatment. In this group, 38% had pulmonary metastases; 77% had hepatic metastases; CBR12 was 92% at the time of this report. A quarter of the patients experienced a PR. Mean time to radiographic progression for responders was 38 weeks (19-57). Discordant responses were noted between VM and bone scans. Grade 3 or higher toxicities were compatible with prior studies and observed in 50% of patients. In this advanced mCRPC and relatively heavily pre-treated population, treatment discontinuation due to toxicity was 33%. Eleven of 13 patients were assessable for CTC and imaging. Of the 11 patients, 7 had vsnCTCs detected at baseline. All 7 patients reported subjective improvement that was associated with a decrease in vsnCTCs by 6-8 weeks. In patients who had a PR, no vsnCTCs were detected at 6 weeks while on active treatment. An increase in vsnCTCs was seen prior to visceral progression. Conclusions: Cabozantinib is a TKI with activity in mCRPC with visceral metastases. Toxicity is consistent with previous reports and manageable. The NanoVelcro vsnCTC assay may be a predictive marker of response. Clinical trial information: NCT01834651.