bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of age on sexual preservation after prostate brachytherapy: A prospective evaluation in men without erectile dysfunction.
Authors: Brahmi Tristan , Lapierre Ariane , Samlali Hamza , Selmaji Imad Eddine , Udrescu Corina , Ruffion Alain , Chapet Olivier 
Published: February 2017

105 Background: Sexual preservation is an important issue in the treatment of localized prostate cancer. In this study, we evaluate the long-term incidence of erectile dysfunction (ED) after prostate brachytherapy (PBT), in men without ED. Methods: Between 2006 and 2012, prospective data of patients treated with brachytherapy for a low or intermediate-risk prostate cancer (d’Amico classification), were collected. Erectile function (EF) was assessed with IIEF5 score (5-Item Version of the International Index of Erectile Dysfunction) at six weeks and then every year during the follow-up. No ED was defined by an IIEF5 score ≥ 22/25 and a mild ED by a score between 17 and 21. Results: Up to this point, 70 patients, with an initial IIEF5 ≥22, were analyzed with a mean follow-up of 46.5 months. At 6 weeks and 1, 2, 3 and 4 years after brachytherapy, mean IIEF5 scores in all 70 patients were 24.6, 21.3, 19.7, 19.1 and 17.3, respectively. In ≤ 65 years old group, the scores were 24.7, 20.9, 21.3, 21.1, 19.7 and 20, respectively. In > 65 years old group, the scores were 24.6, 21.8, 21.3, 18.1, 18.2 and 14.9, respectively. The evaluation of ED according to age groups is represented in the table. Conclusions: At 4 years of follow-up after brachytherapy, patients 65 years old and younger have an EF preservation rate >80% with 50% of them having no ED. For patients older than 65 years, the rate of EF preservation decreased at 50% after 4 years of follow up with only few of them having no ED. This difference between the 2 groups of age is probably more related to an age effect than a brachytherapy toxicity. At the time of the meeting, more data and results will be available. [Table: see text]
Development and validation of an ADT resistance signature to predict adjuvant hormone treatment failure.
Authors: Karnes Jeffrey , Ashab Hussam Al-Deen , Trock Bruce J. , Ross Ashley , Tsai Harrison , Tosoian Jeffrey J. , Erho Nicholas , Choeurng Voleak , Yousefi Kasra , Haddad Zaid , Abdollah Firas , Klein Eric A. , Nguyen Paul L. , Feng Felix Yi-Chung , Dicker Adam , Den Robert Benjamin , Davicioni Elai , Jenkins Robert B. , Lotan Tamara L. , Schaeffer Edward M. 
Published: February 2017

106 Background: Androgen deprivation therapy (ADT) is one of the main treatment options for locally advanced and metastatic prostate cancer. Neuroendocrine prostate cancer (NEPC) is inherently less sensitive or even resistant to ADT. NEPC can be observed de novo (e.g., small cell prostate cancer) but more commonly arises after exposure to ADT. We hypothesized that a gene expression signature of NEPC when measured in primary tumor specimens (RP) of prostatic adenocarcinoma may be useful for predicting patients with innate resistance to ADT. Methods: Expression profiles of 1023 PCa patients treated with RP were obtained from the Decipher GRID database. These were split into training (n=529) and validation (n=494) sets and stratified by the receipt of adjuvant ADT (n=243) or no adjuvant ADT (n=780). A literature review of ADT resistance and neuroendocrine genes identified 1,557 genes as candidates. This set was further filtered, using logistic regression to select a 52-gene ADT resistance signature (ARS). ARS was trained using a generalized linear model with lasso regularization. Survival c-index and Kaplan Meier was used to compare survival differences between treated and untreated patients with high and low ARS scores (defined by median split). Results: In validation cohorts, the ARS was predictive of metastasis in cohorts receiving adjuvant ADT (10-year metastasis free survival c-index of 0.69 (95% CI 0.59-0.78) as compared to 0.45 (95% CI 0.29-0.61) in patients not treated with ADT). Similarly in a separate cohort of untreated patients that received no ADT until after metastatic onset, ARS was not prognostic (c-index 0.53). Among ADT treated patients, those with low ARS scores had a 10 year MFS of 87%, versus 70% in those with high ARS scores (p<0.001). In the subset of men who received ADT after metastatic onset and who developed castrate-resistant prostate cancer (CRPC, n = 41), median time to treatment failure was 1 year in patients with high ARS compared to 2 years for those with low ARS scores (p=0.07). Conclusions: A 52-gene ADT resistance signature was developed which showed significant differences in metastasis-free survival among adjuvant hormone treated but not untreated patients.
Comparative study of late rectal toxicity in veterans undergoing low-dose rate prostate brachytherapy treated with or without supplemental external beam radiotherapy.
Authors: Serrano Nicholas A , Moghanaki Drew , Asher David , Karlin Jeremy , Schutzer Matthew , Chang Michael G. , Hagan Michael Philip 
Published: February 2017

112 Background: Supplemental external beam radiation therapy (sEBRT) is often prescribed in men undergoing low dose rate (LDR) brachytherapy for prostate cancer. A population of patients was analyzed to assess the effect of sEBRT on late rectal toxicity. It was hypothesized that sEBRT+LDR would be associated with a higher risk of late rectal toxicity, compared to LDR brachytherapy alone. Methods: This retrospective cohort study examined LDR brachytherapy patients, treated with or without sEBRT, with a minimum of 5 years follow-up. All were treated at a credentialed Veterans Affairs medical center that enrolled many of these patients on RTOG 0234. Longitudinal assessments were evaluated using the Computerized Patient Record System, and toxicities were coded using the CTCAE v4.0. The Kaplan-Meier method was used for analysis. Results: Median follow-up was 7.5 years for 245 consecutive patients from 2004 and 2007. sEBRT was administered to 33.5%. Follow-up beyond 5 years was available for 89%. Overall rates of grade ≥ 2 and ≥ 3 rectal toxicities were 6.9% and 2.9%, respectively. The risk of grade ≥ 2 rectal toxicity was 2.8-fold higher for patients receiving sEBRT (1.1 - 7.2, 95% CI, p = 0.02). The risk of grade ≥ 3 rectal toxicity was 11.9-fold higher for patients who received sEBRT (1.5 - 97.4, 95% CI, p = 0.003). Six out of 7 patients with a grade ≥ 3 rectal toxicity received sEBRT, including one who required an abdominoperineal resection due to radiation proctopathy. The median post-LDR D90, V150, V200, and R100 values were 103.3%, 59.4%, 30.1%, and 0.5 cc. The minimum R100 associated with a grade ≥ 2 toxicity was 0.2 cc, and the minimum R100 for a grade ≥ 3 toxicity was 0.4 cc. Grade ≥ 2 rectal toxicity was seen in 3% vs 13% of patients who had post-implant dosimetry of R100 < 1 cc vs R100≥ 1 cc, respectively. Conclusions: In a cohort of LDR brachytherapy patients with high rates of follow-up, sEBRT+LDR was associated with significantly higher risk of grade ≥ 2 and ≥ 3 late rectal toxicity. This analysis supports previous findings and maintains concern about the supplemental use of EBRT with LDR brachytherapy while its benefit for tumor control has yet to be prospectively validated.
Prostate brachytherapy as salvage for local failure after external beam radiation.
Authors: Baumann Brian Christopher , Baumann John Charles , Christodouleas John Paul , Soffen Edward M 
Published: February 2017

125 Background: Local failure (LF) after external beam radiation (EBRT) for prostate cancer is a serious problem. Most patients receive non-curative androgen deprivation therapy (ADT), but there is a subset with LF who are still potentially curable. There is limited evidence to suggest that prostate brachytherapy (BT) is an effective, potentially curative salvage therapy with acceptable toxicity. We hypothesize that salvage BT following EBRT can achieve high rates of biochemical control with acceptable toxicity. Methods: We analyzed 39 consecutive patients treated from 1998-2013 with salvage BT at 2 centers. All patients had pathologically confirmed LF following previous EBRT without distant mets & a disease-free interval of ≥ 18-24 mo. Salvage BT to the whole prostate was delivered to 29 patients using low-dose rate I-125 or Pd-103 seed implants (median dose 100 Gy with Pd-103) while 10 received HDR BT (median 30 Gy in 6 fractions). Cases were planned as if de novo but to a lower dose. 33 (85%) received neoadjuvant and/or adjuvant ADT as part of their salvage therapy. Biochemical failure (BF) was defined using the Phoenix criteria. Risk factor analysis was conducted to identify characteristics that predict BF after salvage BT. Results: For the 39 patients, median PSA at diagnosis was 8.4, and 21 (54%) had high-risk disease. Median EBRT dose was 70 Gy with 11 patients (28%) receiving ADT. Median PSA nadir following EBRT was 0.8 (range 0 – 2.6). Median time to recurrence was 53 mo (range 18 – 150), and median pre-salvage PSA was 4.8. Median follow-up after salvage BT was 60.1 mo (range 7 – 150). Biochemical failure-free survival, DMFS and OS at 5 & 7 yrs were 76% & 67%; 91% & 85% and 92% & 84%, respectively. On univariate analysis, PSA nadir after EBRT & pre-salvage PSA were significant predictors of BF (p< 0.01 for both). On multivariate analysis, only pre-salvage PSA was a significant independent predictor of BF (p< 0.01). Freedom from late grade 3 GU toxicity at 3 yrs was 83%. There were no late Grade 3 GI toxicities. Conclusions: This is the largest series reporting on salvage prostate brachytherapy plus ADT for local-only failures after EBRT & suggests that salvage BT with ADT offers selected patients prolonged disease-free survival with acceptable toxicity.
Metastasis free survival following salvage radiotherapy versus hormonal therapy alone in patients with biochemical recurrence after radical prostatectomy.
Authors: Kim Jae-Sung , Song Changhoon , Hong Sung Kyu , Byun Seok-Soo , Lee Sang Eun 
Published: February 2017

130 Background: To describe metastasis-free survival (MFS) in patients with biochemical recurrence following radical prostatectomy (RP), and to define clinical prognostic factors for metastasis. Methods: From our institutional database, 1,408 patients underwent primary RP between 2005 and 2011. Of these, 267 patients who had biochemical recurrence (two consecutive PSA ≥ 0.2 ng/mL) and had post-biochemical recurrence follow-up greater than 12 months were used as the study cohort. As an initial management for biochemical recurrence, salvage radiotherapy (SRT) combined with or without androgen deprivation therapy (ADT) was administered to 186 patients, while 33 patients received salvage ADT alone. Remaining 48 patients had been observed without any treatments. We estimated MFS using the Kaplan–Meier method, and investigated factors influencing the risk of metastasis using Cox proportional hazards regression. Results: Median follow-up after RP was 6.0 years, and after biochemical recurrence was 4.2 years. At last follow-up, 28 of 267 patients (10.5%) had developed metastasis, while 5-year MFS rate was 88.6%. No one developed metastasis in patients under observation. SRT resulted in an improved 5-year MFS rate (89.3% vs. 76.7%; p =0.022) compared with salvage ADT alone. This inferiority of salvage ADT alone compared with salvage SRT was marginally significant in the multivariate analysis (hazard ratio [HR] 2.24; 95% confidence interval [CI] 0.93–5.36; p = 0.071). Gleason score ≥8 (HR 4.10; 95% CI 1.77–9.51; p = 0.001) and seminal vesicle invasion (HR 2.37; 95% CI 1.06–5.30; p = 0.036) were significantly associated with MFS in the multivariate analysis. Conclusions: In patients undergoing prostatectomy, MFS after biochemical recurrence is variable and is most strongly influenced by Gleason score and seminal vesicle invasion. These parameters serve to stratify patients into different risk groups with respect to metastatic progression. Salvage ADT alone should be used with caution with select patients.
Nature of intrafractional and interfractional prostate motion during stereotactic radiation.
Authors: Perumal Karthikeyan , Potharaju Mahadev 
Published: February 2017

152 Background: To characterize the intra-fraction and inter-fraction prostate motion as tracked by the X-ray images of the implanted gold fiducials during stereotactic radiotherapy with CyberKnife. The published data have analysed the linear and angular prostate motion intrafraction and interfraction prostate motion among patients. We sought to quantify the same within each patient. Methods: Twenty Five patients with localized prostate cancer treated with CyberKnife radiosurgery between January 2013 and August 2015 were studied retrospectively. A data set constitutes the deviations derived from X-ray images obtained between two consecutive couch motions. Results: Included in the analysis were 3926 data sets. A total of 210 non-coplanar fields were used per fraction. The mean total treatment time for all fields per fraction was 36.13 minutes. The detected and corrected movements over all were in a range of ± 10.1 mm in linear direction (Right: mean 1.1±0.4 mm; Left: mean 1.0±0.6 mm; Superior: mean 0.7±0.3 mm; Inferior: mean 1.6±0.6 mm; Anterior: mean 1.6±0.7 mm; Posterior: mean 0.5±0.3 mm with maximum (max) movement range of Right max 9.9±6.4 mm, Left max 7.1±3.4 mm, Superior max 8.6±5.4 mm, Inferior max 10.1±8.5 mm, Anterior max 9.2±6.5 mm, Posterior max 8.4±2.9 mm) and angular movements were in a range of ± 6.7 deg in all directions (Right Angle: mean 0.6±0.3 deg; Left Angle: mean 0.6±0.3 deg; Head Up(H-U): mean 1.3±0.6 deg; Head Down(H-D): mean 1.4±0.6 deg; Counter-Clockwise movement (CCW): mean 0.7±0.3 deg; Clockwise movement (CW): mean 0.5±0.3 deg with max rotation range of Right angle max 2.4±2 deg, Left angle max 2.7±2 deg, H-U max 10.2±3.5 deg, H-D max 6.7±4.8 deg, CCW 4±2.9 deg, CW max 2.8±2.4 deg). There was an unpredictable change in prostate motion inter-fraction in each patient. But, a unique observation is that a predictable pattern exists for prostate motion intra-fraction within a patient. Change in the linear or angular prostate motion intra-fraction in any direction is not erratic. Conclusions: The linear and rotational prostate motion intra-fraction in any direction has a predictable pattern and any change is gradual and not erratic. The motion shows secular trend during the course of treatment.
Initial acute toxicity report of post-prostatectomy proton therapy for prostate cancer patients undergoing adjuvant or salvage radiotherapy.
Authors: Deville Curtiland , Both Stefan , Gabriel Peter Edward , Tochner Zelig , Vapiwala Neha 
Published: February 2017

154 Background: Purpose is to report acute genitourinary (GU) and gastrointestinal (GI) toxicities associated with post-prostatectomy proton beam radiotherapy (PBT). Methods: The first 50 patients undergoing post-prostatectomy PBT on a prospective, IRB-approved, institutional protocol for image-guided radiotherapy were assessed. Patients received a median dose of 70.2 Gy relative biological effectiveness (RBE) in 1.8 GyRBE daily fractions using traditional, laterally-opposed beams to the prostate bed only, as defined by RTOG consensus guidelines, passive scattering or pencil beam scanning technique, and 100 cc water-filled endorectal balloon, from 10/2011 to 7/2015. One patient received concurrent androgen deprivation. Acute toxicity was scored by CTCAE v4.0. Results: The Table summarizes the clinical characteristics. Median age was 62 years and median months from surgery were 23. Passive scattering was used for 16% of cases and pencil beam scanning for 84%. A GyRBE dose of 70.2 was used for 88% of cases, 66.6 for one case, and 75.6 for the remaining 10% with gross local recurrence. All patients completed treatment and there were no acute grade 3 or greater GU or GI toxicities. Regarding GU, most reported grade 1 (78%) toxicity, 18% grade 2, and 4% none (grade 0). Regarding GI, most patients (54%) reported no toxicity (grade 0), 36% grade 1, and 10% grade 2. Conclusions: Our results report for the first time to our knowledge, the clinical feasibility and favorable GU and GI toxicity profile of post-prostatectomy PBT. Future studies with larger patient numbers are planned to further validate our preliminary findings. [Table: see text]
Genomic profiling of metastatic prostate cancer through analysis of circulating tumor DNA (ctDNA).
Authors: Gourdin Theodore Stewart , Lilly Michael B. 
Published: February 2017

174 Background: We have performed genomic analysis of circulating tumor DNA (ctDNA) to identify actionable anomalies in 55 patients with metastatic prostate cancer. Methods: A publically-accessible assay (Guardant Health) was used to analyze 68 known cancer genes for anomalies (missense mutations, amplifications) by a digital PCR technique. The racial profile included Caucasian (27), African-American (27), Asian (1) patients. Most subjects (82%) had CRPC and had been treated with multiple forms of androgen deprivation and chemotherapy. Results: Genomic anomalies were found in 52/55 subjects. 127 missense mutations and 78 amplifications were identified in 35 genes. Missense mutations in each gene were overwhelmingly single (98/127). African-American patients each had an average of 3.9 genomic anomalies, whereas Caucasian patients each had an average of 2.7 anomalies (p = NS). Anomalies most commonly involved TP53 (43.2%), AR (43.4%), MYC (21.8%), BRAF (21.8%), and DNA repair genes (BRCA1, BRCA2, or ATM; 16.4%). Taxane-based chemotherapy was given to 24/55 subjects with mCRPC. These 24 patients were grouped by TP53 status (WT, n = 13; MUT, n = 11) and progression-free survival (PFS) was determined by PCWG2 criteria (PSA or imaging). Data for PFS vs time were presented as Kaplan-Meier plots and compared by the log rank test. Median PFS during taxane chemotherapy was approximately twice as long for subjects with MUT TP53, compared with that of subjects with WT TP53 (p = 0.013; HR = 2.5 [1.1-6.0]). Conclusions: 1. Genomic analysis on ctDNA from patients with metastatic prostate cancer is feasible and identifies anomalies in most patients. 2. Within the limits of the assay, ctDNA analysis provides similar findings to those identified by analysis of FFPE tissue (Robinson et al., Cell, 2015). 3. ctDNA analysis can identify missense mutations that are associated with an improved PFS from taxane-based chemotherapy. ctDNA analysis may help clinicians to judge the potential benefits of chemotherapy in subjects with mCRPC.
Phase Ib trial of cabazitaxel and tasquinimod in men with heavily pretreated metastatic castration resistant prostate cancer (mCRPC): The CATCH trial.
Authors: Armstrong Andrew J. , Healy Patrick , Szmulewitz Russell Zelig , Winters Carolyn , Harrison Michael Roger , Martinez Elia , Mundy Kelly , Halabi Susan , George Daniel J. 
Published: February 2017

190 Background: Cabazitaxel resistance develops within a few months of treatment initiation in most men with mCRPC in post-docetaxel, and thus combination therapy with other active agents may improve outcomes. Tasquinimod is an oral immunomodulatory agent with anti-angiogenic and anti-tumor in preclinical models of PC and clinical activity in phase II and III trials. Methods: We conducted a phase I dose escalation trial of cabazitaxel plus tasquinimod in men with mCRPC. Cabazitaxel was dosed at 25 mg/m2 every 3 weeks with low dose prednisone and PEG-filgrastim support, and tasquinimod dose levels included 0.25, 0.5, and 1.0 mg, using a 3 week within-patient dose escalation for dose levels 2 and 3, starting all patients at 0.25 mg once daily. The primary objective was to define the recommended phase II dose (RP2D) based on safety and dose limiting toxicity. Preliminary efficacy (PSA decline, PFS) and pharmacokinetic interactions were key secondary objectives. Results: We enrolled 25 men with mCRPC who had failed docetaxel across 3 dose levels. Median PSA at entry was 220 ng/dl. The RP2D was 0.5 mg tasquinimod based on excess DLTs (2 of 3 men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation). Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function test abnormalities. The proportion of men with a > 30% PSA decline was 63% (95% CI: 41%, 81%). The median composite PFS was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with 6 men receiving > 10 cycles. Best overall RECIST responses (CR+PR) were observed in 3 men (12%), stable disease in 12 (48%). No unexpected adverse events were observed and no pharmacokinetic interactions were observed. Conclusions: The RP2D was cabazitaxel 25 mg/m2 with prednisone and PEG-filgrastim every 3 weeks with tasquinimod 0.25 mg once daily for 3 weeks followed by 0.5 mg. Preliminary evidence of efficacy over cabazitaxel alone is based on observed PSA response and PFS data, and a substantial number of men were progression free beyond 10 cycles with good tolerability. Clinical trial information: NCT01513733.
Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.
Authors: Toren Paul , Kim Soojin , Fazli Ladan , Davies Barry , Gleave Martin , Zoubeidi Amina 
Published: February 2017

192 Background: Despite recent advances with newer androgen receptor(AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer continues to remain a clinical problem. Co-targeting approaches are of significant interest to slow the progression of disease and delay the onset of resistance. With both Akt and MEK pathways becoming activated as prostate cancer develops resistance to AR-targeted therapy, this study explores co-targeting these pathways in AR positive prostate cancer models. Methods: Using in vitro models of prostate cancer progression from androgen dependent to castrate resistant and ENZ-resistant disease, we evaluated the effect of Akt and/or MEK inhibition with AZD5363 and PD0325901, respectively, on cell proliferation, apoptosis and downstream signalling pathways. For in vivo models, we tested the combination of Akt and MEK inhibition castrated mice bearing MR49F and 22RV1 cells which are resistant to ENZ. Results: Inhibition of Akt reduced S6 phosphorylation, inhibited growth and induced apoptosis in LNCaP-derived cells; the addition of a MEK inhibitor increased apoptosis and cell cycle arrest, but did not further decrease cell proliferation. In contrast, PTEN wild-type 22RV1 cells demonstrated a greater sensitivity to MEK inhibition, but were generally insensitive to Akt inhibition. In vivo, combination of Akt and MEK inhibition resulted in more consistent tumour growth inhibition of MR49F xenografts and longer disease specific survival than Akt inhibitor monotherapy, with induction of pERK staining being evident in some AZD5363 monotherapy treated tumours. Conversely, 22RV1 xenografts had greater resistance to Akt inhibition and greater sensitivity to MEK inhibition. Conclusions: Our data suggest that combination of Akt and MEK inhibition may improve prostate cancer control in ENZ-resistant prostate cancer. Further, with the major effect in both MR49F and 22RV1 xenografts attributable to one inhibitor, our results also suggest the importance of characterizing the dominant oncogenic pathway in each patient’s tumour in order to select optimal therapy.