bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathways of Transferred Youth Offenders into Adulthood
Authors: Jaspers Yana , Nuytiens An , Christiaens Jenneke , Dumortier Els
Published: March 2017

In this article, the authors discuss the preliminary results of a Belgian research on 210 young offenders transferred to Adult Court in 1999, 2000 and 2001. The long-term judicial pathways of these youngsters, now aged between 30 and 40, are explored. Drawing on the criminal records and detention records of the sample, judicial pathways into adulthood are charted. The results show that the greater part of the sample is still involved in the criminal justice system. More than 50 per cent were convicted at some point in the last 3 years, and almost a third of the population is imprisoned. With this quite unfavourable picture of transferred offenders’ future pathways, we hope to reopen the discussion about transfer policies in Belgium.
Resistance at the Trench
Authors: Samuels Linda C.
Published: March 2017

In the last three decades, five projects have been proposed to bridge the 101 Freeway in downtown Los Angeles; none have come to fruition. Two of significant design merit were selected through international competitions, Steel Cloud in 1988 and the 101 Pedestrian Bridge in 1999. By studying the competition objectives, media portrayal, jury, and winners, this research analyzes why these proposals failed to be implemented in context of the larger planning objectives, politics, agency relationships, and economic contexts of the era. More broadly, this work explores the larger struggle to transform autocentric infrastructure into vibrant and publicly accessible civic space.
Casting and Splinting Management for Hand Injuries in the In-Season Contact Sport Athlete
Authors: Carruthers Katherine H. , O’Reilly Olivia , Skie Martin , Walters John , Siparsky Patrick
Published: March 2017

Context:

Upper extremity injuries are extremely common in contact sports such as football, soccer, and lacrosse. The culture of competitive athletics provides an environment where hand injuries are frequently downplayed in an effort to prevent loss of game time. However, studies have shown that many sport-induced hand injuries do not actually require immediate surgical attention and can be safely treated through immobilization so that the athlete may complete the athletic season. In these cases, appropriate casting and splinting measures should be taken to ensure protection of the injured player and the other competitors without causing loss of game time.

Evidence Acquisition:

Articles published between 1976 and 2015 were reviewed to capture historical and current views on the treatment of hand injuries in the in-season athlete.

Study Design:

Clinical review.

Level of Evidence:

Level 5.

Results:

Although traditionally many sports-induced traumatic injuries to the hand held the potential to be season-ending injuries, experience has shown that in-season athletes do not necessarily need to lose game time to receive appropriate treatment. A thorough knowledge of converting everyday splints and casts into game day, sport-approved protective immobilization devices is key to safely allowing athletes with select injuries to play while injured.

Conclusion:

Protective techniques allow for maximum functionality during gameplay while safely and effectively protecting the injury from further trauma while bony healing takes place.
Effect of ulexite concentrator waste on the physical and mechanical properties and sintering behaviour of floor tile bodies
Authors: Köseoğlu K.
Published: March 2017

The effect of ulexite concentrator waste on the physical and mechanical properties and sintering behaviour of a standard floor tiles (FT) body fired at 1080°C was studied. The linear firing shrinkage, water absorption and fired bending strength of the floor tile/tiles were determined. X-ray diffraction analyses identified quartz, albite, mullite and hematite phases in the floor tiles containing 3 wt.% waste material. The FT body with the smallest water absorption (∼0.2%), the greatest bending strength (∼335 kgf/cm2) and the second greatest linear firing shrinkage values had optimal composition. In light of the excellent physical-mechanical properties and the results of the scanning electron microscopy-energy dispersive X-ray analyses, the authors determined that the sintering temperature of the FT body containing 3 wt.% ulexite concentrator waste was reduced by 100°C.
President's Page
Authors: Lawyer Lee
Published: March 2017

It is always a treat for me to move from my “From the Other Side” column to the President's Page. It feels like a step up. Simultaneously, I need to get a little more serious. I am the Council Chair — or better stated, I am the chair of the Council.
Integration of seismic and well-log data using statistical and neural network methods
Authors: Ma Y. Zee , Gomez Ernest , Luneau Barbara
Published: March 2017

In the last two to three decades, the use of seismic attributes for reservoir characterization and modeling has grown exponentially. Now, a dozen or more attributes are often extracted from seismic data to predict reservoir properties. Meanwhile, an increasing trend of acquiring more wireline logs provides more and more data to describe reservoir properties. Both statistical methods and artificial neural networks (ANNs) are often used to extract information and make predictions. Although statistical methods and ANNs provide powerful tools for geoscience data integration, they also have pitfalls. We present principal component analysis (PCA) and ANNs for facies classifications and porosity prediction. We also show the use and limitations of these methods and the importance of integrating the geologic and petrophysical knowledge.
SEG News
Authors: Blythe Natalie
Published: March 2017

Recognizing the importance of the Middle East region for both SEG and the oil and gas industry, a delegation of SEG representatives, led by SEG President Bill Abriel, visited the region in early January. The trip was an opportunity for SEG to showcase its involvement in the region, engage with top leaders from various oil and gas companies and academic institutions, and promote the array of SEG offerings to those in the geosciences community. Tom Agnew, SEG associate executive director of programs, and Yogaani Bhatia, SEG Middle East regional manager, accompanied Abriel on the trip.
Memorial
Authors: Nelson H. Roice , Kessler David
Published: March 2017

Richard L. Coons, a geophysical expert on seismic velocities, the presalt section of the South Atlantic, and fault shadows on the Texas shelf, died 22 December 2016 at the age of 78 from complications associated with Parkinson's disease.
Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial
Authors: Arcangeli Giorgio , Saracino Biancamaria , Arcangeli Stefano , Gomellini Sara , Petrongari Maria Grazia , Sanguineti Giuseppe , Strigari Lidia
Published: March 2017

Purpose

To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa).

Patients and Methods

This single-institution, randomized clinical trial, conducted from January 2003 to December 2007, enrolled 168 patients with high-risk PCa who were randomly assigned in a 1:1 ratio to conventional (80 Gy in 40 fractions in 8 weeks) or hypofractionated radiotherapy (62 Gy in 20 fractions in 5 weeks) to prostate and seminal vesicles. The primary outcome measure was late toxicity. Additional outcomes were freedom from biochemical failure (FFBF), prostate cancer–specific survival (PCaSS), and overall survival (OS), evaluated on an intention-to-treat basis.

Results

A total of 85 patients were assigned to conventional and 83 to hypofractionated radiotherapy. At a median follow-up of 9 years (interquartile range, 7.5 to 10.1 years), no differences was observed in physician-assessed late gastro intestinal and genitourinary toxicity greater than or equal to grade 2 ( P = .68 and .57, respectively) were found between the two arms. The 10-year FFBF rate was 72% in the hypofractionation group and 65% in the conventional fractionation group ( P = .148). Ten-year OS rates were 75% in the hypofractionation group and 64% in the conventional group, respectively ( P = .22). The same features for 10-year PCaSS were 95% and 88%, respectively ( P = .066). Hypofractionation, pretreatment prostate-specific antigen level, Gleason score, and clinical tumor stage for FFBF, and hypofractionation and Gleason score for PCaSS were significant prognostic variables on the multivariate analysis.

Conclusion

Long-term findings showed that hypofractionated radiotherapy failed the intent of either reducing physician-assessed late toxicity or maintaining the same efficacy. A postrandomization analysis, however, revealed that hypofractionation was a significant prognostic factor for FFBF and PCaSS, when adjusted for clinical prognostic variables.
Implications of prostate cancer with diabetes mellitus on patient outcomes and care: A matched case-control study.
Authors: Karlin Nina J. , Kosiorek Heidi , Verona Patricia M. , Amin Shailja , Cook Curtiss B.
Published: March 2017

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Background: Diabetes mellitus (DM) has been associated with an increased risk of mortality among patients with many types of cancers. The aim of this case-control study was to determine the impact of DM on short-term overall survival in prostate cancer patients, and to examine the impact of prostate cancer on glycemic control in DM. Methods: 276 patients with newly diagnosed prostate cancer from 2007-2014 with DM were identified from the Institutional Cancer Registry and matched to 276 prostate cancer patients without DM according to age and year of prostate cancer diagnosis. The file was linked to the electronic medical record to obtain information on DM and cancer therapies, and laboratory results. Results: The mean age of the entire prostate cancer cohort was 72 years, most (93%) were white, the most common Gleason score (in 52%) was 7, and the majority (56%) were tumor stage 2. No differences in age, race/ethnicity, Gleason score, or tumor stage were detected between patients with and without DM, although DM patients had higher body mass index (P = .031). Among those with DM the mean hemoglobin A1c (HbA1c) was 6.7%. In Kaplan-Meier survival analysis (median follow-up time of 43.7 months), 5-year overall survival was estimated at 88% for DM patients versus 93% in non-DM patients. Hazard ratio (for matched pairs) was 1.64 (95% CI: 0.77-3.46, P = .20). Moreover, mean HbA1c and glucose values among DM cases did not significantly change over 1 year (P ≥ .13). Mean glucose among DM patients was significantly (p < 0.01) higher compared to non-DM patients. Conclusions: DM did not adversely impact survival in prostate cancer patients. In addition, prostate cancer or its treatment does not appear to affect glycemic control. Both patients and their providers can be reassured that the two concurrent diagnoses do not adversely interact to worsen short term outcomes.
Long-term aspirin use and intratumoral gene expression in prostate cancer.
Authors: Stopsack Konrad Hermann , Ebot Ericka M. , Downer Mary K , Rider Jennifer R. , Mucci Lorelei
Published: March 2017

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Background: Pharmacoepidemiologic studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that prostate cancer tissue from regular aspirin users at cancer diagnosis compared to nonusers is characterized by specific transcriptional changes. Methods: We analyzed tumor whole-transcriptome data from men diagnosed with prostate cancer during prospective follow up of the Physicians Health Study 1 (PHS1, n1 = 150), initially a randomized-controlled trial of aspirin for prevention of cardiovascular disease and cancer. We compared the expression of putative aspirin target genes ( PTGS2, CTNNB1, MYC, AXIN2, PTGER3) between regular aspirin users ( ≥ 3 x 324 mg/week) and non-users at cancer diagnosis. We used Gene Set Enrichment Analysis to identify Gene Ontology biological process gene sets (total, 3609) associated with aspirin use. Leading edge genes of ≥ 3 functionally related gene sets were summarized in a meta-gene score. Results were validated among prostate cancer patients from the Health-Professionals Follow-up Study (HPFS, n2 = 254; aspirin use, ≥ 2 x/week). Results: Regular aspirin use was common (65% in PHS1; 45% in HPFS) and not associated with age, stage, and Gleason grade. In PHS1, none of the predefined genes were associated with aspirin use (all p > 0.05). 26 gene sets were downregulated in aspirin users at a false discovery rate (FDR) < 0.25 (9 at FDR < 0.05). 11 gene sets were clustered functionally around ribosome function and protein translation. A “ribosome” score of 96 genes was higher in aspirin users compared to nonusers (difference, 35.5 standard deviations [SD]; p = 0.0001). There was no dose-dependency for cumulative duration of aspirin use before cancer diagnosis ( ptrend = 0.17) or time since stopping use among non-users at diagnosis ( p = 0.32). In HPFS, neither the pre-defined target genes (all p > 0.18) nor the score were associated with aspirin use (difference, –9.8 SD; p = 0.18). Conclusions: Although RNA acetylation and resulting intratumoral gene expression changes due to aspirin use may be biologically plausible, we were unable to corroborate this association in two-long term prospective studies. Short-term trials might assess if aspirin has direct effects on tumor gene expression.
Comparison of biochemical recurrence-free survival after radical prostatectomy among men in active surveillance following grade reclassification and men newly diagnosed with similar grade disease.
Authors: Diniz Clarissa P. , Carter Ballentine , Epstein Jonathan I. , Mamawala Mufaddal
Published: March 2017

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Background: Stakeholders in a Patient-Centered Outcomes Research grant questioned the clinical implications of biopsy grade reclassification (GR) while on active surveillance (AS). Methods: We conducted a retrospective analysis of men undergoing radical prostatectomy (RP) from 1995-2015 at Johns Hopkins and identified 4 groups; 76 men in AS underwent RP following GR from Gleason score (GS) 6 to GS 7(3+4) [grade group 2], 2947 men underwent immediate radical prostatectomy (IRP) following a diagnosis of grade group 2, 122 men in AS underwent RP following GR to GS ≥ 7(3+4) [grade groups ≥ 2], and 4433 men underwent IRP following a diagnosis of grade groups ≥ 2. Biochemical recurrence free survival (bRFS) was the outcome of interest that was assessed using Kaplan Meir curves and a multivariate Cox regression model. Results: Men on AS had a higher proportion of low volume cancer (p <0.001; p <0.001) as compared to the IRP groups for both biopsy grade group 2 and biopsy grade groups ≥ 2, respectively. On the Kaplan Meier curve, bRFS was higher for men in the AS cohort compared to IRP group for both biopsy grade group 2 (p = 0.071) and for biopsy grade groups ≥ 2 (p = 0.046). However, on the multivariate Cox model adjusting for age at treatment, cancer volume, and PSAD, the difference in bRFS between the AS and IRP group was no longer significant; HR = 0.61 (95% CI, 0.23 to 1.67) for biopsy grade 2, HR = 0.77 (95% CI, 0.41 to 1.46) for biopsy grades ≥ 2. Conclusions: AS patients that are reclassified to grade group 2 and those reclassified to grade group 2 or above have a higher chance of bRFS after treatment as compared to those undergoing IRP with similar grades. This could help inform decisions regarding the risk of entering an AS program. [Table: see text]
Nationwide analysis: Changes in the natural history of low risk localized prostate cancer.
Authors: Thomas Helgstrand John , Klemann Nina , Toft Birgitte Grønkaer , Vainer Ben , Røder Martin Andreas , Iversen Peter , Brasso Klaus
Published: March 2017

12

Background: Increased use of prostate-specific antigen (PSA) has introduced an increase in PCa incidence and a lead time and stage migration at diagnosis, altering the natural history of PCa. Contemporary PCa patients are likely younger and have smaller tumor burden at diagnosis. We investigated if changes in the PCa landscape have altered the course of low-risk localized PCa. Methods: In the Danish Prostate Cancer Registry (DaPCaR), patients diagnosed from 1995 to 2011 with localized (T1-2, N0/X, M0) PCa with Gleason score ≤ 6 were identified. Patients were stratified into three periods of diagnosis; 1995-2000 (period 1), 2001-2005 (period 2) and 2006-2011 (period 3). Competing risk analysis treating PCa and other-cause death as competing events was performed. Results: Of the 5,660 patients identified, 35.9% had undergone radical prostatectomy (RP). From period 1 to period 3, the median age at diagnosis decreased from 72.2 to 66.0 years and the median PSA decreased from 16.2 to 8.6 ng/mL. From period 1 to period 3, the 5-year risk of PCa-death decreased from 14.3% (95% CI: 12.1-16.4%) to 1.3% (95% CI: 0.83-1.7%), p < .0.0001 and the risk of other cause death decreased from 18.1% (95% CI: 15.8-20.5%) to 7.2% (95% CI: 6.2-8.2), p = 0.0001. In patients undergoing RP, the 5-year risk of PCa-death decreased from 0.67% (95% CI: 0.67-2.0%) for patients diagnosed in period 1 to 0.45% (95% CI: 0.0055-0.84), for patients diagnosed in period 3, p = 0.92. For patients not undergoing RP, the 5-year risk of PCa death decreased from 16.6% (95% CI: 14.1-19.1) to 2.0% (95% CI: 1.2-2.7%), p < 0.0001. Conclusions: In a nationwide cohort of patients with low risk localized PCa, the 5-year risk of PCa-death significantly decreased when comparing patients diagnosed during 2006-2011 to those diagnosed during 1995-2000. This was mainly driven by patients not undergoing RP. In the most recently diagnosed group, the difference in 5-year PCa-death between patients undergoing RP and not undergoing RP was small (0.45% vs. 2.0%). Our data demonstrate that the impact of PSA induced lead-time and stage migration has diminished the absolute effect of RP on the risk of 5-year PCa-death because contemporary low-risk localized patients have a significantly better prognosis.
Early toxicity in a prospective phase I/II trial of MRI-assisted focal boost integrated with HDR monotherapy for low- and intermediate-risk prostate cancer.
Authors: D'alimonte Laura , Helou Joelle Antoine , Morton Gerard , Chung Hans T. , McGuffin Merrylee , Ravi Ananth , Loblaw Andrew
Published: March 2017

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Background: There is growing evidence for the use of High Dose Rate (HDR) brachytherapy as monotherapy for the treatment of low and intermediate risk prostate cancer patients. With the increasing availability of magnetic resonance imaging (MRI) there is an opportunity to further escalate dose to the dominant intraprostatic lesion (DIL). We report acute toxicity of this prospective phase I/II trial. Methods: Eligible patients had low- and intermediate risk prostate cancer, IPSS < 16, were medically eligible for HDR brachytherapy treatment and had an identified DIL on multiparametric MRI (mpMRI) prior to brachytherapy treatment. Patients were treated with 19 Gy delivered in one fraction to the whole prostate. A 0-5mm expansion was applied to the DIL to define the PTV DIL, with a DIL PTV D90 to receive > 23Gy based on previous experience. Toxicity was assessed using CTCAE v.4.0 at baseline, 6 weeks 3, 6, 9 and 12 months post brachytherapy. Results: A total of 34 patients have undergone HDR monotherapy treatment with an integrated DIL boost with a median follow up of 6 months. The median age was 67 years (range 46-80). At presentation, median PSA was 6.1 ng/mL (range 2.5-16.4). Three, 26, and 6 patients had low, low intermediate and high intermediate risk disease. Baseline characteristics were PIRAD 5 (n = 21) and PIRAD 4 (n = 13), median prostate volume was 38 cc (range 18-54). The median DIL volume was 2.8 cc (range 1.14-7.8). The median DIL D90 was 27 Gy (range 19-35.8). No patients experienced acute or late grade 2+ GI toxicity. The percentage of acute grade 2 GU toxicity were as follows; retention 62%, frequency 18%, urinary tract pain 6%. One patient had acute clot retention requiring catheterization x1 day and has been catheter-free since. Late grade 2 GU toxicity (alpha blockers) was reported in 6/16 patients at 6 months. Conclusions: The use of mpMRI to define and further escalate dose to the DIL using HDR monotherapy is feasible with minimal acute toxicities. Further long term follow up is required to determine the efficacy of treatment, and impact on quality of life and late toxicities. Clinical trial information: NCT02623933.
Multimodal image and mapping guided focal salvage high-dose-rate brachytherapy for local recurrent prostate cancer.
Authors: Guerif Stephane Gilles , Didas Ossama , Tasu Jean Pierre , Boissonnade Odile , Cheze-Le Reste Catherine , Debaene Bertrand , Berger Antoine
Published: March 2017

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Background: Image guided brachytherapy and mapping biopsy could reduce the toxicity of the total salvage brachytherapy. This study evaluate the tumor control and the tolerance of a focal real time salvage high-dose-rate (HDR) brachytherapy to treat the local relapse as defined on transperineal mapping biopsy, multipara-metric MRI and Choline PETSCAN on the same treatment planning. Methods: Between October 2013 and June 2016, Twenty-nine patients with local relapse on Choline PET Scan after a primary irradiation had a salvage HDR Brachytherapy (2 fractions of 10 Gy within 4-6 hours in one implant) without hormone. One month before brachytherapy All patients had real time transperineal randomized European regions standardised magnetic resonance imaging (MRI) prostate biopsies and targeted biopsies with a fusion of T2 MRI sequence /CholinePETscan (50 % SUV) to intraoperative transrectal ultrasound one month before brachytherapy. We used Flex Focus 400 ultrasound machine BK, Vitesse 3.0 and 3 D navigation with EXII Stepper in order to use the result of mapping biopsy for real time HDR brachytherapy treatment planning study. Tumor control was measure with phoenix definition and Kaplan-Meier. The GU and GI toxicity were measure with CTCAE V 3. Results: 13 Low risk, 10 Intermediate risk, 8 High risk, initially treated with 3 Iodine brachytherapy ( 160 GY), 15 EBRT ≥ 78 Gy and 7 EBRT ≤ 70 gy were include. The number of biopsy (mean volume, 21 cm3; SD, 6.7). Prostate Volume (mean volume, 29.7 cm3; SD, 12.5). CTV Volume (mean volume, 13.3 cm3; SD, 6.7). Mean dose to 90% of the prostate was 11.4 Gy (SD, 1.45). Mean dose to 90% of the CTV was 21.1 Gy (SD, 1.45). Mean dose to 90% of the CTVmri was 27.6 Gy (SD, 3.4). The biologic disease free survival at 2 years is 65 % (Kaplan-Meier). Disease without hormone survival at 2 years is 86,5%. The chronic toxicity ( > 6 mois) was 6 Gu and 4 GI for grade ≤ 2 and 1 GU grade 3 (total incontinence). Conclusions: Focal, mapping and multimodal image guided salvage HDR brachytherapy for recurrent prostate cancer is a feasible therapy. This approach has to be evaluated in multicenter cohort.
Prostate specific antigen five years following stereotactic body radiation therapy (SBRT) for low and intermediate risk prostate cancer: An ablative procedure?
Authors: Kataria Shaan , Koneru Harsha , Guleria Shan , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Suy Simeng , Dritschilo Anatoly , Lynch John , Kole Thomas Pedicino , Collins Sean P.
Published: March 2017

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Background: Our previous work on early PSA kinetics following prostate SBRT showed that an initial rapid and then slow PSA decline may result in very low PSA nadirs. This retrospective study sought to evaluate the PSA nadir 5 years following SBRT for low and intermediate risk prostate cancer (PCa). Methods: 65 low and 80 intermediate risk PCa patients were treated definitively with SBRT at Georgetown University Hospital between January 2008 and October 2011. All patients were treated to 35-37.5 Gy in 5 fractions delivered via the CyberKnife Radiosurgical System. Patients who received androgen deprivation therapy were excluded from this study. Pre- and post-treatment PSA and total testosterone levels were obtained during routine follow up visits. Biochemical relapse was defined as a PSA rise > 2 ng/mL above the nadir and analyzed using the Kaplan Meier method. The PSA nadir was defined as the lowest PSA value prior to biochemical relapse or as the lowest value recorded during follow up. Prostate ablation was defined as a PSA nadir < 0.2 ng/mL. Univariate logistic regression analysis was used to evaluate relevant variables on the likelihood of achieving a PSA nadir < 0.2 ng/mL. Results: The median age at the start of SBRT was 72 years. These patients had a median prostate volume of 36 cc with a median 25% of total cores involved. At a median follow up of 5.8 years, 84% and 37% of patients achieved a PSA nadir ≤ 0.5 ng/mL and < 0.2 ng/mL, respectively. Five low and 8 intermediate risk patients experienced a biochemical relapse; those who did not experience a biochemical relapse, achieved a median PSA nadir of 0.2 ng/mL. There was no difference between the 5-year bRFS rate for low (96.6%) and intermediate risk (97.4%) patients and the median time to PSA nadir was 36 months. Initial PSA (p = 0.024) and a lower testosterone at the time of the PSA nadir (p = 0.049) were found to be significant predictors of achieving a PSA nadir < 0.2 ng/mL. Conclusions: SBRT for low and intermediate risk PCa is a convenient treatment option with low PSA nadirs and a high rate of early bRFS. Less than 40% of patients achieved an ablative PSA nadir. Thus, the role of further dose escalation is an area of active investigation.
The CHAPPP study: Changing care with PSMA-PET for prostate cancer—A retrospective study of the role of PSMA imaging in altering treatment pathways.
Authors: Schmidt Andrew , Goh Jeffrey C. , Bhatt Manoj , Thomas Paul , Suder Aneta
Published: March 2017

13

Background: The low sensitivity of standard imaging (SI) techniques in detecting metastases (Ms) may lead to unnecessary local treatment for patients (Pts) with newly diagnosed or recurrent prostate cancer (PC). Ga-68-PSMA (Prostate Specific Membrane Antigen)-PET-CT is a novel imaging technique with increased sensitivity in detection of PC especially at low PSA values and may change the decision to pursue primary local or salvage treatment. This study quantified changes in definitive local treatment secondary to occult Ms detected on Ga-68-PSMA not visualized on SI. Methods: A retrospective study was performed of 509 consecutive PSMA scans (and 481 Pts) at our tertiary cancer centre, the Royal Brisbane and Women’s Hospital between Sept 2014 and Dec 2015. PSMA imaging was compared with a CT scan and bone scan to determine whether PSMA results altered the decision to pursue local treatment. Results: 81 (16%) Pts had PSMA-PET-CT scan and no Ms on SI, 40 prior to definitive local treatment and 41 as work up for recurrence. 9/40 Pts (23%) undergoing primary work-up had PSMA-identified Ms not visible on SI and altered these patients treatment pathway (mean PSA 20.5 ng/mL). Because of PSMA-diagnosed Ms, 3 did not receive local treatment. 4 had pelvic nodal involvement and received definitive radiotherapy (RT) including nodal fields. 2 Pts proceeded to radical prostatectomy with the addition of lymph node dissection. 41 Pts investigated for recurrence following local treatment had SI for comparison, (mean PSA 4.7, range 0.11 – 35 ng/mL). 11/41 (27%) were found to have distant or nodal Ms not visualized on SI. 7/11 with prior surgery did not proceed to salvage RT and the remaining Pts who had Ms were referred for an earlier medical oncology opinion. In total 20/81 (25%) of Pts had a direct change in treatment due to the additional information conferred by PSMA imaging. Conclusions: PSMA is more sensitive in the detection of prostate cancer Ms for patients being evaluated for primary treatment or looking for recurrence following local treatment. These results show clinically meaningful changes in management with avoidance of local treatment because of enhanced detection of metastases.
AR nuclear localization and microtubule bundling as markers of docetaxel and cabazitaxel sensitivity in metastatic castration-resistant prostate cancer (mCRPC): Prospective biomarker analysis from TAXYNERGY.
Authors: Giannakakou Paraskevi , Antonarakis Emmanuel S. , Galletti Giuseppe , Worroll Daniel , Stewart John , Zaher Atef , Szatrowski Ted P. , Zhou Wei , Ballman Karla V. , Vanhuyse Marie , Gjyrezi Ada , Tasaki Shinsuke , Bai Yang , Portella Luigi , Kirby Brian J. , Sonpavde Guru , Eisenberger Mario A. , Nanus David M. , Saad Fred , Tagawa Scott T.
Published: March 2017

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Background: A better understanding of taxane sensitivity/resistance in mCRPC is needed to optimize treatment. Preclinically, taxane efficacy has been linked to the ability of microtubules (MT) to inhibit AR nuclear trafficking. In this prospective biomarker study, we used circulating tumor cells (CTCs) from patients (pts) in TAXYNERGY to perform real-time analysis of AR nuclear localization (ARNL) and MT stabilization (bundling; MTB) in order to predict taxane sensitivity. Methods: TAXYNERGY (NCT01718353) is a phase 2 trial randomizing chemo-naïve mCRPC pts 2:1 to docetaxel or cabazitaxel, with a switch to the alternative taxane in the absence of a ≥ 30% PSA drop by C4. Here we present the co-primary biomarker endpoints. CTCs at baseline (C1D1) were compared to CTCs after 1 week of taxane treatment (C1D8), and were analyzed by multiplex confocal microscopy for %ARNL (integrated AR intensity in the cell and nuclear areas) and MTB (assessed for increase compared to C1D1 on a scale from 0–3 from no to most MTB increase). Associations between %ARNL and MTB with clinical outcomes were sought. Results: Of 63 randomized pts, 26 had evaluable CTCs both at C1D1 and C1D8. At C1D8, mean %ARNL was significantly lower in pts achieving a ≥ 50% PSA drop by C4 vs those without (44% vs 64%; p = 0.004). A taxane-induced decrease in mean %ARNL (C1D8 vs C1D1) was associated with a higher rate of ≥ 50% PSA response (73% vs 13%; p = 0.009); mean %ARNL decreased by 18% in responders and increased by 2% in non-responders (p = 0.02). Finally, a taxane-induced increase in mean MTB trended higher in pts achieving a ≥ 30% PSA drop by C4 vs those without (0.69 vs 0.09; p = 0.09); increase in mean MTB score was indicative of response and observed in pts who did not require a taxane switch after C4 (0.75 vs 0.09; p = 0.06). Conclusions: We provide the first prospective data suggesting that taxane-induced shifts in ARNL and MTB (measured in CTCs) may serve as an early biomarker of taxane sensitivity. Consistent with preclinical data, AR nuclear exclusion caused by microtubule bundling may be a clinically-actionable marker of taxane efficacy. Funding: Sanofi Genzyme. Clinical trial information: NCT01718353.
Germline DNA repair mutations in metastatic castration-resistant prostate cancer: Therapy response and applicability of circulating tumor DNA.
Authors: Struss Werner J. , Annala Matti , Warner Evan W , Beja Kevin , Vandekerkhove Gillian , Wong Amanda , Gleave Martin , Chi Kim N. , Wyatt Alexander William
Published: March 2017

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Background: Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to Androgen Receptor (AR) targeted therapy. The aim of this study was to determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies, and secondly to establish whether biallelic DNA-repair gene loss is detectable in matched circulating tumor DNA (ctDNA). Methods: We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In affected patients, matched plasma ctDNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Results: 24/319 (7.5%) patients had deleterious germline mutations, with BRCA2 (n = 16), PALB2 (n = 2) and CDK12 (n = 2) being the most frequent. Patients (n = 22) with mutations in genes linked to homologous recombination were heterogeneous at initial presentation but after starting ADT progressed to mCRPC with a median time of 12.3 months (95% CI 5.1-18.4). The median time to progression on first and second line AR-targeted therapy in the mCRPC setting was 3.2 months (95% CI 1.9-4.4) and 1.0 month (95% CI 0.8-1.1), respectively. For patients receiving chemotherapy as their initial therapy for mCRPC (n = 8) the median PFS was 7.5 months (95% CI 6.5-8.2). 10/11 evaluable patients with germline BRCA2 mutations had somatic deletion of the intact allele in ctDNA. Conclusions: mCRPC patients with germline DNA repair defects exhibit transient responses to AR-targeted therapy. Biallelic gene loss was robustly detected in ctDNA suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.
Genomic classifier to augment the role of pathological features in identifying optimal candidates for adjuvant radiation therapy in patients with prostate cancer: Development and internal validation of a multivariable prognostic model.
Authors: Abdollah Firas , Dalela Deepansh , Santiago-Jimenez Maria , Yousefi Kasra , Karnes Jeffrey , Ross Ashley , Den Robert B. , Freedland Stephen J. , Schaeffer Edward M. , Dicker Adam , Briganti Alberto , Davicioni Elai , Menon Mani
Published: March 2017

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Background: Despite documented oncological benefit, postoperative adjuvant radiotherapy (aRT) utilization in prostate cancer (PCa) patients is still limited in the US. We aimed to develop and internally validate a risk stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Methods: Our cohort included a total of 512 PCa patients treated with RP at one of four US academic centers between 1990-2010. All patients had ≥ pT3a disease, positive margins, and/or pathologic lymph node invasion (LNI). Multivariable Cox regression analysis (MVA) tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk stratification tool. Our study adhered to the TRIPOD guidelines for development of prognostic models. Results: Overall, 21.9% patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT vs. initial observation (p < 0.001). Pathological T3b/T4 stage, Gleason score 8-10, LNI and Decipher score > 0.6 were independent predictors of CR (all p < 0.01) Cumulative number of risk factors was 0, 1, 2, and 3-4 in respectively 46.5, 28.9, 17.2, and 7.4% of patients. Adjuvant RT was associated with decreased CR rate in patients with ≥ 2 risk factors (10-year CR rate 10.1% in aRT vs. 42.1% in initial observation, p = 0.008), but not in those with < 2 risk factors (p = 0.23). Conclusions: Utilizing the novel model to indicate aRT might reduce overtreatment, decrease unnecessary side effects, and reduce risk of CR in the subset of patients (~25% of all patients with aggressive pathological disease) who really benefit from this therapy.
Genetic polymorphisms to predict progression-free survival in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone therapy: Results from the NCI 9012 trial.
Authors: Albany Costantine , Daignault-Newton Stephanie , Skaar Todd C , Ipe Joseph , Siddiqui Javed , Twardowski Przemyslaw , Stein Mark N. , Kunju Lakshmi Priya , Chinnaiyan Arul M. , Montgomery Robert B. , Antonarakis Emmanuel S. , Shevrin Daniel H. , Whang Young E. , Caram Megan Veresh , Smith David C. , Feng Felix Yi-Chung , Stadler Walter Michael , Hussain Maha
Published: March 2017

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Background: Abiraterone is a CYP17 inhibitor approved for treatment of men with mCRPC. The NCI 9012 trial evaluated abiraterone alone with or without the PARP inhibitor veliparib in mCRPC patients. We hypothesized that germline genetic variation in the androgen axis and other metabolic enzymes would predict response to veliparib + abiraterone vs. abiraterone alone. Methods: A randomized trial cohort of (148) men with advanced mCRPC treated with abiraterone with or without veliparib was genotyped for 120 DNA polymorphisms in genes involved in androgen metabolism using Lifetech Open array chips. Blood for pharmacogenomic SNP analysis were collected at pre-treatment from each subject into 10-mL EDTA tube. Polymorphisms were tested using Cox models without treatment for prognostic testing and with treatment arm for predictive testing. Results: Genotyping was completed in 143 of 148 men; all were treated with abiraterone; 72 without veliparib (Median PFS: 10.3m) and 71 with veliparib (Median PFS: 11.3m). Polymorphisms in separate genes (SLCO2B1, KIF3C CYP19A, ESR1) were significantly (P ≤ .025) associated with progression-free survival (PFS) during abiraterone (q-value < 0.69). Polymorphisms in (CYP11A1, HSD17B4, ABHD13;LIG4, CYP19A1, HSD17B4, TRMT11) were predictive for PFS in patients treated with combination of abiraterone/veliparib compared to abiraterone alone (p-value < 0.025; q-value < 0.28). Conclusions: This analysis examines the influence of inherited variations on the efficacy of abiraterone, establishing the importance of pharmacogenomics on individual’s response to this therapy. Genotyping patients at these loci could be predictive of improved PFS to valiparib in combination with abiraterone. Further analysis of the association of more than one polymorphisms compared to zero or one with PFS associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one is ongoing. Clinical trial information: NCT01576172.
Changes in prostate cancer detection rate of fusion versus systematic biopsy over time: A single center experience.
Authors: Calio Brian P. , Sidana Abhinav , Sugano Dordaneh , Jain Amit L , Maruf Mahir , Merino Maria J , Turkbey Baris , Choyke Peter L. , Wood Bradford J. , Pinto Peter A.
Published: March 2017

15

Background: To determine the effect of learning curves and changes in fusion platform during 9 years of NCI’s experience with multiparametric MRI (mpMRI)/TRUS fusion biopsy. Methods: A review was performed of a prospectively maintained database of patients undergoing mpMRI followed by fusion biopsy (Fbx) and systematic biopsy (Sbx) from 2007−2016. The patients were stratified based on the timing of first biopsy in 3 groups. Cohort 1 included patients biopsied between 7/2007−12/2010, accounting for learning curve at our institution. Cohort 2 included patients biopsied from 1/2011 up to the debut of UroNav (Invivo) platform in 5/2013. Cohort 3 included patients biopsied after 5/2013. Clinically significant (CS) disease was defined as Gleason 7 (3+4) or higher. Cancer detection rates (CDR) between Sbx and Fbx during different time periods were compared using McNemar’s test. Age and PSA standardized CDRs were calculated for comparison between 3 cohorts. Results: 1528 patients were included in the study with 219, 549 and 761 patients included in 3 respective cohorts. Mean age, PSA and race distribution were similar across 3 cohorts. In cohort 1 there was no significant difference between CDR of CS disease by Fbx (24.7%) vs Sbx (21.5%), p = 0.377. Fbx was significantly better than Sbx in detection of CS disease in cohort 2 and cohort 3 (31.5% vs 25.3%, p = 0.001; 36.5% vs 30.2%, p < 0.001, respectively). There was significant decline in detection of low risk disease by Fbx compared to Sbx in the same period (cohort 2: 14.2% vs 20.9%, p < 0.001; cohort 3: 12.5% vs 19.5%, p < 0.001). Age and PSA standardized CDR of CS cancer by Fbx increased significantly between each successive cohort (cohort 1 and 2: 5.2%, 95% CI [2.1-8.5]), 2 and 3 (5.2%, 95% CI [1.8-8.6]). Conclusions: Our results show that after an early learning period using Fbx, CS prostate cancer was detected at significantly higher rates with Fbx than with Sbx, and low risk disease was detected at lower rates. Advances in software allowed for even greater detection of CS disease in the last cohort. This study shows that accuracy of Fbx is dependent on multiple factors; surgeon/radiologist experience and software improvements together produce improved accuracy.
Circulating tumor cells (CTCs) and plasma cell free DNA (cfDNA) androgen receptor amplification (ARamp)-based prognosis in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Li Jian , Du Meijun , Hillman David W. , Tan Winston , Carlson Rachel , Wang Liguo , Wang Liewei , Liu Minetta C. , Zhang Huijuan , Zhang Peng , Wang Liang
Published: March 2017

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Background: Plasma cfDNA ARcopy number variations (CNV) have been suggested to have prognostic significance in mCRPC stage. We compared plasma AR amplification ( ARamp) with CTC counts (the only FDA approved prognostic marker in mCRPC stage) in a prospective trial of patients (pts) progressing on androgen deprivation therapy. Methods: Plasma and CTC counts were obtained concurrently as part of a prospective clinical trial in mCRPC stage pts initiating abiraterone acetate (NCT# 01953640). Plasma cfDNA was purified using DNA Blood Mini Kit (Qiagen, Valencia, CA) and AR CNVs were detected using QuantStudio3D digital PCR system (Life Technologies, Carlsbad, CA, USA). CTC enumeration was performed using the FDA cleared CellSearch platform. The distributions of overall survival (OS) time based on ARamp status and CTC counts ( < 5 vs ≥ 5 cells) were estimated using the Kaplan-Meier method. Log-rank tests were used to test association of ARamp status and CTC counts with overall survival (OS). Univariate and multivariate logistic regression models and ROC evaluated association of OS at 24 months by ARamp status and CTCs ≥ 5. Results: Between 05/2013 and 09/2015, 92 pts were enrolled of which complete CTC, plasma and outcome data was available for 70 pts. Median age of the cohort (range) was 72 yrs (39-91); Median PSA–16.2 ng/ml (range: 0.9-2026.0); Median CTC count was 2.0 (range: 0-372); 58/70 pts had bone metastases; 38/70 had high volume and 32/70 had low volume metastatic disease at the time of sample collection. The median (range) follow up time at the time of this analysis was: 26.5 (7.9-37.0) months at which time 28/70 patients had died. ARamp was present in 19/70 pts while 51/70 did not have amplification. 24/70 had CTCs ≥ 5. A significant association of increased ARamp status with OS (p < 0.0001, log-rank test; AUC: 0.66) as well as with CTC counts ≥ 5 (p = 0.001, log-rank test; AUC: 0.67) was observed. Combining CTC status and plasma ARamp status the AUC was 0.75. Conclusions: Plasma cfDNA ARamp status and CTC counts have comparable and clinically meaningful prognostic marker value in mCRPC stage patients.
Circulating androgen receptor and serum chromogranin A in castration-resistant prostate cancers (CRPC) patients treated with abiraterone and enzalutamide.
Authors: Conteduca Vincenza , Salvi Samanta , Casadio Valentina , Lolli Cristian , Gurioli Giorgia , Schepisi Giuseppe , Martignano Filippo , Menna Cecilia , Burgio Salvatore Luca , Testoni Sara , Attard Gerhardt , De Giorgi Ugo
Published: March 2017

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Background: Circulating aberrations (copy number/point mutation] of androgen receptor ( AR) as well as serum chromogranin A (CgA) have been associated to treatment response and clinical outcome in CRPC patients (pts) treated with abiraterone (abi)/enzalutamide(enza). Methods: We determined AR aberrations by digital PCR, Taqman and targeted-next generation sequencing on pre-treatment plasma from 169 CRPC pts treated with abi 1g/od (n = 96) and prednisone 5mg/bid or enza 160mg/od (n = 73) (Romanel, 2015; Salvi, 2015; Salvi, 2016). All pts were subdivided into 3 groups using receiver-operating characteristic (ROC) curves (Burgio, 2014; Conteduca, 2014) to evaluate properly the impact of CgA levels: serum CgA level was normal when < 120 ng/ml (group A,n = 76); within 3 times the upper normal value(UNV) when between 120 and 360(group B,n = 57), more than 3 times UNV when > 360(group C,n = 36). The primary endpoint was the correlation between AR aberrations and CgA level. The secondary endpoints were progression-free/overall survival (PFS/OS) and PSA response rate (RR) ( > 50% PSA decline after 12 weeks of therapy) stratified by AR status and CgA level. Results: We observed AR gain in 57(33.7%) of 169 pts, 29(30.2%) of 96 pts treated with abi and 28(38.3%) of 73 treated with enza. Circulating AR status was independent from baseline CgA levels in all pts (p = 0.36). In only AR-normal pts, we showed a significant survival difference among 3 CgA groups (P < 0.0001), particularly Group C vs. A+B [HR (hazard ratio) 5.1, 95%CI (confidence interval) 2.37-10.96 and HR 3.7 95%CI 1.79-7.69, respectively for PFS/OS]. We reported no difference of PFS/OS in AR-gained pts (P = 0.6 and P = 0.1, respectively with HR~0.6 in all CgA groups). In addition, group C vs. A+B had a significant PSA RR [P = 0.03 odds ratio (OR) 2.7 95%CI 1.02-7.30] in AR-normal pts. No PSA RR difference was observed in AR-gained pts (P = 1.0 OR 0.97 95%CI 0.18-5.26). Conclusions: In CRPC pts treated with abi/enza, baseline CgA levels may be an additional predictive/prognostic factor, especially in a particular set of CRPC pts with normal plasma AR status and worse treatment outcome. This association needs a prospective larger study.
Indomethacin to inhibit AKR1C3 intracrine androgen production and sensitizes prostate cancer (PCa) to enzalutamide.
Authors: Pan Chong-xian , Liu Chengfei , Lara Primo , Evans Christopher P. , Dall'Era Marc , Yap Stanley , Lou Wei , Gao Allen
Published: March 2017

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Background: Enzalutamide (Enza) improves the treatment of metastatic castration-resistant PCa (mCRPC). Acquired resistance is the most common cause of treatment failure. Our objective was to determine mechanisms of resistance to Enza and develop novel therapy to overcome resistance. Methods: Enza-resistant PCa cells were established through continuous culture of C4-2B cells with Enza. Global gene expression array and western blots were used to assess gene expression in cell lines and validated in clinical specimens using Oncomine and GEO databases. The therapeutic effects of indomethacin were determined in cell culture and in mice carrying CWR22Rv1 xenografts. A Phase I/II clinical trial with Enza plus indomethacin has been approved by IRB. Results: Steroid biosynthesis pathways, especially AKR1C3, were significantly elevated in Enza resistant cells and was associated with high production of androgens. AKR1C3 was also highly expressed in metastatic and recurrent CaP and in Enza-resistant xenograft tumors. Overexpression of AKR1C3 conferred resistance to Enza. Inhibition of AKR1C3 expression by its specific shRNAs or AKR1C3 enzymatic activity by indomethacin re-sensitized Enza-resistant CaP cells to Enza treatment both in vitro and in vivo. Combination of indomethacin and Enza resulted in significant inhibition of Enza-resistant tumor growth. Indomethacin treatment in one patient with mCRPC induced tumor shrinkage and PSA decrease. In a Phase I/II trial funded by the Department of Defense, patients with mCRPC, good performance status (ECOG 0-2) and vital organ function, and no history of Enza or indomethacin treatment will be recruited. The co-primary objective is to assess the toxicity and prostate-specific antigen (PSA) response ( ≥ 50% reduction). We will also assess the overall response as determined by the Prostate Cancer Working Group 2 criteria, progression-free survival and molecular correlative studies. Conclusions: AKR1C3 activation is a critical resistance mechanism associated with Enza resistance. Indomethacin targets AKR1C3 and intratumor androgen synthesis, and can be potentially used as a therapeutic agent for mCRPC. Clinical trial results will be presented. Clinical trial information: to be registered.