bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

117 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

120 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

122 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

123 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

134 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

140 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

142 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.