bluuebunny/crossref_metadata_2025_split huggingface dataset:
The value of AKR1C3 in predicting the therapeutic efficacy of abiraterone for patients with metastatic castration-resistant prostate cancer.
Authors: Zhao Jinge 
Published: March 2019

313 Background: AKR1C3 is a multifunctional enzyme playing a significant role in androgen synthesis and metabolism. Previous studies have proved that the activation of AKR1C3 was associated with resistance to abiraterone through increasing the intracrine androgen synthesis. However, clinical validation is still lacking as to the prognostic value of AKR1C3 in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone. Methods: Data of 117 patients with mCRPC between 2016-2018 in our center were retrospectively analyzed. AKR1C3 was detected by the immunohistochemical staining from the 12-core prostate biopsy. Kaplan-Meier curves and COX regression were used to analyze the association between AKR1C3 and the treatment outcomes of abiraterone. The endpoints of this study were PSA progression-free survival (PSA-PFS) and radiograph progression-free survival (rPFS). Results: In total, AKR1V3 was detected in 40/117 (34.2%) cases. The positive AKR1C3 was significantly associated with shorter PSA-PFS for mCRPC patients treated with abiraterone (median PSA-PFS: 6.2 Mo vs. 11.1 Mo, p < 0.001). Those with positive AKR1C3 were also accompanied with obviously poorer rPFS compared to those with negative AKR1C3 staining, despite that the difference was not statistically significant (median rPFS: 11.1 Mo vs. 21.8 Mo, p = 0.250). Multivariate COX regression indicated that, AKR1C3 was an independent prognosticator of rapid PSA progression for the abiraterone treatment (HR,95%CI: 2.612, 1.54-4.44, p < 0.001). Conclusions: This is the first study verifying the adverse prognostic significance of AKR1C3 for mCRPC patients receiving abiraterone treatment. Our results suggested that, AKR1C3 was closely related to early treatment failure of abiraterone, and thus, was worthwhile to be routinely described in pathological report.
Clinical significance of AR amplification from CF DNA among Japanese castration-resistant prostate cancer patients.
Authors: Sakamoto Shinichi , Ando Keisuke , Takeshita Nobushige , Yamamoto Satoshi , Komiya Akira , Nishio Kazuto , Ichikawa Tomohiko , Imamura Yusuke 
Published: March 2019

314 Background: We study the prognostic ability of androgen receptor amplification (AR amp) from cf DNA in Japanese castration-resistant prostate cancer (CRPC) patients. Methods: Multiple sets of serums were obtained from 38 castration-resistant prostate cancer patient at Chiba University hospital. Serum cfDNA was purified using a cobas cfDNA Sample Preparation Kit. AR copy number was measured using the QX100 Droplet Digital PCR System. Factors associated with progression-free survival (PFS) and Overall Survival (OS) were statistically studied. Results: The number of patients received Enzalutamide (Enza)/Abiraterone (Abi)/Docetaxel (Doc) were 33/25/11. Regarding PFS, the presence of AR amplification, Bone Scan Index (BSI), PSA was significant factors on univariate analysis. On multivariate analysis, AR amplification was an independent prognostic factor (HR. 8.9, p=0.003). Regarding OS, PSA and AR amp was significant factors. On multivariate analysis, AR amp (HR 4.2, p=0.028) was an independent prognostic factor. AR amp was related to the young age, high bone metastasis, high PSA, while no association was identified related the visceral metastasis. Overall, the presence of AR amp was negatively related to the initial ADT periods (r=-0.28). In contrary, among primary resistance cases (initial treatment periods <1 year), AR amp positively related to the treatment periods (r=0.31). Higher nadir testosterone (>15 ng/dL) was related to the higher AR amp (p=0.0169). AR amp was related to the treatment resistance in Enza (p=0.0216), while no relation was observed in Abi or Doc. Conclusions: AR amp significantly correlated with the poor prognosis. Higher serum testosterone level may predict the presence of AR amp in cf DNA. [Table: see text]
Continuous infusion 5-fluorouracil (5FU) as a novel treatment for heavily pretreated prostate cancer patients: An update.
Authors: Manogue Charlotte , Cotogno Patrick , Moses Marcus Marie , Barata Pedro C. , Layton Jodi Lyn , Sartor A. Oliver , Lewis Brian E. 
Published: March 2019

319 Background: Currently patients failing multiple conventional therapies enroll on clinical trials but in many cases, despite a good performance status, patients may not qualify for trial enrollment. CRPC tumor cells typically express prostate specific membrane antigen (PSMA), a folate hydrolase which increases cell folate uptake (Yao et al. Prostate 70:305, 2010). We hypothesize that 5FU, functioning as an anti-folate, antagonizes the downstream effects of PSMA over-expression. Herein we present an update to our 5FU experience in heavily pretreated mCRPC. Methods: Data was retrospectively collected at Tulane Cancer Center for patient treatment history, disease history, performance status and laboratory parameters. All patients were treated with continuous infusion of 5-fluorouracil at a dose of 200mg/m2-day. Results: 24 patients at Tulane Cancer Center were treated with 5FU between Oct/2013 and Oct/2018. The median age was 72, patients had an median of 6 lines of prior therapy, and 37.5% had liver metastatic disease. The 30% and 50% PSA response rates were 41.6% and 29% respectively. Of the PSA responders, 100% had some level of PSA decline after 7 days of therapy with a median time to best PSA response of 2.6 months (95% CI 0.2-5.1). Median time on treatment was 11 weeks for the entire cohort and 18.5 weeks for patients with a ≥30% PSA decline; 20.8% of patients remained progression free by PSA at 4 months. Improvement in performance status as well as transfusion independence were noted in a subset of patients with myelophthistic anemia due to prostate cancer. No grade > 3 AEs were attributable to 5FU. Conclusions: 5FU is a relatively inexpensive and well tolerated therapy that shows benefit in some heavily pretreated patients. Additionally, the ability to quickly assess the potential for response, and lack of > grade 3 adverse events makes it a reasonable option for this population.
Incorporating mpMRI Biopsy data into established pre-RP nomograms: Potential impact of an increasingly common clinical scenario.
Authors: Leong Joon Yau , Chandrasekar Thenappan , Tham Elwin , Teplitsky Seth , Lallas Costas D. , Gomella Leonard G. , Trabulsi Edouard John 
Published: March 2019

32 Background: Current pre-radical prostatectomy (RP) nomograms predicting lymph node involvement (LNI) are based on systematic 12-core prostate biopsies (PBx). With the introduction of mpMRI, cognitive or fusion biopsies have become prevalent, often in the absence of systematic cores. We examine the practical application of MR biopsy data using established pre-RP nomograms and the potential implications on RP intra-operative decision making. Methods: Utilizing a prospectively maintained single institution database, all patients who underwent MRI-based PBx prior to RP were identified. Each patient was assessed using the MSKCC Kattan nomogram and the Briganti nomogram using the following iterations: 1) Targeted [T] (targeted cores alone), 2) Targeted & Systematic [TS] and 3) Targeted Augmented [TA]. The TA iteration utilized targeted core data alone and assumed negative remaining systematic cores for a total 12 core. Nomogram outcomes, specifically risk of LNI, was compared across iterations. Clinically significant impact was defined as a change in risk above or below 2% (Δ2) or 5% (Δ5), based on current guidelines recommendations for lymph node dissection. Results: 69 men met inclusion criteria (6 targeted, 63 systematic + targeted PBx). In the 6 men with targeted only biopsies, using the Kattan and Briganti nomograms, Δ2 occurred in 1 patient (16.7%) and Δ5 in 1-2 patients (16.7-33.3%); in all, TA iteration LNI was lower than the T iteration. In the 58 patients with positive targeted biopsy cores, Δ2 and Δ5 were 8.62-32.76% and 25.86-37.93%, respectively. In the subset of 52 patients with both targeted and systematic biopsies, using their TS nomogram as an internal validation, the TA iteration was a better approximation of their TS outcomes than their T iteration in 48% (Kattan) and 67% (Briganti) of patients. Conclusions: mpMRI-based PBx results, and in particular those from targeted biopsy cores alone, yield significantly different results using established pre-RP nomograms. Therefore, future nomograms must better incorporate MRI biopsy data and provide guidelines on how to account for targeted cores. In the interim, augmenting targeted biopsy data may bridge the gap.
Genomic changes of AR in ctDNA prior to enzalutamide in men with mCRPC after abiraterone acetate.
Authors: Ko Leta , Lilly Michael B. , Hahn Andrew W , Nussenzveig Roberto , Moses Marcus Marie , Ledet Elisa , Manogue Charlotte , Cotogno Patrick , Lewis Brian E. , Layton Jodi Lyn , Agarwal Neeraj , Sartor A. Oliver , Barata Pedro C. 
Published: March 2019

320 Background: Approximately 20-30% of men with metastatic castration-resistant prostate cancer (mCRPC) seem to respond to enzalutamide (ENZA) after prior exposure to abiraterone acetate and steroids (AA). The impact of genomic changes in androgen receptor (AR) gene in ctDNA and subsequent response to ENZA after prior AA exposure, is not entirely known. Methods: We performed a retrospective analysis of 28 mCRPC who were treated with ENZA after prior exposure to AA. Patients had NGS testing of ctDNA (Guardant 360) done post-AA and prior to ENZA. AR changes were defined by either amplification (amp; copy number ≥1) and/or mutations (mut; allele fraction ≥0.3%) in the AR gene. The primary endpoint of this study was time to PSA progression on enzalutamide. Correlations between genomic data and clinical outcomes were evaluated. Results: The 28 mCRPC patients had a median age of 67 (47-86), and 66.7% had a Gleason score 8-10. Metastases were found in bone (93%), lymph nodes (35.7%) and viscera (35%). Patients received ENZA after a median of 1 (1-5) treatment for CRPC. Patients were treated with prior AA for a median of 11.0 months (1.2-51.9) and median initial PSA at time of ENZA initiation was 35 ng/mL (1.52-356). The median time from ctDNA testing to ENZA start date was 0.9 months (range 0-5.6). Somatic changes in AR genes were detected in 36% (5/10 AR amp, 4/10 AR mut, 1/10 both). Other common alterations included 39% TP53, 11% DNA repair genes (2/3 BRCA2, 1/3 ATM), 7% PTEN. With a median follow-up of 8.9 months, 32% achieved PSA response (≥50%) and median time to PSA progression was 1.6 months (95% CI 1.0-2.2). On univariate analysis, lower Gleason scores (p = 0.021) and lack of AR changes (p = 0.042) were associated with PSA response to ENZA. Conclusions: In this cohort, responses to ENZA were associated with the absence of AR changes in ctDNA and less aggressive phenotypes. Prospective validation of this genomic association is required.
Clinical outcomes of a Dutch prospective observational registry of metastatic castration resistant prostate cancer (mCRPC) patients treated with radium-223 (Ra-223).
Authors: Louhanepessy Rebecca , Badrising Sushil , van der Noort Vincent , Coenen Jules L. L. M. , Hamberg Paul , Beeker Aart , Wagenaar Nils , Lam Marnix G.E.H. , Celik Filiz , Loosveld Olaf , Oostdijk Ad , Zuetenhorst Johanna Maria , Vegt Erik , Zwart Wilbert , Bergman Andre M. 
Published: March 2019

323 Background: In 2012 the ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit of mCRPC patients treated with Ra-223 over placebo. To date clinical outcomes of Ra-223 treatment in a non-study population have not been prospectively evaluated. Methods: The ROTOR registry aimed to include 300 patients in 20 Dutch hospitals prior to Ra-223 treatment at the physician’s discretion. Clinical parameters collected included: positioning of Ra-223, Adverse Events (AE’s; CTCAE v4.03), Skeletal Related Events (SRE) and survival data. SRE was defined as radiotherapy to a bone metastasis, a new pathological fracture, spinal cord compression and/or bone surgery. Progression-Free Survival (PFS) was defined as survival until radiological or clinical progression, subsequent treatment or death. Results: Between April 2014 and September 2017, 305 patients were included of whom 300 were evaluable. The mean age of patients was 72.6 (range 46.3-91.5) years, 255 (85%) had ≥ 6 bone metastases and 197 (65.5%) were pretreated with taxanes and/or abiraterone or enzalutamide (214 (71.3%)). Two-hundred and ninety (96.7%) patients were treated with Ra-223. Twenty-nine (9.7%), 104 (34.7%), 96 (32%) and 66 (22%) patients received Ra-223 as a first, second, third, ≥ fourth mCRPC treatment line, respectively. Patients received an average of 4.6 (SD 1.8) cycles of Ra-223, while 140 (46.7%) completed all six cycles. After a median follow-up of 13.2 months, PFS was 5.1 (CI 4.5-5.8) months and OS 15.2 (CI 12.8-17.6) months. Eighty-two (27.3%) patients were hospitalized during Ra-223 treatment (Serious AE). Grade ≥ 3 anemia, neutropenia and thrombocytopenia was found in 54 (18.0%), 8 (2.7%) and 11 (3.7%) patients, respectively. Other frequent AE’s (all grades) were nausea (90 (30%)), diarrhea (83 (27.7%)) and fatigue (178 (59.3%)). SREs were observed in 46 (15.3%) patients; 22 (7.3%) received radiotherapy, 6 (2%) developed pathologic fractures, 17 (5.6%) spinal cord compression and 1 (0.3%) received bone surgery during Ra-223 therapy. Conclusions: The non-study ROTOR population had characteristics, all grade AEs and OS comparable with the treatment arm of ALSYMPCA. Clinical trial information: NCT03223597.
Retrospective review of 11C-choline detected thoracic lesions in prostate cancer.
Authors: Rehman Muneeb , Mansfield Aaron Scott 
Published: March 2019

325 Background: Prostate cancer recurrence is detected by serum measurements of prostate specific antigen (PSA). Upon PSA elevation, locating sites of recurrence is important to guiding treatment and affecting patient outcomes. The imaging modalities in current practice have varying sensitivities and specificities and often miss early recurrent disease. 11C-choline positron emission tomography (11C-PET) may be able to detect occult disease and guide treatment decisions earlier in the clinical course. We assessed a case series of patients who underwent 11C-PET imaging and were identified to have thoracic disease to estimate the benefit of detection with this modality. Methods: Clinical records were retrospectively reviewed of seventy patients from thoracic oncology teams at Mayo Clinic in Rochester, Minnesota. Patients who had thoracic +/- extra-thoracic metastases on 11C-PET imaging were followed, noting changes in treatment and PSA trends to look for biochemical recurrence of disease. Results: Seventy patients with thoracic metastases discovered on 11C-PET imaging were initially identified. Median time to choline-avid disease from original diagnosis was 82 (IQR: 40-129) months with a median PSA at time of choline of 7.4 (IQR: 3.1-15.7). 11C-PET findings showed 28 patients with metastases limited to the thorax and 42 patients with thoracic and extra-thoracic metastases. After 11C-PET imaging, 1 patient underwent localized therapy only (radiation and surgery), 44 patients underwent systemic therapy only (chemotherapy or hormonal therapy), 19 patients underwent both localized (cryotherapy, radiation, or surgery) and systemic therapy, 3 patients underwent no further treatment, and 3 patients were lost to follow up. After a median follow-up of 36.5 (IQR: 13-52) months, 30 patients had no recurrence and 20 had evidence of biochemical recurrence. For those who underwent local therapy (N=21), 11 had no recurrence of disease. Conclusions: Choline-based imaging may earlier identify metastatic disease that is amenable to local therapy. Further studies are needed to validate the effectiveness of 11C-PET in identifying early, responsive metastatic prostate cancer and its utility in affecting patient outcomes.
Multi-institutional analysis of synchronous prostate and rectosigmoid cancers.
Authors: Jacobs Corbin , Trotter Jacob , Palta Manisha , Wu Yuan , Willett Christopher , Lee W. Robert , Czito Brian G. 
Published: March 2019

33 Background: Synchronous prostate cancer (PC) and rectosigmoid (RS) cancer (RSC) is a challenging clinical situation. Methods: A retrospective review of Duke University and Durham VA charts was performed for men with adenocarcinomas of the prostate and RS colon from 1988-2017. Synchronous presentation was defined as symptoms, diagnosis (dx), or treatment (tx) of PC/RSC within 12 months. The primary endpoint was overall survival (OS), calculated from latest dx date. Univariate and multivariate (MVA) Cox regression was performed using STATA 15.1. Results: Among 31,883 men with PC identified, 330 (1%) also had RSC. 54 (16%) were considered synchronous (median age 67, IQR 62-72). PC was more commonly the first dx (59%), and 15 (28%) underwent prostatectomy (n=13) or radiotherapy (RT, n=2) before a dx of synchronous RSC. 26%, 57%, and 17% had stage I, II-III, and IV RSC, respectively. Prostatectomy, LAR, APR, and combined surgery for both PC/RSC was performed in 17 (31%), 24 (44%), 10 (19%), and 2 (4%) men, respectively. 35 (65%) received RT with median RS dose of 50.4 Gy (IQR 50.4-54 Gy) and prostate boost to 66 Gy (IQR 61-72 Gy). 34 (63%) received 5-FU based chemotherapy, 23 (43%) received ADT, and 9 (17%) received no PC-specific tx. After a median follow up of 43 (IQR 21-93) months, there were 34 deaths: 18 (53%) due to RSC, 2 (6%) due to PC, 3 (9%) due to grade 5 toxicity, 7 (21%) due to another malignancy, and 4 (12%) due to unknown cause without recurrence. Grade 5 toxicities resulted from sequential hepatectomy/LAR, combined prostatectomy/APR, and myocardial infarction while on ADT. Crude late grade ≥3 toxicities include 9 (17%) GI and 6 (11%) GU. Two anastomotic leaks <2.3 years after LAR occurred in men who received neoadjuvant prostate RT boost of 70.6-76.4 Gy. Stages II-III (HR 4.3, p=0.02) and IV (HR 16, p<0.01) for RSC but only stage IV (HR 31, p<0.01) for PC were significantly associated with OS on MVA. Among 30 men with stage II-III RSC and non-metastatic PC, 5-FU based chemotherapy (HR 0.34, p=0.04) but no PC-specific tx was significantly associated with OS on MVA. Conclusions: Synchronous RSC is a greater contributor to mortality than PC. Men aged ≥50 with localized PC should undergo colorectal cancer screening prior to tx to evaluate for synchronous RSC.
Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.
Authors: Zaghloul Mohamed S. , Christodouleas John Paul , Hwang Wei-Ting , Smith Andrew , Abdalla Ahmed , William Hany , Baumann Brian Christopher 
Published: March 2019

351 Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before & after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) & late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT & 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) & 15 months for PORT (range 5-70). There were 2 local failures for PORT & none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) & 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) & 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) & 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS & OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local & distant disease. Clinical trial information: 01734798.
Evaluation of submicron particle docetaxel directly injected into uro-oncologic xenografts.
Authors: Dizerega Gere , Maulhardt Holly , Peterson Lauren M , Frost Michael , Tornio Ashley , Dafoe Sara , Drummond Leanne 
Published: March 2019

360 Background: We evaluated intratumoral (IT) injection of submicron particles of pure docetaxel (NanoDoce) into clear cell renal carcinoma (768-O [R]), transitional cell bladder carcinoma (UM-UC-3 [B]) and prostate carcinoma (PC-3 [P]) xenografts implanted into immunocompromised rats and mice. Methods: Animals received IT NanoDoce and IV docetaxel per Table. Treatments were 7 days apart. Animals were followed up to 60 days post-treatment initiation. Tumor size, clinical signs and body weight were assessed 2-3 times per week. In the 786-O and UM-UC-3 studies, tumor site tissues were analyzed for docetaxel levels and H&E and IHC (CD11b, CD45r) was evaluated. Results: Tumor volume decreases with 2 and 3 doses of NanoDoce were significantly greater than (R, B) or similar (P) to IV docetaxel and better than vehicle (p < 0.05). High tissue levels of docetaxel were detected in all NanoDoce-treated animals with evaluable tumor tissue. In these animals, histology confirmed tumor volume findings; IHC showed (peri)tumor-infiltrating immune cells in all NanoDoce-treated animals. Comparators exhibited limited to no infiltration. NanoDoce-treated UM-UC-3 tumor injection sites were typically cleared of tumor and contained lymphoid structures. No lymphoid structures were seen in comparators and all had residual tumor. Conclusions: Local presence of persistent, therapeutic levels of docetaxel from IT NanoDoce creates a unique disruption of the tumor microenvironment. IT injection of NanoDoce may kill tumor cells through direct and indirect means. NanoDoce directly inhibits tumor cell mitosis, and in reducing tumor burden, indirectly promotes immune cell-mediated tumor clearance. Clinical testing of NanoDoce in urogenital tumors is underway. [Table: see text]