bluuebunny/crossref_metadata_2025 huggingface dataset:
Artificial intelligence for streamlined immunofluorescence-based biomarker discovery in prostate cancer.
Authors: de la Calle Claire Marie , Nguyen Hao Gia , Hosseini-Asl Ehsan , So Clarence , Socher Richard , Xiong Caiming , Xue Lingru , Carroll Peter , Cooperberg Matthew R.
Published: February 2020

279

Background: Immunofluorescence (IF) performed on tissue microarrays (TMA) is used for biomarker discovery but is limited by the arduous and subjective human visual assessment with an IF microscope. We aim to implement deep learning-based artificial intelligence (AI) models to automate and speed up the analysis of numerous biomarkers and generate prediction models of recurrence and metastasis after surgery. Methods: A TMA was constructed consisting of 648 samples (424 tumors, 224 normal tissue) generated from prostatectomy specimens. IF staining was performed on the TMA using anti Ki-67, ERG antibodies and analyzed for differential expression using “gold standard” manual microscopy and using an AI algorithm. Analysis was done blinded to any clinicopathological data. For manual microscopy, relative mean fluorescence intensity of cancerous versus normal tissue was determined. The AI algorithm was generated using a training cohort of digitized images. To do so the Otsu method thresholding algorithm combined with mean shift clustering was employed to find cell centers, followed by a level-set algorithm, to compute cell boundaries.These predictions were then combined with pixel predictions of a fully convolutional deep model to refine the regions of overlapping epithelium, stroma, and artifact. The algorithm was then validated using a separate cohort. Results from the algorithm were then compared to the data from manual microscopy. Results: Ki-67 and ERG expression levels generated by the algorithm showed only a 5% variance compared to the manually generated results. The algorithm was able to pick out which tumor were positive for ERG with 100% accuracy in spite of variance from artifacts. The algorithm also had the ability to improve its accuracy after each iteration of modifications and feedback through the training cohort. Conclusions: The AI algorithm produced similar outcomes than manual quantification with high accuracy but with more efficiency, cost effectiveness and objectivity. We are now developing more complex algorithms that will include the differential pattern of expression of PTEN, MYC and others with the objectives of streamlining biomarker discovery.
Does size matter? Lesion size as an indicator of number of cores needed to detect clinically significant prostate cancer.
Authors: Lebastchi Amir H. , O'Connor Luke P. , Wang Alex Z. , Yerram Nitin , Gurram Sandeep , Hale Graham , Bloom Jonathon B. , Gold Samuel A. , Rayn Kareem N. , Mehralivand Sherif , Wood Bradford J. , Shih Joanna H. , Turkbey Baris , Pinto Peter A.
Published: February 2020

283

Background: MRI/US fusion guided prostate biopsy (FBx) has been shown to detect clinically significant prostate cancer (csCaP) at higher rates and with fewer cores than standard prostate biopsy. Size plays an important role in assigning a suspicion level (PI-RADS) to lesions identified on MRI. However, tumor characteristics may pose challenges to accurately characterizing the lesion despite the size. This study sought to determine if there are size cutoffs at which a lesion may be accurately characterized as clinically significant cancer with a single biopsy core. Methods: A retrospective analysis of a prospectively maintained database of all patients undergoing FBx at an academic referral center between May 2014 and January 2018 was conducted. At least two FBx cores were taken from each lesion identified on mpMRI. GEE-based univariate logistic regression model with exchangeable correlation was used determine if size was a significant predictor of positive and negative agreement. Predictability of size as a significant continuous predictor was quantified by AUC. Size thresholds at which multiple cores per lesion are needed to avoid missing > 2% of csCaP were calculated, allowing for a 25% discordance rate. Results: An analysis of a total of 1141 FBx of 2200 lesions was performed during the study time interval. Size was a significant predictor of both positive (OR = 2.43, 1.83-3.23, p < 0.01) and negative (OR = 0.58, 0.44-0.76, p < 0.01) agreement of csCaP. AUC% for positive and negative agreement was 65.8 and 57.6, respectively. Size thresholds of 0.65 and 1.70 cm limited CS cancers missed by skipping a second targeted biopsy core to 2% while allowing for a 25% discordance. Conclusions: These data indicate that clinically significant prostate cancer in lesions less than 0.65 cm and greater than 1.70 cm may be characterized with a single targeted biopsy core, sparing 33.5% of lesions (21% patients) a double core targeted biopsy.
Detection of clinically significant prostate cancer after negative fusion and systematic biopsy.
Authors: Twum-Ampofo Jeffrey , Ceraolo Carl , Gusev Andrew , Feldman Adam S.
Published: February 2020

288

Background: MRI/Ultrasound fusion biopsy of the prostate has enhanced the detection of clinically significant prostate cancer (csPCa). Detection of csPCa is greatest when fusion and systematic biopsies are combined. However, the finding of a negative fusion and negative systematic biopsy in patients with suspicious lesion on imaging raises the question of either falsely positive imaging or a false negative biopsy. Methods: We retrospectively reviewed our database of patients undergoing MRI/transrectal US-guided fusion biopsy. All images were graded according to the Prostate Imaging Reporting and Data System version (PIRADS) 2.0. Patients underwent targeted biopsy followed by systematic 12-core double sextant biopsy within the same session. csPCa was defined as Grade Group (GG) ≥2 PCa. Patients with no prostate cancer (PCa) found on biopsies were followed. MRI studies with PIRADS v2 score ≤ 2 were considered to have no MRI evidence of PCa. Results: A total of 400 patients had at least one PIRADS ≥3 lesion and underwent fusion/systematic biopsy. Of these, 113 (28.3%) patients had no evidence of PCa on either fusion or systematic biopsy. Median follow-up was 32.5 months. 44 (39%) patients underwent repeat MRI and of these, 24 (54%) had no evidence of PCa on repeat MRI. PIRADS lesion disappearance was associated with lower PSA Density (PSAd) (0.12 vs 0.20; P = 0.0319) and decreased progression to repeat biopsy (8.33% vs 95%; P < 0.0001). Patients who had a repeat biopsy had a greater PSAd ( 0.21 vs 0.12; P = 0.0054). Of 113 patients with negative initial biopsy, 23 (20.4 %) underwent repeat biopsy: 16 (14.2 %) had PCa and 11 (9.7%) had csPCa. Thus, 48% of patients who underwent repeat biopsy had csPCa. Among patients with a PCa on repeat biopsy, cancer was sampled by MRI targeted cores in 80% of patients. Conclusions: Despite a negative initial fusion/systematic biopsy, at least 10% of patients were subsequently diagnosed with clinically significant PCa. The combination of elevated PSAd and the persistence of a suspicious lesion on repeat MRI appears selective for previously missed PCa. However, after negative fusion biopsy, repeat MRI yields a high rate of PIRADS lesion disappearance in patients with low PSAd.
Advancing age and the risk of adverse pathology at radical prostatectomy in men with biopsy Gleason score 6 prostate cancer.
Authors: Kim Daniel , Chen Ming-Hui , Huland Hartwig , Graefen Markus , Tilki Derya , D'Amico Anthony Victor
Published: February 2020

289

Background: We evaluated the impact of age > 65 years versus younger on the odds of finding adverse pathologic features (pT3/T4 and/or R1 and/or Gleason score 8, 9, 10) at radical prostatectomy (RP) among men with biopsy Gleason score 6 prostate cancer (PC). Methods: The study cohort comprised 3191 men with biopsy Gleason score 6 PC treated with a RP between February 28, 1992 and February 15, 2016 at the Martini-Klinik Prostate Cancer Center. Multivariable logistic regression was used to evaluate the impact of age > 65 years versus younger on the adjusted odds ratio (AOR) of finding adverse pathology at RP adjusting for pre-RP prostate specific antigen (PSA), clinical tumor category, year of diagnosis, percent positive biopsies (PPB), and PSA density (PSAd). Results: Men age > 65 years as compared to younger had significantly lower median PPB (16.67% vs 20.0%; p = 0.01) and PSAd (0.13 ng/mL vs 0.15 ng/mL; p < 0.0001). Yet, while both increasing PPB (AOR 1.018, 95% CI 1.013, 1.023; p- < 0.0001) and PSAd (AOR 4.28, 95% CI 1.66, 11.01; p = 0.003) were significantly associated with an increased odds of finding adverse pathology at RP, men age > 65 years versus younger had a higher odds of adverse pathology at RP (AOR 1.28, 95% CI 1.002, 1.62; p = 0.048). Conclusions: Despite a more favorable median PPB and PSAd, men with biopsy Gleason score 6 PC and who are age > 65 years compared to younger men are at higher risk for having adverse pathology at RP and may benefit from a multiparametric MRI and targeted biopsy before proceeding with active surveillance. If higher grade/stage disease is discovered and treatment indicated then this information could guide both the use and duration of supplemental androgen deprivation therapy in men considering radiation therapy.
Comparison of micro-ultrasound and multiparametric MRI imaging for prostate cancer: A multicenter prospective analysis.
Authors: Klotz Laurence , Lughezzani Giovanni , Sanchez Andrrea , Staerman Frederic , Cash Hannes , Gaston Richard , Sanchez-Salas Rafael , Klein Eric A. , Eure Gregg
Published: February 2020

296

Background: This study aims to compare the sensitivity, specificity, NPV and PPV of mpMRI with the novel high-resolution micro-ultrasound imaging modality. This approach offers the benefits of simplicity, a single intervention for imaging and biopsy, leveraging the low cost of ultrasound. Micro-ultrasound may be used to image suspicious lesions and target biopsies in real-time with or without additional MRI-based targets. Methods: Data from 9 sites was aggregated, totaling 866 subjects presenting for ExactVu micro-ultrasound guided biopsy with available mpMRI studies. Samples in all subjects were taken from mpMRI targets and micro-ultrasound targets, with up to 12 systematic samples filled in. Various strategies were used for mpMRI target sampling including cognitive fusion with micro-ultrasound, separate software-fusion systems, and software-fusion using the micro-ultrasound FusionVu system. Clinically significant cancer was considered any Gleason Sum > 6 and targeted samples were taken for PI-RADS > 2 or PRI-MUS1 > 2 lesions. Results: Overall, 39% of all biopsy cases were positive for clinically significant PCa. mpMRI demonstrated 89% sensitivity and NPV of 77%. Compared to mpMRI, micro-ultrasound sensitivity (95%) and NPV (87%) were higher. Micro-ultrasound was less specific (21% vs 23% for mpMRI) with similar PPV (44% vs 43%). The aggregate effect demonstrates higher sensitivity for csPCa with micro-ultrasound compared to mpMRI (p<0.01). Conclusions: Micro-ultrasound is an attractive option for screening and targeted biopsy. Sensitivity and NPV appear superior to MRI, but specificity is mildly reduced. Further larger-scale studies are required for validation of these findings. References: Ghai, S. et al., “Assessing Cancer Risk in Novel 29 MHz Micro-Ultrasound Images of the Prostate”, Journal of Urology, 2016 Aug;196(2):562-9. Clinical trial information: NCT03938376.
The deleterious association between proton pump inhibitors and prostate cancer specific death.
Authors: Goldberg Hanan , Moshin Faizan , Saskin Refik , Kulkarni Girish S. , Berlin Alejandro , Kenk Miran , Wallis Christopher J.D. , Chandrasekar Thenappan , Klaassen Zachary William Abraham , Saarela Olli , Penn Linda , Alibhai Shabbir M.H. , Fleshner Neil Eric
Published: February 2020

309

Background: Proton pump inhibitors (PPIs) are a commonly prescribed class of medications. Although in-vitro and in-vivo data have shown PPIs to have anti-tumor effects, more recent studies suggest an increased cancer risk in several solid organs. Pantoprazole, a commonly prescribed PPI, has been shown to harbor a protective effect in human prostate cancer (PCa) cells. We aimed to investigate the effect of pantoprazole and other PPIs on PCa-specific death and additional PCa outcomes. Methods: In this retrospective, population-based cohort study, data were incorporated from the Institute for Clinical and Evaluative Sciences to identify all men aged 66 and above with a history of a single negative prostate biopsy between 1994 and 2016. We used multivariable Cox regression models with time-dependent covariates, to assess the effect of PPIs on PCa diagnosis, androgen deprivation therapy (ADT) use, and PCa-specific death. All models included other medications with a putative effect on PCa. All models were adjusted for age, rurality, comorbidity, and year of patient study inclusion. Results: Overall, 21,512 men were included, with a mean follow-up time of 8.06 years (SD 5.44 years). A total of 10,999 patients (51.1%) used a PPI. A total of 5,187 patients (24.1%) were diagnosed with PCa, 2,043 patients (9.5%) were treated with ADT, and 805 patients (3.7%) died from PCa. Pantoprazole was associated with a 3.0% (95% CI 0.3%-6,0%) increased rate of being treated with ADT for every six months of cumulative use, while any use of all other PPIs was associated with a 39.0% (95% CI 18.0%-64.0%) increased PCa-specific mortality. No significant association was found with PCa diagnosis. Conclusions: Upon validation of the potentially negative association of PPIs with PCa outcomes, the expansive use of PPIs may need to be reassessed, especially in PCa patients.
A randomized phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy (RT) for intermediate and high-risk prostate cancer (PC): Quality-of-life results (QoL) in SPCG-13 trial.
Authors: Kellokumpu-Lehtinen Pirkko-Liisa , Hjälm-Eriksson Marie , Thellenberg-Karlsson Camilla , Astrom Lennart , Franzen Lars , Fransson Ann-Sofie , Leskinen Markku J. , Huttunen Teppo , Ginman Claes
Published: February 2020

313

Background: Six docetaxel cycles did not improve PSA relapse free survival as an adjuvant treatment after radical RT (Kellokumpu-Lehtinen EURURO-8532). Here we report SPCG-13 trials QoL results. Methods: A total of 376 PC patients (T2 with Gleason score (GS) 4+3, PSA>10; T2, GS 8-10 any PSA; or any T3) were randomised to receive either 6 cycles of docetaxel 75mg/m2 every 3 weeks (Arm A, n=188) or surveillance (Arm B, n=188) after radical RT NTC006653848. Neoadjuvant/adjuvant ADT was mandatory. Primary end-point was a rising PSA > 2 ng/ml above the nadir. Patients were followed for 5 years with PSA every 3 months for two years and thereafter every 6 month. FACT-P QoL questionnaires were used at baseline, during and after docetaxel treatment and in the follow-ups (at 1 year, 2 years and 4 years after treatment) in both groups, and analysed using analysis of variance (ANOVA) models. Results: Median follow-up was 59.4 months (range 1 to 111 months). 147 (78.2%) patients completed all six cycles in arm A. Mean age was 66.2 years in Arm A and 66.4 years in Arm B. The total QoL scores at baseline did not differ between the Arms (mean 119.0, SD±18.9, n=177 vs 118.2, SD±18.1, n=180). In Arm A the total score declined to 116.3 (SD+15.2), at 24 weeks and was 118.5 (SD±21.3) after chemotherapy. In Arm B at 24 weeks the QoL score had increased to 123.3 (SD±19.2) and was significantly higher than in Arm A (estimated difference of 8.2 with p<0.0001, ANOVA model adjusted for baseline). However, in the first follow-up (1 year) the QoL score was same in both Arms (123.7 vs 123.6, respectively, p=0.344, ANOVA model adjusted for baseline) and remained at the same level during further follow-ups. The decline in QoL scores during the docetaxel treatment were seen only in two sub-scores; functional and physical. Conclusions: Adjuvant docetaxel did decrease the QoL of patients during the treatment. However, in the later follow-ups it increased to the same level as those patients without docetaxel treatment. These results further support our conclusions of showing no benefit from docetaxel as adjuvant treatment in this patient group after radical curative treatment. Clinical trial information: RT NTC006653848.
Quality of life outcomes from a phase III trial exploring optimal sequencing of androgen deprivation therapy with external beam radiotherapy in localized prostate cancer.
Authors: Roy Soumyajit , Grimes Scott , Eapen Libni , E Choan , Malone Kyle , Craig Julia , Morgan Scott Carlyle , Malone Shawn
Published: February 2020

315

Background: Dose-escalated prostate radiotherapy (PRT) with androgen deprivation therapy (ADT) is a standard curative treatment for localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. We report the patient-reported health related quality of life (HR-QoL) outcomes from a phase III study exploring optimal sequencing of PRT with ADT in LPCa. Methods: Newly diagnosed LPCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA < 30 ng/mL were randomized to receive PRT (76 Gy/38 fractions) with 6 months (mos) of ADT starting 4 mos prior to RT (NAHT arm) or concurrently with RT (CAHT arm). HR-QoL was assessed using EORTC QLQ-C30 and PR25 at baseline, q2 mos while on ADT, q4 mos for year 1 and 2 after ADT, q6 mos from year 3 to 5 and annually thereafter. Linear mixed modelling was applied to compare change in score (relative to baseline) over time. Wilcoxon rank-sum test was used to identify between-group difference in absolute scores, at 18, 36 and 60 mos. The statistical and clinical significance was set at p≤0.01 and 10-point threshold, respectively. Results: Overall 432 men were enrolled in the study and 393 (194 in NAHT and 199 in CAHT arm) were eligible for HR-QoL evaluation. There was a significant difference in the change in score of sleep disturbance due to urinary bother (least-squared mean: 3.9 vs. 7.6, P = 0.001) between the two arms. Although there were statistically significant differences in absolute scores of global QoL (18, 60 mos), cognitive (18, 60 mos), social and emotional functions (60 mo), sexual intimacy (18 mo) and fatigue (60 mo) favoring NAHT, the only clinically meaningful difference was noted in ejaculatory dysfunction at 18 (mean: 52.5 vs. 64.6), 36 (60.2 vs. 49.2) & 60 mos (61.4 vs. 50.9), respectively. Conclusions: We did not find any notable difference between the two arms with respect to score change over time in any of the HR-QoL metrics except sleep disturbance due to urinary bother. Clinically meaningful difference was noted only in the late absolute ejaculatory dysfunction score which favored the NAHT arm. Based on these findings, both NAHT and CAHT with PRT are reasonable standards of care for LPCa. Clinical trial information: DC-990-0082.
Stereotactic body radiation therapy with androgen deprivation therapy for unfavorable-risk prostate cancer.
Authors: Patel Sagar Anil , Switchenko Jeffrey M. , Zhang Chao , Rose Brent Shane , Fischer-Valuck Benjamin Walker , Jani Ashesh B. , Chen Ronald C. , Royce Trevor Joseph
Published: February 2020

332

Background: Current ASTRO consensus guidelines do not support routine use of SBRT in higher risk PC. However, the NCCN permits selective use of SBRT with ADT for unfavorable intermediate (UIR) and high (HiR) risk PC in cases where conventional/moderately fractionated radiation therapy (EBRT) present medical or social hardship. How SBRT+ADT compares to EBRT+ADT in UIR and HiR men is unknown. Methods: Men >40 years old with localized PC treated with RT and concomitant ADT for curative intent between 2004-2015 were analyzed from the National Cancer Database. Patients treated with brachytherapy or who lacked ADT or risk stratification data were excluded. A total of 558 men treated with SBRT (5 fractions, ≥7 Gy/fraction) versus 40,797 men treated with moderate or conventional EBRT (dose ≥60 Gy with ≤3 Gy/fraction) were included. Patients were stratified by UIR and HiR using NCCN criteria. Kaplan Meier and Cox proportional hazards were used to compare overall survival (OS) between RT modality, adjusting for age, race, and comorbidity index. Results: With a median follow up of 62 months, there was no difference in 5-year OS between men treated with SBRT versus EBRT regardless of risk group (UIR: 87.2% SBRT versus 87.0% EBRT, p=.40; HiR: 80.4% SBRT versus 80.8% EBRT, p=.21). On multivariable analysis, there was no difference in risk of death for men treated with SBRT compared to EBRT (UIR: adjusted HR 1.09, 95% CI 0.68-1.74, p=.72; HiR: adjusted HR 0.93, 95% CI 0.76-1.14, p=.51). Conclusions: We found no difference in survival between SBRT+ADT and standard of care EBRT+ADT for UIR or HiR PC. Randomized trials of SBRT versus EBRT, with standard concomitant ADT, in these risks groups are needed. If prospectively validated, more widespread use of SBRT for higher risk PC may be warranted, especially in an era of cost-effective care.
Predicting biochemical recurrence after prostatectomy: Can machine learning beat CAPRA score? Results of a multicentric retrospective analysis on 4,700 patients.
Authors: Sargos Paul , Leduc Nicolas , Giraud Nicolas , Gandaglia Giorgio , Roumiguie Mathieu , Ploussard Guillaume , Niazi Tamim , Chaddad Ahmad , Beauval Jean-Baptiste
Published: February 2020

343

Background: Recent advances in machine learning algorithms and deep learning solutions paved the way for improved accuracy in survival analysis. We aim to investigate the accuracy of conventional machine learning and deep learning methods in the prediction of 3-year biochemical recurrence (BCR) as compared to CAPRA score prediction. Methods: A total of 5043 men who underwent RP between 2000 and 2015 for clinically localized PCa iwere analyzed retrospectively. Three-year BCR was predicted using the following models: CAPRA score, Cox regression analysis, logistic regression, k-nearest neighbor, random forest and densely connected feed-forward neural network classifier. The discrimination of the models was quantified using the C-index or the area under the receiver operating characteristics curve. Results: Patients with CAPRA score 2 and 3 accounted for 64% of the population. C-index measuring performance for the prediction of the three-year BCR for CAPRA score was 0.63. C-index values for k-neighbor classifier, logistic regression, Cox regression analysis, random forest classifier and densely optimized neural network were respectively 0.55, 0.63, 0.64, 0.64 and 0.70 (pairwise, adjusted p-value < 0.01). After inclusion of available post-surgical variables, C-index value reached respectively 0.58, 0.77, 0.74, 0.75 and 0.84 (pairwise, adjusted p-value < 0.05). Conclusions: Our results show that CAPRA score performed poorly in intermediate-risk patients undergoing RP. Densely connected neural networks with simple architecture further increased predictive power with low computational cost. In order to predict 3-years BCR, adding post-surgical features to the model greatly enhanced its performance.
Trends and oncological outcome of testosterone recovery after androgen deprivation therapy in prostate cancer patients who received external beam radiotherapy.
Authors: Takei Akinori , Sakamoto Shinichi , Tamura Takaaki , Wakai Ken , Maimaiti Maihulan , Imamura Yusuke , Komiya Akira , Nakatsu Hiroomi , Akakura Koichiro , Ichikawa Tomohiko
Published: February 2020

345

Background: Although androgen deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) is standard treatment for high risk prostate cancer (PC) patients, the shift of testosterone (TST) levels after ADT and the optimal duration of ADT is unclear. TST recovery and outcome were studied in PC patients who received EBRT with ADT. Methods: Eighty-two patients who underwent EBRT with ADT for PC were retrospectively analyzed. Serum TST levels after ADT terminations were studied. Cox proportional hazard models and the Kaplan-Meier method were used for statistical analysis. Results: Median age, baseline TST, nadir TST, and duration of ADT were 73 years, 456 ng/dL, 16 ng/dL, and 26 months, respectively. ADT duration of 33 months (HR 0.13; p=0.0018), nadir TST of 20 ng/dL (HR 0.35; p=0.0112), and TST >50 ng/dL at 6 months after ADT termination (HR 0.21; p=0.0075) were significantly associated with TST recovery to normal levels (200 ng/dL) on multivariate analysis. ADT duration of 33 months (HR 0.31; p=0.0023) and nadir TST of 20 ng/dL (HR 0.38; p=0.0012) were significantly associated with TST recovery to supracastrate level (50 ng/dL) on multivariate analysis. In high risk PC patients, ADT≤ 2 year group showed shorter time to TST recovery to supracastrate levels compare to those of ADT>2 year group (HR 4.21; p=0.0022) without affecting biochemical recurrence (p=0.49) and overall survival (p=0.674). Conclusions: ADT duration of 33 months and nadir TST of 20 ng/dL predicted the TST recovery to suparacastrate levels. Less than 2 year of ADT provided better TST recovery without affecting the oncological outcome in high risk patients.[Table: see text]
Natural history of an immediately detectable PSA following radical prostatectomy: A description of a contemporary cohort.
Authors: Lonergan Peter Eoin , Washington Samuel L. , Cowan Janet E. , Nguyen Hao , Cooperberg Matthew R. , Carroll Peter
Published: February 2020

356

Background: Radical prostatectomy (RP) can provide good long-term oncological outcomes in patients with localized and locally advanced prostate cancer (PCa). After RP, prostate specific antigen (PSA) represents the corner stone for follow-up of patients. A persistently detectable PSA immediately following RP is an unfavourable prognostic factor. We described the natural history of the management and outcomes in men with a detectable PSA in an academic cohort. Methods: A retrospective review of prospectively collected clinical and pathologic data from consecutive patients who underwent RP for non-metastatic PCa between 2000 and 2018 was performed. A detectable PSA was defined as PSA ≥ 0.05 ng/ml between 2-6 months post-surgery. Biochemical recurrence (BCR) was defined as two consecutive PSA values ≥ 0.2 ng/ml after 6 months post-surgery or any salvage treatment for a rising PSA. Second recurrence was defined as additional treatment after post-RP salvage treatment. Outcomes were defined as time to other cause mortality (OCM) or prostate cancer specific mortality (PCSM). Results: We identified 499 men with a detectable PSA within 6 months following RP. Median PSA at diagnosis was 7.95 ng/ml (IQR 5.57-12.97). Median CAPRA-S score was 5 (IQR 2-7). Median follow-up was 41 months (IQR 20-77). 296 (59%) underwent salvage treatment for a rising PSA at a median of 5 months. 33 (23%) of these men required further treatment (10 for bone metastases) at a median of 7 months. 203 (41%) of men with an immediately detectable PSA did not undergo any further treatment after RP. Treatment-free survival after post-RP salvage (31 on ADT and 2 underwent salvage RT) in men with a detectable vs undetectable PSA was 86% vs 92% at 1 year, 78% vs 89% at 3 years, 72% vs 86% at 5 years and 70% vs 76% at 10 years (Log-rank p =0.02). Prostate cancer specific survival in men with a detectable vs undetectable PSA was 100% vs 100% at 1 year, 99% vs 100% at 3 years, 96% vs 100% at 5 years and 91% vs 99% at 10 years (Log-rank p < 0.01). Conclusions: This report describes the natural history of the management and outcomes in men with a detectable PSA following RP. We demonstrate that men with a detectable PSA after RP may have excellent long-term outcomes.
Adjuvant docetaxel after definitive radiotherapy for high-risk prostate cancer: A meta-analysis of randomized clinical trials.
Authors: Manneh Kopp Ray , Lema Mauricio , Ibatá Linda
Published: February 2020

374

Background: In order to improve long term results for high-risk prostate cancer, several clinical trials have tested the addition of docetaxel chemotherapy. The outcomes of this trials have not led to clear conclusions. We conducted a meta-analysis of randomized phase 3 trials testing the efficacy of docetaxel after radiotherapy in high risk prostate cancer patients. Methods: A systematic review of PubMed (Medline), Embase and the Cochrane Library was conducted. We followed the PRISMA guidelines, three investigators independently selected the articles and verified inclusion criteria. We compared the overall survival and disease-free survival between the intervention group (adjuvant chemotherapy with docetaxel) and the control group (without adjuvant chemotherapy) by calculating the hazard ratio (HR) with 95% confidence intervals (CIs). Pooled effects were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Results: 382 publications were identified, four phase III trials (STAMPEDE, RTOG0521, SPCG-13, GETUG 12) comparing docetaxel vs standard of care after radiotherapy for high-risk prostate cancer fulfilled the inclusion criteria with data from 2034 patients (1135 in placebo group and 899 in adjuvant docetaxel group). Heterogeneity was not found between the included studies for OS (I 2 0%), but it was found between studies for disease-free survival (I2 60%). Adjuvant docetaxel chemotherapy showed overall survival benefit when compared to ADT alone (HR 0,72 95% CI 0,54-0,96). Adjuvant docetaxel also improved the disease-free survival when compared to ADT alone (HR 0,74 95% CI 0,64-0,86). No evidence of publication bias was observed. Conclusions: This meta-analysis shows that docetaxel after definitive radiotherapy in high-risk prostate cancer is likely to be more effective than standard of care in terms of overall survival and disease-free survival. Further prospective studies are needed in order to increase the sample that would lead to show a more robust data.
Surveillance of postchemotherapy subcentimeter residual retroperitoneal mass (RRM) in metastatic nonseminomatous germ cell tumor (mNSGCT).
Authors: Cotner Cody , Hilton Susan , Mamtani Ronac , Guzzo Thomas J. , Vaughn David J.
Published: February 2020

391

Background: Approximately 30 – 60% of patients with mNSGCT treated with cisplatin-based chemotherapy (CBCT) achieve a complete response (CR), defined as normalization of serum tumor markers with either no RRM or a RRM < 1 cm. While there is universal agreement that patients with a RRM ≥ 1 cm should undergo retroperitoneal lymph node dissection (RPLND), many institutions, including ours, recommend surveillance for patients who achieve a CR. However, studies have not defined which axis of the RRM should be considered when making this decision. Methods: The electronic medical records (2007 – 2017) at the Hospital of the University of Pennsylvania (HUP) were searched to identify good-risk mNSGCT patients treated with CBCT who achieved a CR and underwent surveillance. Consistent with RECIST 1.1, we define a CR as no RRM or a RRM < 1 cm in the transaxial short axis (TSA). We do not consider the transaxial long axis (TLA) or the craniocaudal axis (CCA). A post-hoc review was performed by a blinded radiologist and the RRM dimensions in the TSA, TLA, and CCA were recorded. Differences in the frequency of recurrence between groups with a RRM < 1.0 cm and ≥ 1.0 cm in the TLA and CCA were assessed using the Fischer exact test. Results: 39 patients met study criteria and were included. At a median follow-up of 50.8 months, only 2 patients (5.1%) recurred. Both were successfully treated with RPLND and salvage chemotherapy. Post-hoc review of imaging: median TSA 6 mm (range, 0-11); median TLA 8 mm (range, 0-14); median CCA 11 mm (range, 0-34). Thirteen (33%) and 27 (69%) patients had a RRM ≥ 1 cm in the TLA and CCA, respectively. There were no statistically significant differences in the risk of recurrence between patients with a RRM < 1.0 cm and ≥ 1.0 cm in the TLA (p=0.54) or CCA (p=0.53). Conclusions: Surveillance is an effective strategy in patients with mNSGCT and a post-chemotherapy RRM < 1.0 cm in the TSA. Our study suggests that referencing the TSA and not the TLA or CCA in this decision-making may avoid unnecessary post-chemotherapy RPLND.
Prognostic significance of rate of tumor marker (TM) decline during high-dose chemotherapy (HDCT) for relapsed germ cell tumors (rGCT).
Authors: Adra Nabil , Althouse Sandra K. , Abonour Rafat , Abu Zaid Mohammad Issam , Liu Hao , Hanna Nasser H. , Einhorn Lawrence
Published: February 2020

403

Background: Rate of serum TM decline is prognostic in patients (pts) with GCT receiving first-line chemotherapy. We investigated the prognostic value of TM decline in rGCT treated with HDCT+peripheral-blood stem-cell transplant (PBSCT). Methods: 462 consecutive pts with rGCT treated with HDCT+PBSCT at Indiana University between 1/2004-1/2019. All pts were planned for 2 consecutive HDCT courses with carboplatin+etoposide per protocol (N Engl J Med 2007;357:340-8). Pts with elevated AFP and/or hCG were included (N=347). Slope and half-life (T1/2) were calculated for weekly AFP+hCG during HDCT starting with peak value at days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized satisfactory (SAT). Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier. Uni- and multivariable analysis using Cox regression model was performed. Results: 347 pts had elevated TM: 312 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (292), mediastinum (26), retroperitoneum/other (29). Metastatic sites included retroperitoneum (277), lung (233), liver (83), brain (77), and bone (21). At initiation of HDCT, 77 pts had elevated AFP, 222 elevated hCG, and 48 elevated both AFP+hCG. Median AFP 9 (1-21,347) and hCG 113 (1-178,140). 314 pts (91%) completed 2 planned cycles of HDCT. Overall, 46/347 pts had SAT decline (13 for AFP; 30 for hCG; 3 for both). Pts with SAT TM decline had superior outcomes compared to UNSAT: 2-yr PFS 69% vs 45% (p=0.006) and 2-yr OS 75% vs 51% (p=0.006). When evaluating each TM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 74% vs 47% (p=0.002). There was statistically non-significant difference for AFP: 2-yr PFS 48% vs 42% (p=0.65). In univariable analysis, UNSAT decline of hCG, but not AFP, was an adverse prognostic factor for PFS: HR=2.51 (95% CI, 1.40-4.51); p=0.002. Multivariable analysis will be presented. Conclusions: SAT rate of TM decline, particularly in hCG, predicts superior outcomes in rGCT undergoing HDCT+PBSCT. Pts with UNSAT TM decline are at higher risk for relapse and death.
Origin of a second malignancy harboring isochromosome 12p [i(12p)] in patients with history of testicular germ cell tumor (TGCT).
Authors: Hwang Michael J. , Siddiqui Bilal A. , Merriman Kelly W. , Uthup Joma , Ward John Francis , Karam Jose A. , Wood Christopher G. , Pisters Louis L. , Zhang Miao , Tu Shi-Ming
Published: February 2020

412

Background: The cumulative incidence of subsequent solid malignant neoplasm (SMN) after treatment of TGCT is about 10% over a 25-year period. i(12p) has been used to define tumor of germ cell origin. We evaluated the prevalence of i(12p) on various subsequent SMN in patients with a history of TGCT. Methods: From the Tumor Registry database at MD Anderson, we identified 655 TGCT patients who developed a second (third or fourth) malignancy between January 1990 and September 2018. Of those 114 SMN from the GI tract, GU system, chest, brain, sarcomas or melanomas between 2011 and 2017, 43 had tumor tissue available at our institution and of sufficient quality for fluorescence in situ hybridization (FISH) of i(12p). Results: Our cohort comprised 43 patients, excluding 2 cases (#6 and 7) whose SMN tested positive and their non-tumor controls negative for i(12p). Diagnosis of primary TGCT and SMN: age, mean 41 yrs (range 20-68 yrs) and 59 yrs (range 34-86 yrs), respectively, and interval of 18 yrs (range 0-57 yrs). Of those 43 cases (5 did not hybridize), 5 (11%) harbored i(12p), while 16 (37%) had additional copies of chromosome 12 without apparent gain of 12p. Conclusions: Prevalence of i(12p) on subsequent SMN in our patient cohort with a history of TGCT was 11%. Detection of i(12p) in those patients with TGCT in general and with nonseminomas in particular suggests somatic transformation, emphasizes importance of a complete surgical resection of residual teratomatous tumor after chemotherapy, and implicates a stem-cell origin and nature (e.g., plasticity, heterogeneity, dormancy) of cancer. *deceased; Rx – initial treatments; S – seminoma; NS – nonseminoma; BEP – bleomycin, etoposide, cisplatin; CEB – carboplatin, etoposide, bleomycin; XRT – radiation therapy. Groot HJ, Lubberts S, de Wit R, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504-13.
Circulating tumor (ct)-DNA alterations in patients with testicular germ cell tumors.
Authors: Agarwal Archana , Nassar Amin , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , Lanman Richard B. , Talasaz AmirAli , Sweeney Christopher , Sonpavde Guru
Published: February 2020

415

Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assessment allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 40 patients (pts) with advanced testicular GCTs from multiple institutions in the USA that underwent ctDNA analysis using the Guardant (G)-360 platform were eligible and a total of 48 samples were collected. 36 pts had one sample, 3 pts had 2 samples, 1 pt had 6 samples. De-identified demographic data were collected in addition to data for ctDNA alterations. G360 employed a CLIA-certified ctDNA panel that assessed single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 40 patients with testicular GCTs, 13pts (33%) were post systemic therapy. The median age was 36 years (range 20-61). 199 ctDNA alterations were detected in 35 patients (87.5%) across 41 genes. Among the 199 alterations, 102 were believed to be pathogenic and detectable in 26 samples from 25 pts (62.5) (%). The most common pathogenic somatic alterations were KRAS (n = 16/102, 16%), TP53 (n = 16/102, 16%), CCND2 (n = 9/102, 9%), CDK6 (n = 9/102, 9%), MET (n = 9/102, 9%), and RAF1 (n = 6/102, 6%). Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to study the evolution of resistance to cisplatin-based chemotherapy and new potentially actionable alterations.
Incidence and risk factors for contralateral testicular tumor.
Authors: Blok Joost Marijn , Groot Harmke J. , Huele Eline H. , De Wit Ronald , Gietema Jourik A. , Groenewegen Gerard , Witjes Fred , Van den Berg Hetty , Nuver Janine , Tromp Jacqueline Maria , De Brouwer Peter , Smilde Tineke Jacoba , Aarts Maureen J.B. , Vanneste Ben G.L. , Bosch Ruud J.L.H. , Horenblas Simon , Schaapveld Michael , Meijer Richard P.
Published: February 2020

419

Background: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a metachronous contralateral testicular tumor (CLTT). It is unclear whether the histology of the primary tumor and treatment with platinum-based chemotherapy are associated with the risk of CLTT. The primary aim of this study was to analyze the association between number of chemotherapy cycles and risk of CLTT. Methods: We evaluated the incidence of metachronous CLTT (≥2 months after diagnosis of primary TGCT) in a nationwide cohort consisting of patients diagnosed with TGCT between 1989 and 2007. Standardized incidence ratios (SIRs) were computed to compare CLTT incidence with TGCT in the general population and the cumulative incidence of CLTT was estimated. We analyzed the association between treatment with chemotherapy and risk of CLTT in a multivariate Cox-model. Results: The entire cohort consisted of 4,755 patients (seminoma: n=2,612; 54.9%, nonseminomatous germ cell tumor [NSGCT]: n=2,143; 45.1%). The median age at diagnosis was 33 years (IQR 26-40). A total of 1,047 patients (22.0%) were treated with platinum-based chemotherapy for their primary TGCT (seminoma: n=189, NSGCT: n=858). Median follow-up was 17.0 years (IQR 12.7-22.0). A CLTT was diagnosed in 136 patients. The median interval to CLTT diagnosis was 6.1 years (range 0.8-19.7). The overall 20-year cumulative incidence was 3.4% (95% CI 2.8-4.0) and was higher after seminoma (4.0%; 95% CI 3.3-4.9), compared to NSGCT (2.6%; 95% CI 1.9-3.4). The SIRs were for seminoma: 22.1 (95% CI 17.8-27.1), for NSGCT: 8.6 (95% CI 6.3-11.6) and for the entire cohort: 14.6 (95% CI 12.2-17.2). In multivariate analysis, the risk of developing a CLTT decreased with age (HR 0.93; 95% CI 0.90-0.96), was lower after NSGCT (HR 0.58; 95% CI 0.35-0.96), and decreased with every additional cycle of chemotherapy (HR 0.74; 0.64-0.85). This corresponds to a 26% lower risk of CLTT per extra chemotherapy cycle. Conclusions: TGCT patients have an almost 15 times higher risk of developing a CLTT, compared to the general population. The risk is 2 times higher after a seminoma, compared to NSGCT, and decreases with every additional cycle of chemotherapy. Especially in high risk patients, lifelong self-examination is advised.
Outcomes of adult urogenital sarcomas: Analysis of surveillance, epidemiology, and end results (SEER) database 2004 to 2015.
Authors: Nutalapati Snigdha , Chen Quan , Huang Bin , Patel Reema Anil , Bilen Mehmet Asim , Myint Zin
Published: February 2020

423

Background: Urogenital sarcomas are rare type of soft tissue sarcomas and represent only 1-2% of all genitourinary cancers. Given the paucity of literature, we aimed to study the clinical characteristics and factors impact outcomes of adult urological sarcomas. Methods: Adult males aged ≥ 20 years with sarcomas primarily originating from urogenital sites were identified from national SEER database between 2004-2015. Descriptive analysis was performed for all cases. Survival analysis, including Kaplan Meier estimates and Cox regression were performed. Results: A total of 1177 genitourinary sarcomas were identified. Urinary bladder (20.56%) was the most common primary site followed by spermatic cord (20.31%) and kidney (17.33%). The most common histological subtype was liposarcoma (32.9%) followed by leiomyosarcoma (32.0%). 10-year survival rate was highest for liposarcoma 58.3% (95% CI 50.3-65.5) followed by leiomyosarcoma 40.2% (95% CI 32.0-48.2), rhabdomyosarcoma 37.3% (95% CI 22.6-52.1), synovial sarcoma 22.7% (95% CI 5.6-46.6), carcinosarcoma 8.9% (95% CI 4.3-15.4) and 0% for angiosarcoma. Median follow up was 23 months and overall median survival was 54 months. There was a significant overall survival difference by age, race, primary sites, histological subtypes, grade, stage, insurance status, geographic, socioeconomic status and treatment in both univariate and multivariate analysis. On multivariate analysis, factors associated with unfavorable prognosis include age > 75 years (HR 3.9, 95% CI 2.9-5.2), distant metastasis (HR 2.0, 95% CI 1.5-2.7), ureteral sarcomas (HR 6.2, 95% CI 2.3-17.1) and having Medicaid insurance (HR 1.7, 95% CI 1.2-2.3).Surgery alone (HR 0.5, 95% CI 0.4-0.7) or in combination with chemotherapy (HR 0.4, 95% CI 0.3-0.6) or radiation (HR 0.4, 95% CI 0.3-0.6) had favorable prognosis compared to non-surgical approach. Conclusions: Urinary bladder is the most common primary sites of all urological sarcomas. Our study showed age > 75, poorly differentiated histology, angiosarcoma subtype, ureteral primary site, distant metastasis, poor socioeconomic status, Appalachian area and radiation alone were associated with less favorable outcomes.
Germline DNA copy number polymorphism to predict the efficacy of BCG therapy for non-muscle invasive bladder cancer.
Authors: Yamamoto Yoshiaki , Ozawa Sho , Samoto Masahiro , Mori Junichi , Inoue Ryo , Yano Seiji , Hirata Hiroshi , Matsumoto Hiroaki , Matsuyama Hideyasu
Published: February 2020

431

Background: Bacillus Calmette-Guerin (BCG) intravesical instillation is the most effective immunotherapy for non-muscle-invasive bladder cancer (NMIBC), however there are few reliable markers to elucidate the efficacy of BCG therapy. Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in NMIBC treated with BCG therapy remains unclear. FAM81A located on 15q22.2 was reported as one of tumor-associated ETS shared target genes in prostate cancer. PCSK6 located on 15q26.3 was reported to regulate proliferation and tumor progression in several cancers. The purpose of this study is to determine the prognostic value of CNPs for NMIBC treated with BCG therapy. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the efficacy of immunotherapy. Methods: Array comparative genomic hybridization (CGH) was performed to search for candidate whole genome-wide CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate the effect of BCG therapy for 57 Japanese patients with NMIBC treated with BCG intravesical instillation. Results: Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with disease progression in NMIBC treated with BCG. The means of the relative copy numbers of patients with CNP and those without it were 1.58 and 2.10 for FAM81A ( P < 0.0001), and 1.06 and 1.80 for PCSK6 ( P < 0.0001), respectively. Univariate Cox proportional hazards regression analysis showed that FAM81A ( P = 0.0022), and PCSK6 ( P = 0.0147) copy number had a significant effect on progression-free survival. In multivariate analyses, FAM81A copy number was an independent prognostic factor for progression-free survival ( P = 0.0419, RR = 7.59, 95% CI, 1.07–153.42). The combination of FAM81A or PCSK6 CNP was the most significant prognostic biomarker to predict the efficacy of BCG therapy for NMIBC ( P = 0.0002). Conclusions: Germline DNA CNPs may be a potential new biomarker for estimating the efficacy of BCG therapy in Japanese patients with NMIBC.