bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of the nicotinamide riboside kinase NAD+ salvage pathway in a model of sarcoplasmic reticulum dysfunction
Authors: Doig Craig L. , Zielinska Agnieszka E. , Fletcher Rachel S. , Oakey Lucy A. , Elhassan Yasir S. , Garten Antje , Cartwright David , Heising Silke , Alsheri Ahmed , Watson David G. , Prehn Cornelia , Adamski Jerzy , Tennant Daniel A. , Lavery Gareth G.
Published: February 2020

Background

Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation.

Methods

We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO.

Results

H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability.

Conclusions

These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved.
Management of recurrent unilateral lumbar disc herniation in a single level: unilateral versus bilateral pedicle screws fixation with interbody fusion
Authors: Ahmed Omar El Farouk , Morad Sherif H. , Abdelbar Ahmed S.
Published: February 2020

Background

Lumbar interbody fusion procedure is a recognized surgical technique in management of a variety of lumbar pathologies including recurrent lumbar disc prolapse. Interbody fusion augmented by pedicle screw fixation has been considered to improve fusion rates and clinical outcomes. Interbody fusion is commonly associated with better fusion potentials through applying the bone graft in the load bearing, vascular position of the anterior, and middle spinal columns. However, it still remains unknown whether interbody fusion with unilateral pedicle screw fixation (UPSF) is superior to that with bilateral pedicle screw fixation (BPSF).

Aim of the work

The aim of this study is to evaluate the efficacy and safety of unilateral versus bilateral pedicle screw fixation associated with interbody fusion for the management of single level unilateral recurrent lumbar disc prolapse as regard the clinical and biomechanical results, operation time, intraoperative blood loss, and postoperative stay.

Material and methods

This observational prospective comparative study of the two groups who were operated either unilateral (group A /15 patients) or bilateral (group B/15 patients) pedicle screw fixation with interbody fusion was done. Patients were followed up for 1, 6, ad 12 months.

Results

Significant improvement in functional outcome of the two groups was noted compared to preoperatively, except in early postoperative period where the back VAS and ODI in the unilateral group was better than bilateral group. However, on further follow up, no significant difference was noticed. There was no significant difference comparing fusion rate, complication rate, and duration of hospital stay between the two groups at postoperative follow-up. There was significantly less blood loss, and significantly shorter operation time in the unilateral PS fixation group as compared with the bilateral PS fixation group in our study.

Conclusion

Our study suggested that TLIF with unilateral PS fixation was as safe and effective as that with bilateral PS fixation for the management of recurrent single level lumbar disc prolapse; it showed better clinical outcome scores of ODI and back VAS, and a significant reduction of the intraoperative blood loss as well as the operation time, without significant differences considering fusion rate, complication rate, and duration of hospital stay between the two groups at postoperative follow-up. However, BPSF with TLIF likely causes more degeneration at the cranial adjacent segment compared with UPSF techniques. Nevertheless, the long-term follow up is required to demonstrate the impact of these findings.
Enzalutamide (E) re-challenge as second-line in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with first-line enzalutamide + docetaxel (D): Preliminary results of a post-progression analysis of CHEIRON trial.
Authors: Caffo Orazio , Aieta Michele , Palesandro Erica , Macerelli Marianna , Mucciarini Claudia , Nicodemo Maurizio , De Giorgi Ugo , Sartori Donata , Fratino Lucia , Iacovelli Roberto , Rossetti Sabrina , Scapoli Daniela , Morelli Franco , Carrozza Francesco , Nole Franco , Zagonel Vittorina , Messina Carlo , Gasparro Donatello
Published: February 2020

123

Background: CHEIRON trial was a phase II study which randomized previously untreated mCRPC pts to receive D 75 mg/m2 IV d1 q3w for 8 courses alone or plus E 160 mg PO daily. As per protocol, E was administered in experimental arm for only 24 wks until D conclusion. The study met its primary endpoint since the rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002). The clinicians were asked to consider an E re-challenge as first post-progression treatment for those pts without disease progression at the chemotherapy end in the experimental arm. We presented the preliminary analysis of E activity in post-progression setting of CHEIRON DE arm. Methods: We evaluated all patients enrolled in the experimental arm, focusing on pts who received E as first post-progression treatment. We collected data concerning the treatment duration and disease control and compared the outcomes of pts treated with E re-challenge with those of pts who received other treatments at the time of first progression after experimental therapy. Results: Among the 120 pts who received DE experimental arm, 101 did not show a disease progression and 82 received a second-line active treatment: 54 (66%) were treated with E, the other received abiraterone (10 pts), cabazitaxel (13 pts), and radium 223 (5 pts). The median interval between the end of DE and the start of E re-challenge was 7.6 mos (range 0.9-18.4 mos). At a median follow-up of 15.5 mos, the median duration of E re-challenge was 9.8 mos (range 1.9-30.9) with 22 pts still on treatment. Pts who received E rechallenge showed a median progression free survival of 11.4 mos which was significantly longer compared to 4.5 mos showed in pts who received other treatments (p < 0.0001). The median overall survival was 20.4 mos and 12.3 mos, respectively (p = NS). Conclusions: In pts who received first-line DE in the CHEIRON trial, the reintroduction of E after a per-protocol discontinuation demonstrated to be feasible, with a prolonged disease control compared to the other post-progression therapeutic options. Clinical trial information: NCT02453009.
Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Long-term follow up of secondary endpoints.
Authors: Maughan Benjamin Louis , Hahn Andrew W , Nussenzveig Roberto , Hoffman John , Morton Kathryn , Gupta Sumati , Batten Julia Anne , Thorley Jared , Hawks Josiah , Santos Victor Sacristan , Nachaegari Gayatri , Wang Xuechen , Boucher Kenneth M. , Haaland Benjamin , Agarwal Neeraj
Published: February 2020

125

Background: RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, men with mCRPC and a significant decline in serum bone metabolism markers (BMM) had improved survival with atrasentan, a bone targeting agent (PMID 24565955). We hypothesized that RA+EZ is safe, and decrease bone metabolism markers compared to EZ alone. Here we report the long-term follow up of the secondary clinical endpoints. Methods: In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment; 2) safety. Secondary objectives: changes in 4 other markers of bone resorption or formation, and PSA progression free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results: After a safety lead in phase (n=8), 39 men were randomized (2:1) to RA+EZ vs EZ. Median follow up is 19.3 months (range 3 – 24 months). Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057) and met the primary endpoint (2018 ESMO annual meeting: Annals of Oncology). There was a consistent trend regarding PSA-PFS, rPFS and OS favoring RA+EZ over EZ. . . (Table). Notably, no bone fractures have occurred in either group with extended follow up. Conclusions: The use of RA+EZ was safe with a longer follow up with no increase in skeletal related events including fractures. All secondary endpoints, numerically favored RA+EZ vs EZ. Clinical trial information: NCT02614859.
Non-rising PSA disease progression on C-11 choline PET/CT imaging in patients receiving second generation hormone therapies (2nd-HT).
Authors: Ahmed Mohamed E. , Andrews Jack R. , Dundar Ayca , Jimbo Masaya , Joshi Vidhu B. , Motterle Giovanni , Karnes Jeffrey , Kwon Eugene D. , Bryce Alan Haruo , Kendi Ayse T. , Bold Michael S.
Published: February 2020

144

Background: Despite having well-recognized limitations, urologists often rely on serial PSA testing as a marker for treatment response or disease progression. To determine if PSA was indeed a reliable marker for treatment response or disease progression, we compared PSA levels against C-11 choline PET/CT in the evaluation of patients with advanced prostate cancer treated with second generation hormonal therapy (2nd-HT). Methods: We retrospectively identified 239 patients who were undergoing treatment with 2nd-HT (enzalutamide or abiraterone) for advanced prostate cancer. While on treatment, patients underwent serial PSA testing and C-11 choline PET/ CTs every 3 – 6 months. Paradoxical response was defined as increasing blood pool-corrected SUVmax of known choline-avid lesions and/or identification of new choline-avid lesions, despite stable or down-trending PSA. Results: Median (IQR) age was 70.4(64.3 – 75.7) years and median (IQR) primary Gleason Score was 8 (7 – 9). In our study, 19% of patients (n = 46/239) who were receiving 2nd-HT exhibited paradoxical response. Median (IQR) PSA and corrected SUVmax at baseline evaluation were 1.3 ng/mL (0.3 – 12.8 ng/mL) and 3.5 (1.8 – 5.8), respectively. Median (IQR) PSA and corrected SUVmax at the time of paradoxical response were 0.4 ng/mL (0.1 – 5.4 ng/mL) and 4.5 (2.8 – 6.8), respectively. The median duration of 2nd-HT treatment prior to detection of paradoxical response was 4.8 months (2.9 – 10.1 months). No significant difference was noted between patients receiving enzalutamide versus abiraterone (p = 0.35). Independent predictors of paradoxical response were prior primary systemic treatment (i.e. hormonal/chemo-hormonal therapy versus local therapy) and patient’s age at time of 2nd-HT initiation on univariate and multivariate analysis. Conclusions: Our retrospective review demonstrated prostate cancer disease progression discordant with PSA down-trending in 19% of patients receiving 2nd-HT. We conclude that in this subset of patients with advanced prostate cancer, PSA may not be a reliable marker of treatment response of disease progression, and routine radiographic evaluation in these patients is warranted.
New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.
Authors: Lawrence Mitchell , Clouston David , Frydenberg Mark , Murphy Declan G. , Pezaro Carmel Jo , Pook David William , Thorne Heather , Sandhu Shahneen Kaur , Toivanen Roxanne , Taylor Renea , Risbridger Gail ,   kConFab, CASCADE, MURAL
Published: February 2020

151

Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.
Plasma circulating tumor DNA (ctDNA) based clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kohli Manish , Tan Winston , Zheng Tiantian , Wang Amy , Huo Yelia , Montesinos Carlos , Wong Calvin , Du Pan , Jia Shidong , Yu Jianjun
Published: February 2020

160

Background: mCRPC is a heterogeneous disease state with variable survival and molecular markers that define survival continue to be determined. We applied a 120 gene panel based targeted next-gen sequencing (NGS) approach to probe plasma ctDNA based outcomes for survival. Methods: mCRPC chemo-naive patients (pts) were enrolled in a prospective study and plasma cell free DNA (cfDNA) extracted. ctDNA fractions estimated based on somatic variants. NGS of plasma cfDNA was performed using HiSeq X Ten on a panel of 120 genes (PredicineLDT). Clinical and molecular prognostic factors were determined for overall survival (OS). Cox proportional hazard regression was used to estimate hazard ratios (HR) at the univariate level and only significant associations included in multivariate analysis (significance at P<0.05). Results: 96 mCRPC pts were enrolled. 17/96 pts failed NGS QC. Median cfDNA, ctDNA yields for 79/96 pts are provided in Table. Median follow up for study cohort was 92.5 months (mon) (Range:62.3-109.6); median survival time was 25.9 mon (95% CI:19.9, 31.4) and 72/79 pts had died. TMPRSS2-ERG fusion was detected in 18/79 pts. Significant alterations associated with OS are listed in Table. 49/59 pts underwent subsequent docetaxel chemo. In chemo treated pts significant copy number alterations predictive of survival included AR amplification (p=0.01, HR=2.0, 95% CI[1.2, 3.5], RB1 loss (p=3.20E-06, HR=5.0, 95% CI[2.4, 10.6], PTEN(p=0.009, HR=2.6, 95% CI[1.2, 5.4]), CDH1(p=0.001, HR=4.3, 95% CI[1.6, 11.4]). Conclusions: ctDNA yield in mCRPC state was the most significant prognostic factor for survival, Several specific plasma genomic perturbations were observed topredict docetaxel efficacy and need further evaluation.[Table: see text]
Association of high plasma glutamine levels with outcome in metastatic castration-resistant prostate (mCRPC) patients treated with taxanes.
Authors: Pereira Diaz Veronica , Marin Mercedes , Jiménez Natalia , Reig Oscar , Victoria Iván , Esposito Francis , Prat Aleix , Mellado Begona
Published: February 2020

164

Background: Cancer cells may metabolize glutamine to fulfill their metabolic needs. In prostate cancer it has been shown that androgen receptor signaling promotes glutamine metabolism by increasing the expression of the glutamine transporters, and that stromal glutamine may promote tumor growth. Methods: We retrospectively tested glutamine levels in frozen plasma samples from mCRPC patients treated with taxanes, which were included in a prospective biomarker study in our institution. Glutamine levels were determined by a bioluminescent assay. Optimal cut-offs for glutamine levels were assessed using maximally selected log-rank statistics to determine low and high level groups. Pre-treatment glutamine level was correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Seventy eight mCRPC patients treated with taxanes were included. Median age was 70.3 (55.8-83.5) years and median follow-up was 13.1 (0.2-53.9) months. Glutamine was tested in 88 plasma samples: 69 from pre-docetaxel and 19 pre-cabazitaxel treatment (10 patients had both samples). High glutamine levels significantly correlated with worst PSA-progression-free survival (PFS) (median 2.8 vs 4.7 months, hazard ratio [HR] 1.8, 95%CI 1.1-2.7, P= 0.012) and overall survival (OS) (median 12.4 vs 20.4, HR 2, 95%CI 1.2-3.3, P= 0.006). In a multivariate analysis, high plasma glutamine levels were independently associated with shorter PSA-PFS (HR 2.3, 95%CI 1.4-3.7, P< 0.001) and OS (HR 2.2, 95%CI 1.3-3.7, P= 0.003). Patients with high glutamine levels were more likely to present PSA progression to taxanes than those with low levels (odds ratio [OR] 3, 95%CI 1.2-7.7, P= 0.016). Moreover, samples from patients treated with abiraterone or enzalutamide before taxanes (51 samples from 43 patients) had significantly higher glutamine levels (T-test, P= 0.014) than those without these prior therapies. Conclusions: Glutamine can be detected in plasma of mCRPC patients and higher levels are associated with adverse clinical outcome, supporting the relevance of metabolism in prostate cancer progression.
Association of neuroendocrine (NE) mRNA expression profiling in hormone-sensitive tumors samples with adverse clinical outcome in castration-resistant prostate cancer (CRPC) patients.
Authors: Orrillo Mayra , Jimenez Natalia , Reig Oscar , Castellano Giancarlo , Font Albert , Domenech Montserrat , Rodriguez-Vida Alejo , Carles Joan , Suarez Cristina , Ferrer Laura , Gonzalez Nuria , Sala Nuria , Rodriguez-Carunchio Leonardo , Diaz Sherley , Prat Aleix , Marin Mercedes , Mellado Begona
Published: February 2020

165

Background: NE dedifferentiation is associated to clinical aggressiveness and resistance to androgen receptor inhibition in prostate cancer. We investigated impact of a NE expression signature in the clinical outcome of mCRPC patients treated with taxanes. Methods: This is a multicenter retrospective study. A customized panel of 45 NE-related gene signature was tested in total RNA from formalin-fixed paraffin-embedded hormone-sensitive tumor samples, by the nCounter platform (Nanostring Technologies). Patients were grouped according to their molecular profile by unsupervised clustering. Expression levels were correlated with taxanes response and clinical outcome. Independent association with survival was evaluated by multivariate Cox modeling. Results: Eighty seven patients were included in the study, 79 were treated with docetaxel and 8 with cabazitaxel. Median age was 64.8 (44-88.3) years and median follow-up was 20.7 (1.17-74.4) months. High expression of the NE signature was associated with a shorter time of CRPC development (N=60, median 12.8 vs 21.6, HR 2.4, 95%CI 1.3-4.3, P=0.003) and shorter OS from CRPC diagnosis (median 24.1 vs 41.33, HR 2.3, 95%CI 1.4-3.8, P=0.001). Moreover, according to the outcome to taxanes, high NE signature correlated with lower PSA-PFS (median 6.6 vs 10.1 mo P=0.047, HR 1.6, 95%CI 1-2.7, P=0.05) and OS (median 19 vs 22 mo, HR 1.8, 95%CI 1.1-2.8, P=0.014), and it was independently associated to a lower OS (HR 1.9, 95%CI 1.1-3.2, P=0.016). Conclusions: NE-related gene expression in hormone-sensitive tumor samples is associated with adverse clinical outcome and lower taxane benefit in metastatic CRPC patients. Thus, molecular characterization of primary tumors may be useful to guide treatment strategies in metastatic prostate cancer.
Genomic alterations in visceral versus nonvisceral “metastatic” site tumor tissue in metastatic prostate cancer (mPC).
Authors: Esther John , Swami Umang , Chipman Jonathan , McFarland Taylor Ryan , Hahn Andrew W , Sirohi Deepika , Sharma Prayushi , Nussenzveig Roberto , Agarwal Neeraj , Maughan Benjamin Louis
Published: February 2020

167

Background: Men with mPC with visceral metastasis, as compared to non-visceral disease have inferior outcomes regardless of therapy (PMID: 25403629). Herein, we hypothesize that visceral versus non-visceral metastasis sites differ with regards to underlying genomic alterations (GA). These GA possibly drive metastasis to visceral sites and mediate a more aggressive disease. Identifying these GA may guide future trial designs by better stratifying patients and predicting therapy responses. Methods: In this retrospective analysis, inclusion criteria were: diagnosis of mPC and comprehensive genomic profiling of metastatic tissue by CLIA certified lab. Liver and lung were defined as visceral while bone and lymph nodes were defined as non-visceral metastasis. Evaluated GA were p53, RB1, PTEN, AR, TMB, CDK12, SPOP, MYC, MET, BRCA genes, BRAF, ARID1A. Fisher’s Exact Test was used to compare GA in visceral and non-visceral tumor tissue. Results: Overall 54 men with mPC with visceral (n=8) and non-visceral (n=46) metastatic tissue biopsies were evaluated. Visceral biopsies included liver (3) and lung (5). Non-visceral biopsy sites included lymph nodes (33) and bone (13). Men with or without visceral metastasis had similar baseline characteristics (Fisher’s Exact Test and Wilcoxon Rank Test; Table). Visceral tumor tissue had a significantly greater odds of having RB1 mutation [OR = 12.09; 95% CI = (1.12, 178.21); p-value 0.02] as compared to non-visceral tumor tissue. Conclusions: RB1 GA were more common in visceral as compared to non-visceral metastatic sites in mPC. RB1 loss is associated with ineffectiveness to CDK4/6 inhibitors (PMID 26633733). These hypothesis-generating data suggest that men with mPC with visceral metastasis may not optimally benefit by enrollment on CDK4/6 inhibitor trials. BLM, NA: equal contribution.[Table: see text]
Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.
Authors: Dong Baijun , Fan Liancheng , Yang Bin , Chen Wei , Li Yonghong , Wu Kaijie , Zhang Fengbo , Li Lei , Yao Xudong , Xue Wei
Published: February 2020

173

Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA(ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level(CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of PARPi. However, these patients seemed to benefit from chemotherapy, espeacially platnium-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.
Distinctive landscape of genetic mutation in patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Zhao Jinge , Sun Guangxi , Zhu Sha , Dai Jindong , Zhang Mengni , Chen Junru , Zhang Xingming , Zhu Xudong , Zhang Haoran , Wang Zhipeng , Ni Yuchao , Zhao Xiaochen , Shen Pengfei , Chen Ni , Zeng Hao
Published: February 2020

192

Background: Intraductal carcinoma of the prostate (IDC-P) is an independent predictor associated with poor prognosis in men with prostate cancer (PCa) of different stages. Yet, little is known concerning the characteristics of IDC-P at genetic level. The object of this study is to determine the mutation characteristics of patients with IDC-P, aiming at identifying new therapeutic targets for the treatment of IDC-P. Methods: Totally, data of 104 and 35 patients histopathological documented with prostatic adenocarcinoma concomitant with and without IDC-P were included into the current study, respectively. cfDNA was extracted from blood samples for the PCa-related mutation testing through a 90-gene NGS panel. The mutation frequency of different genes was compared between IDC-P positive and negative cases. Results: Almost all the pathogenetic germline mutations were detected from patients with IDC-P [15/104 (14.4%) vs. 1/35 (2.9%), p=0.064]. Pathogenetic germline BRCA2 mutations were all found in IDC-P positive patients [10/104 (9.6%) vs.0/35 (0.0%), p=0.057]. Besides, in terms of somatic mutations, men with IDC-P had significantly higher proportion of mutations in EGFR [30/104 (28.9%) vs. 2/35 (5.7%), p=0.005], KMT2C [20/104 (19.2%) vs. 1/35 (2.9%), p=0.019] and NCOR2 [19/104 (18.3%) vs. 0/35 (0.0%), p=0.006]. Three high frequently mutated sites of EGFR were identified in men with IDC-P, i.e. p.L861Q (12/104, 11.5%), p.L858R (11/104, 10.6%) and p.G719A/C (12/104, 11.5%). These mutated sites have been proved to be associated with therapeutic response from EGFR tyrosine kinase inhibitors (TKIs) in the treatment of lung carcinoma. Conclusions: Patients with IDC-P are candidates for germline and somatic mutations testing for the high frequency of mutations. Germline DDRs and somatic EGFR mutations were frequently occurred in IDC-P positive patients. Though further verification is needed, these mutations had great potential to be used as therapeutic targets in treating patients with IDC-P.
Mismatch repair deficiency in metastatic prostate cancer (PC): Response to PD-1 blockade and standard therapies.
Authors: Graham Laura , Montgomery Robert B. , Cheng Heather H. , Yu Evan Y. , Alva Ajjai Shivaram , Schweizer Michael Thomas
Published: February 2020

194

Background: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant PC (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct, yet clinically relevant subgroup’s natural history and response to treatment. Methods: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic PC. Clinical and pathologic characteristics at time of diagnosis and response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. Results: 28 men with MMRd and/or MSI-high metastatic PC were identified. 14 (50%) men had M1 disease at diagnosis and 19 (76%) of 25 men that underwent prostate biopsy had a Gleason score (GS) ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.7-NR mos) after median follow up of 43.6 mos (95% CI: 25.8-65.2 mos). PSA responses to standard therapies were similar to historic controls (Table). 17 patients received pembrolizumab and 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who had a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression. Conclusions: MMRd PC is associated with high GS and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high.[Table: see text]
Multiparametric magnetic resonance imaging of multifocal prostate cancer to reveal intra-prostatic genomic heterogeneity and novel radio-genomic correlates: Results of the Smarter Prostate Interventions and Therapeutics (SPIRIT) study.
Authors: Bauman Glenn , Correa Rohann , Aref-Eshghi Erfan , Alfano Ryan , Sadikovic Bekim , Bartlett John , Boutros Paul Christopher , Pautler Stephen E. , Chin Joseph , Gaed Mena , Kassam Zahra , Lemus Jose Gomez , Moussa Madeleine , Ward Aaron
Published: February 2020

20

Background: Multi-focality and heterogeneity in prostate cancer can confound the selection of appropriate clinical management. Our study aimed to explore radio-genomic correlations using multiparametric magnetic resonance imaging (mpMRI) against a histopathologic reference standard. Methods: Eight men with prostate cancer who underwent mpMRI followed by prostatectomy were selected for this pilot. Whole-mount histopathology was digitized and co-registered to corresponding MRI slices using a validated high-fidelity methodology.(1) Foci, including central/transitional and peripheral zone lesions were identified by a pathologist, and contoured on digitized histopathology specimens and these digitized maps were used to guide macrodissection of the individual foci for genomic copy-number aberration (CNA) analysis. Correlation of radiomics signatures with the histologic findings and genomic analysis was performed. Results: We found a broad range of CNAs revealing inter-patient and intra-prostatic heterogeneity. Recurrently-altered loci ( e.g., 8p21) containing genes of known significance ( e.g., NKX3-1) were observed. Only radiomic features derived from apparent diffusion coefficient (ADC) independently correlated with both Gleason grade (Rho=-0.62, p=0.003) and median CNA burden (Rho=-0.68, p<0.001). While greater CNA burden expectedly correlated with higher grade, intermediate-grade (Gleason score 3+4 or 4+3) lesions appeared more like either high-grade (Gleason scores ≥4+4) or low-grade (Gleason score 3+3) disease when clustered based on CNA and ADC metrics. Conclusions: These findings suggest ADC derived radiomic metrics may be a useful imaging biomarker across both central and peripheral zone lesion and could aid in further characterization of intra-prostatic biologic heterogeneity. These proof-of-principle data reveal novel radio-genomic correlations that could supplement histologic grading and conventional imaging, thus warranting expanded study and validation. 1) Int J Rad Oncol Biol Phys. 2016; 96(1):188-96.
Elevated circulating CCL2 in prostate cancer patients.
Authors: Lin Justin , Caress Amanda , Ahmed Farzana , Taylor Nicole , Gong Yixuan , Oh William K.
Published: February 2020

201

Background: Monocyte chemoattractant protein 1 (CCL2 or MCP-1), a chemokine secreted by monocytic cells, is critical in recruiting Treg and MDSCs into the tumor microenvironment and in regulating prostate cancer (PCa) migration and proliferation. In this study, we examined circulating CCL2 levels in healthy vs PCa patients and used an in vitro coculture model to identify the source of the elevated CCL2. Methods: Serum CCL2 concentrations were evaluated via ELISA in 59 patients (19 health controls, 20 “treatment naïve” PCa, 20 mCRPC). Monocytic leukemia cells (U937) were either directly cocultured with PC3 PCa cell line or cultured in the PC3 conditioned medium (CM). The induction of CCL2 mRNA in the cultures was examined by qPCR. The secretion of CCL2 into cell culture supernatants was evaluated via human cytokine array. Neutralizing antibodies to several overexpressed inflammatory cytokines in PC3 cells were added into the PC3 CM to evaluate the contribution of these inflammatory cytokines to CCL2 induction. Results: Circulating CCL2 concentrations were significantly higher in prostate cancer patient serum compared to control patient serum (p=4.4e-6) (Table). To understand the potential source of elevated CCL2, we grew U937 and PC3 in coculture and evaluated with qPCR, revealing that while CCL2 was not expressed in PC3 cells, it was expressed at very low levels in U937 cells. Interestingly, coculture of PC3 with U937 increased CCL2 mRNA expression by over 10-fold, and the result was confirmed at protein levels by human cytokine array. Our results also indicated that IL-6 and GM-SCF were the two major cytokines released by PCa cells to induce CCL2 mRNA in U937 cells and MEK and JAK-STAT signaling were crucial for CCL2 induction. Conclusions: Prostate cancer cells induce CCL2 secretion from monocytes in an IL-6 and GM-CSF dependent manner. Given the critical role of CCL2 in mediating immunosuppressive tumor microenvironments, our study highlighted the CCL2 Concentrations in PCa vs Healthy Serum.[Table: see text]
The impact of time-to-castration resistance on survival in patients with metastatic hormone-naïve prostate cancer: A multicenter retrospective study.
Authors: Okamoto Teppei , Hatakeyama Shingo , Takahashi Masahiro , Narita Shintaro , Ishida Masanori , Hoshi Senji , Kawamura Sadafumi , Ishidoya Shigeto , Shimoda Jiro , Kawaguchi Toshiaki , Tochigi Tatsuo , Mitsuzuka Koji , Tsuchiya Norihiko , Arai Yoichi , Habuchi Tomonori , Ohyama Chikara
Published: February 2020

213

Background: To evaluate the prognostic impact of time to castration resistance (TCR) in patients with metastatic hormone-naïve prostate cancer (mHNPC). Methods: We retrospectively evaluated 283 mHNPC patients with metastatic castration-resistant prostate cancer (mCRPC) who were initially treated with androgen deprivation therapy as metastatic hormone-naïve prostate cancer in 14 hospitals between September 2008 and October 2018. Overall survival (OS) and OS after castration resistance (OS-CR) were compared between the <12 months (TCR <12M) and ≥12 months (TCR ≥12M). The association between the first-line life-prolonging therapy (docetaxel or new androgen receptor-targeted agents: ART) and TCR on OS-CR was investigated using multivariate Cox regression analysis via inverse probability of treatment weighting (IPTW) model. Results: Median age and time to CRPC were 72 years and 12 months, respectively. The number of patients in the TCR<12M and ≥12M groups were 137 and 146, respectively. Of 283, baseline parameters such as age, extent of disease (EOD), hemoglobin (Hgb), lactate dehydrogenase (LDH), and serum albumin levels were significantly differences in between the groups. We observed significantly poor OS and OS-CR in the TCR <12M group than those in the TCR ≥12M group. First-line docetaxel therapy did not significantly improved OS-CR regardless of TCR. Background (age, ECOG PS, GS, Hgb, tumor volume, serum data, and TCR)-adjusted multivariate Cox regression analyses showed that first-line docetaxel therapy was significantly associated with shorter OS-CR than first-line ART therapy in the TCR <12M group. Conclusions: The prognostic impact of TCR on OS was significant. However, the association between the first-line life-prolonging therapy and TCR on OS need further study.
Efficacy of sequential therapy comprising of docetaxel, abiraterone, enzalutamide, and cabazitaxel in patients with castration-resistant prostate cancer.
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu , Naito Yushi , Hattori Kyosuke , Tochigi Kosuke , Yuba Takuma , Kawanishi Hideji
Published: February 2020

239

Background: The sequence of use of life-prolonging therapy (docetaxel, abiraterone, enzalutamide, and cabazitaxel) is unclear in patients with castration-resistant prostate cancer (CRPC). Methods: We retrospectively identified a total of 316 patients diagnosed with CRPC from September 2003 to April 2019 at Nagoya University and its affiliated hospitals. All patients were treated with >2 life-prolonging therapies. We divided these patients into four groups based on the sequence of drug administration. The group of patients who were treated using the sequence of abiraterone to enzalutamide or enzalutamide to abiraterone was termed as AA. The group treated using the sequence of abiraterone or enzalutamide to docetaxel was termed as AD. The group treated using the sequence of docetaxel to abiraterone or enzalutamide was termed as DA. Lastly, the group treated using the sequence of docetaxel to cabazitaxel was termed as DC. We investigated the overall survival (OS) from the time of diagnosis of CRPC. In addition, we estimated combined progression-free survival (combined PFS) defined as the sum of the PFS of each agent. Results: The number of patients in AA, AD, DA, and DC was 106, 69, 130, and 11, respectively. Regarding AA, AD, DA, and DC, the median ages were 72, 70, 68, and 64 years, respectively. The proportion of patients who had de novo distant metastasis was 66%, 65%, 58%, and 73% in AA, AD, DA, and DC, respectively. Further, the median OS was 68.7, 54.5, 68.6, and 22.0 months for AA, AD, DA, and DC, respectively. Notably, no significant differences related to OS were observed between AA and AD ( p = 0.06), AA and DA ( p = 0.24), as well as AD and DA ( p = 0.46). The median combined PFS was 8.6, 10.1, 13.9, and 5.6 months for AA, AD, DA, and DC, respectively. In terms of combined PFS, a significant difference was observed between AA and DA ( p < 0.001) as well as AD and DA ( p = 0.003). OS and combined PFS were significantly poor in DC compared with those in the other groups. Conclusions: No significant differences related to OS were observed regarding the sequence of use of docetaxel, abiraterone, and enzalutamide. Notably, combined PFS was comparatively better in DA than in any other group.
Non-prostate cancer malignancies detected by 18F-Fluciclovine PET/CT.
Authors: Barsky Andrew R. , Ahn Grace S. , Pantel Austin A. , Vapiwala Neha
Published: February 2020

28

Background: Novel imaging modalities such as 18F-fluciclovine PET/CT provide additional sensitivity over conventional imaging modalities in the workup of recurrent prostate cancer (PC). The range of published sensitivity and specificity values for 18F-fluciclovine is broad, however, and NCCN guidelines note the scan’s high false-positive rate. Prior case reports have described incidental detection of non-PC using this modality, including melanoma, oropharyngeal, pancreatic, penile, liver, and breast cancers. Herein, we surveyed our institutional 18F-fluciclovine PET/CT results to assess the rate and histologies of incidentally-detected non-PC. Methods: We retrospectively identified consecutive men with PC who underwent 18F-fluciclovine PET/CT as part of their disease workup. After identifying studies with unequivocal PET-avidity, we assessed for subsequent tissue sampling and/or imaging to confirm a non-PC malignancy. We report these patients’ clinicopathologic data. Results: Three-hundred thirty-six men underwent 18F-fluciclovine PET/CT for PC at our institution between 6/2017-7/2019. Seven (2%) were found to have non-PC malignancies. The diagnoses were: meningioma (n=3, 43%), non-small cell lung cancer (NSCLC) (n=2, 29%), gastric adenocarcinoma (n=1, 14%), and pancreatic neuroendocrine tumor (n=1, 14%). One of the patients with meningioma underwent resection as a result, while the other two were surveilled by MRI. Both cases of NSCLC were biopsied and resected. Tissue sampling was not performed in the gastric or pancreatic cases, as these patients were already known to have these malignancies. Conclusions: In this large institutional series, we found a low rate (2%) yet broad range of non-PC malignancies incidentally detected by 18F-fluciclovine PET/CT performed for PC, including diagnoses not previously reported in the literature. Such detection allowed patients to receive definitive management or appropriate surveillance for the non-PC malignancies. These findings underscore the importance of clinical and/or pathological correlation of positive scan results.
Integrating comprehensive genomic profiling into the clinical management of prostate cancer patients: A single institution community practice experience.
Authors: Shore Neal D. , Haberberger James , Severson Eric Allan , Alexander Brian Michael , Sathyan Pratheesh , Reddy Prasanth , Ramkissoon Shakti H.
Published: February 2020

281

Background: Prostate cancer is a leading cause of cancer-related mortality with a 5-year survival rate of 69%. In this study, we examine the role of integrating CGP, including tissue and liquid biopsy testing, into the clinical management of prostate cancer patients. Methods: We analyzed 140 cases of advanced prostate carcinoma with tissue and ctDNA based Comprehensive Genomic Profiling (CGP). CGP analysis revealed genomic alterations (GAs), TMB and MSI status. Germline testing, using multiple commercially assays was also obtained. Results: The median age of patients tested by tissue-based and liquid-based CGP was 65 years (46 to 85 yrs) and 69 years (51 to > 89 years), respectively. CGP analysis of tissue samples revealed the most commonly altered genes to be TP53 (34.6%), TMPRSS2- ERG (25.9%), PTEN (23.5%), NBN (14.8%), MYC (13.6%), BRCA2 (14.3%) and CDKN2A (13.3%). TMB analysis determined in 77 tissue samples showed a median (mean) value of 2.61 (5.00) mutations/Mb. 3.9% cases (3/77) were found to be hypermutated. MSI status was determined in 74 cases of which 2.7% (2/74) were found to be MSI-High. Of the tissue-based samples tested, 30.9% (25/81) were derived from metastatic sites. Analysis of commonly altered genes between primary vs metastatic tissue samples revealed TP53 mutations were significantly enriched in metastatic tumors. CGP analysis of the 59 liquid biopsy samples revealed the most commonly altered genes to be TP53 (37.3%), NF1 (10.2%), ATM (10.2%), CHEK2 (8.5%) and GNAS (8.5%). Germline testing was performed as described above on a clinically indicated subset of patients, which revealed alterations in BRCA, ATM, CHEK2, BRIP1 and TP53, among others. We are evaluating additional patient samples as part of the data set, which will be added to the final abstract presentation with a cutoff date of 12-31-2019. Conclusions: Genomic testing for high risk and advanced prostate cancer patients per the NCCN recommendations, with somatic testing, using tissue and liquid biopsy testing, as well as germline testing in selected cases, identifies DNA alterations which have potential clinical utility for clinical trial enrollment.
GLUT1 expression in high-risk prostate cancer: Correlation with 18F-FDG-PET/CT and clinical outcome.
Authors: Pouliot Frederic , Meizou Salma , Ringuette Goulet Cassandra , Hovington Helene , Lefebvre Veronique , Lavallée Etienne , Bergeron Michelle , Brisson Hervé , Champagne Audrey , Neveu Bertrand , Lacombe Didier , Beauregard Jean-Mathieu , Buteau François-Alexandre , Riopel Julie
Published: February 2020

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Background: Tumour FDG-uptake is of prognostic value in high-risk and metastatic prostate cancer (PCa). The aim of this study is to investigate the underlying glucose metabolism mechanisms of 18F-FDG-uptake on PET/CT imaging in PCa. Methods: Retrospective analysis was conducted for 94 patients diagnosed with a Gleason sum ≥8 at biopsy who underwent 18F-FDG-PET/CT imaging before radical prostatectomy. GLUT1, GLUT12 and HK2 expression were blindly scored after immunohistochemistry on radical prostatectomy specimens by 3 pathologists. 18F-FDG-uptake in primary lesion was measured by a blinded reader using maximum standardized uptake value (SUVmax). Correlations between GLUT1, GLUT12 and HK2 and SUVmax were assessed using Spearman’s rank correlation test. Survival probabilities were based on the Kaplan-Meier method. Results: With a median follow-up of 4.5 years, 56% (n=53) of patients had biochemical recurrence, 7% (n=7) progressed to castration-resistant PCa (CRPC) disease, 13% (n=12) developed metastasis and 6% (n=6) died. Correlation was found between GLUT1 expression and SUVmax level (r=0.2512, p=0.0182). In addition, SUVmax was significantly higher in tumours with high GLUT1 expression (n=17, 5.74±1.67) than tumours with low GLUT1 expression (n=71, 2.68±0.31, P=0.0037). Also, contrary to GLUT12 and HEX2 expression, a significant association was found between GLUT-1 expression levels and SUVmax index (p=0.004), lymph node status (p=0.046), volume of cancer (P=0.013), CRPC-free survival (p=0.02) and metastasis-free survival (p=0.04). Conclusions: GLUT1 expression in PCa tumours correlates with 18F-FDG-uptake and poor prognostic factors. These results suggest that this transporter is involved in the molecular mechanism of 18F-FDG-uptake in high-risk PCa and raise interest in targeting metabolic dependencies of PCa cells as a selective anticancer strategy.