bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus
Authors: Wang Xue-bin , Cui Ning-hua , Liu Xia’nan , Liu Xin
Published: February 2020

Background

Little is known about whether mitochondria 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM).

Methods

In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs).

Results

Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24–1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19–1.41; modified Gensini scores: OR 1.28, 95% CI 1.18–1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06–0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (Pinteration < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33–1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function.

Conclusion

Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.
Identification of molecular markers associated with the progression and prognosis of endometrial cancer: a bioinformatic study
Authors: Liu JinHui , Feng Mingming , Li SiYue , Nie Sipei , Wang Hui , Wu Shan , Qiu Jiangnan , Zhang Jie , Cheng WenJun
Published: February 2020

Background

Endometrial cancer (EC) is one kind of women cancers. Bioinformatic technology could screen out relative genes which made targeted therapy becoming conventionalized.

Methods

GSE17025 were downloaded from GEO. The genomic data and clinical data were obtained from TCGA. R software and bioconductor packages were used to identify the DEGs. Clusterprofiler was used for functional analysis. STRING was used to assess PPI information and plug-in MCODE to screen hub modules in Cytoscape. The selected genes were coped with functional analysis. CMap could find EC-related drugs that might have potential effect. Univariate and multivariate Cox proportional hazards regression analyses were performed to predict the risk of each patient. Kaplan–Meier curve analysis could compare the survival time. ROC curve analysis was performed to predict value of the genes. Mutation and survival analysis in TCGA database and UALCAN validation were completed. Immunohistochemistry staining from Human Protein Atlas database. GSEA, ROC curve analysis, Oncomine and qRT-PCR were also performed.

Results

Functional analysis showed that the upregulated DEGs were strikingly enriched in chemokine activity, and the down-regulated DEGs in glycosaminoglycan binding. PPI network suggested that NCAPG was the most relevant protein. CMap identified 10 small molecules as possible drugs to treat EC. Cox analysis showed that BCHE, MAL and ASPM were correlated with EC prognosis. TCGA dataset analysis showed significantly mutated BHCE positively related to EC prognosis. MAL and ASPM were further validated in UALCAN. All the results demonstrated that the two genes might promote EC progression. The profile of ASPM was confirmed by the results from immunohistochemistry. ROC curve demonstrated that the mRNA levels of two genes exhibited difference between normal and tumor tissues, indicating their diagnostic efficiency. qRT-PCR results supported the above results. Oncomine results showed that DNA copy number variation of MAL was significantly higher in different EC subtypes than in healthy tissues. GSEA suggested that the two genes played crucial roles in cell cycle.

Conclusion

BCHE, MAL and ASPM are tumor-related genes and can be used as potential biomarkers in EC treatment.
Prediction and identification of novel HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from endocan
Authors: Shao Gaohai , Liu Qingjun , Yang Ling , Feng Guibo , Zhao Wang , Huang Zhongyan , Yang Zhao
Published: February 2020

Background

Prediction and identification of cytotoxic T lymphocyte (CTL) epitopes from tumor associated antigens is a crucial step for the development of tumor immunotherapy strategy. Endocan has been identified as antigen overexpressed in various tumors.

Methods

In this experiment, we predicted and identified HLA-A2-restricted CTL epitopes from endocan by using the following procedures. Firstly, we predicted the epitopes from the amino acid sequence of endocan by computer-based methods; Secondly, we determined the affinity of the predicted peptide with HLA-A2.1 molecule by peptide-binding assay; Thirdly, we elicited the primary T cell response against the predicted peptides in vitro; Lastly, we tested the specific CTLs toward endocan and HLA-A2.1 positive target cells.

Results

These data demonstrated that peptides of endocan containing residues 4–12 and 9–17 could elicit specific CTLs producing interferon-γ and cytotoxicity.

Conclusions

Therefore, our findings suggested that the predicted peptides were novel HLA-A2.1-restricted CTL epitopes, and might provide promising target for tumor immunotherapy.
Correction to: Mobility related physical and functional losses due to aging and disease - a motivation for lower limb exoskeletons
Authors: Grimmer Martin , Riener Robert , Walsh Conor James , Seyfarth Andre
Published: February 2020

The original article contains an error in Fig 3f whereby data is erroneously extrapolated beyond 80 years of age; this also affects statements made elsewhere in the article.
Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort
Authors: Le Cornet Charlotte , Walter Britta , Sookthai Disorn , Johnson Theron S. , Kühn Tilman , Herpel Ester , Kaaks Rudolf , Fortner Renée T.
Published: February 2020

Background

Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7-alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERβ) may impact the association between 27HC and breast cancer risk.

Methods

We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography–mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results

A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1-negative cases, whereas a higher proportion of ERβ-positive cases were Bcl-2 low, relative to ERβ-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ, with the exception of statistically significant heterogeneity by LXR-β status in the subgroup of women perimenopausal at blood collection (p = 0.02).

Conclusion

This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-β, or ERβ.
The effectiveness of additional thoracic paravertebral block in improving the anesthetic effects of regional anesthesia for proximal humeral fracture surgery in elderly patients: study protocol for a randomized controlled trial
Authors: Wang Xiaofeng , Zhang Hui , Xie Zhenwei , Zhang Qingfu , Jiang Wei , Zhang Junfeng
Published: February 2020

Background

The innervation of the shoulder-upper-extremity area is complicated and unclear. Regional anesthesia with a brachial plexus and cervical plexus block is probably inadequate for the proximal humeral surgery. Missing blockade of the T1–T2 nerves may be the reason. We conduct this prospective randomized controlled trial (RCT) to explore whether an additional T2 thoracic paravertebral block (TPVB) can improve the success rate of regional anesthesia for elderly patients in proximal humeral fracture surgery.

Methods/design

The patients aged 65 years or older, referred for anterior-approach proximal humeral fracture surgery, will be enrolled. Each patient will be randomly assigned 1:1 to receive a combined interscalene brachial plexus with superficial cervical plexus block (IC) (combined interscalene brachial plexus with superficial cervical plexus block) or an IC block combined with thoracic paravertebral block (ICTP) block (combined thoracic paravertebral block with brachial plexus and superficial cervical plexus block). The primary outcome is the success rate of regional anesthesia without rescue analgesic methods. The secondary outcomes are as follows: sensory block at the surgical area, proportion of patients who need rescue anesthesia (intravenously administered remifentanil or conversion to general anesthesia), cumulative doses of intraoperative vasoactive medications and adverse events. The total sample size is estimated to be 80 patients.

Discussion

This RCT aims to confirm whether an additional T2 TPVB can provide better anesthetic effects of regional anesthesia with brachial and cervical plexus block in elderly patients undergoing proximal humeral surgery.

Trial registration

ClinicalTrials.gov, ID: NCT03919422. Registered on 19 April 2019.
Geographic and Ethnic Heterogeneity of Germline BRCA1 or BRCA2 Mutation Prevalence Among Patients With Metastatic Pancreatic Cancer Screened for Entry Into the POLO Trial
Authors: Golan Talia , Kindler Hedy L. , Park Joon Oh , Reni Michele , Macarulla Teresa , Hammel Pascal , Van Cutsem Eric , Arnold Dirk , Hochhauser Daniel , McGuinness David , Locker Gershon Y. , Goranova Teodora , Schatz Philipp , Liu Yu-Zhen , Hall Michael J.
Published: February 2020

PURPOSE

Germline BRCA1 and/or BRCA2 mutations (gBRCAms) are risk factors for pancreatic cancer. The extent to which demographic and geographic factors affect the uptake of gBRCAm testing in pancreatic cancer (PC) is unknown.

METHODS

We conducted a retrospective, descriptive analysis of demographic/geographic data from the first 2,206 patients with metastatic PC (mPC) screened for eligibility to enter the phase III POLO trial of maintenance olaparib. No formal statistical tests were performed.

RESULTS

Of 2,167 patients with previously unknown gBRCAm status, 128 (5.9%) had a newly identified gBRCAm; rates were highest in the United States, France, and Israel (9.5%, 7.6%, and 7.4%, respectively). When including patients with a previously known gBRCAm, prevalence rose to 7.2% (or 5.8% after excluding populations enriched in Ashkenazi Jews, who are known to have a high rate of BRCA1 and BRCA2 founder mutations). Patients with a gBRCAm were slightly younger (57.9 v 61.1 years) and more likely to have early-onset mPC than those without. Higher newly identified gBRCAm prevalence was observed among African American (n = 28) versus white (n = 1,808), Asian (n = 218), and other (n = 61) patients (10.7% v 6.1%, 5.0%, and 1.6%, respectively). Of 139 white patients with a gBRCAm, 110 were newly identified during screening; the majority of gBRCAms in African American, Asian, and Hispanic patients (n = 3, n = 11, and n = 5, respectively) were newly identified.

CONCLUSION

We identified substantial geographic and some racial variability in gBRCAm prevalence among patients with mPC, an important consideration given the increased use of familial screening and possible future use of targeted therapies in this setting. Although our study included small numbers of nonwhite patients, prior knowledge of their gBRCAm status was limited compared with their white counterparts, which suggests disparities in genetic testing uptake.
The association of humoral antigen spread (AgS) with cytotoxic T lymphocyte (CTL) activity after sipuleucel-T (sip-T) treatment in two phase II clinical studies: STAMP and STRIDE.
Authors: Petrylak Daniel Peter , Antonarakis Emmanuel S. , Kandadi Harini , Fong Lawrence , Lance Raymond S. , Vu Tuyen , Sheikh Nadeem Anwar , Shore Neal D. , Drake Charles G.
Published: February 2020

112

Background: Sip-T is an FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. Sip-T generates CTL and humoral antigen activity, as measured by CD107a expression on PAP or PA2024 specific CD8+ T cells. These specific CTL activities were correlated with improved overall survival in several studies STAMP (NCT01487863) and STRIDE (NCT01981122) [1]. We examined whether CTL activity enables humoral response generation, hypothesizing that killing a target cell with immunotherapy releases antigens that generate a secondary antibody response, extending the effect. Methods: Using samples from patients who received sip-T in these studies, correlation between CTL activity and AgS responses to primary (PA2024, PAP) and secondary (PSA, LGALS3, LGALS8, KRAS, ERAS, KLK2) antibodies over time was assessed. Using R statistics software, a Wilcoxon signed rank test assessed differences across time (Wk, week: WK0, week 0, etc) and Spearman rank test for correlation between CTL activity and AgS responses. Results: In STAMP, PAP-specific CTL activity at WK0 was positively correlated with LGALS3 antibody responses at WK6, WK10, WK14 and WK26; likewise, PAP-specific CTL activity at WK6 was positively correlated with antibody response to PAP at WK0 (P = 0.035). In STRIDE, PAP-specific CTL activities at WK0 and both PAP- and PA2024-specific CTL activities at WK6 were positively correlated with LGALS8 antibody response at WK52. Plus, PAP- and PA2024- specific CTL activities at WK6 had significant, positive correlation with PA2024 antibody responses at WK0. In both, PA2024-specific CTL activity at WK26 was positively correlated with number of secondary antigen responses at WK10 and WK14. Conclusions: In all, PA2024-specific CTL activity at WK6 was positively correlated with antibody response to primary antigens (PA2024 and PAP) and 4 secondary antigens – PSA, KRAS, ERAS and KLK2 at multiple time points. In summary, treatment with sip-T in mCRPC appears to invoke the tumor immunity cycle, wherein tumor cell death releases compounds that act as secondary epitopes resulting in antigen spread. [1] DOI: 10.1158/1078-0432.CCR-18-0638. Clinical trial information: NCT01487863.
Dose-escalation results of a phase I study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Osborne Joseph , Niaz Muhammad Junaid , Vallabhajosula Shankar , Vlachostergios Panagiotis J. , Thomas Charlene , Molina Ana M. , Sternberg Cora N. , Singh Sharon , Fernandez Escarleth , Babich John , Nanus David M. , Ballman Karla V. , Bander Neil Harrison
Published: February 2020

114

Background: Prostate-specific membrane antigen (PSMA) can be targeted by antibodies (Ab) or small molecule ligands labeled with potent α emitters (e.g. 225Ac). Unlike ligands, Ab biodistribution does not include non-tumor organs such as the salivary glands, kidneys and small bowel. We performed a phase I single ascending dose Ab study. Methods: Eligibility: progressive mCRPC following at least 1 potent AR pathway inhibitor (ARPI; e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function. Baseline 68Ga-PSMA11 PET was performed but not used for eligibility. Single-subject cohorts received a single infusion of 225Ac-J591 until grade (Gr) > 1 attributable toxicity or dose level 5, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to dose level 7 (93.3 KBq/kg). Dose-limiting toxicity (DLT) defined as attributable Gr 4 heme or Gr 3/4 non-heme toxicity. Results: 22 men were treated on 7 dose levels; median age 72.5 (range 58-89), PSA 146.5 (4.8-7168.4); 82% with >2 prior ARPI, 64% chemo, 45% sipuleucel-T, 23% radium-223, 55% prior 177Lu-PSMA. By standard imaging 82% bone, 36% lymph node, 9% liver mets. At the time of data cutoff, 1 of 6 men in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets); he had 4 prior cycles of 177Lu-PSMA. No other attributable Gr >2 non-hematologic or Gr >3 heme AE (including 0 of 6 at the highest dose level). Low Gr temporary AE’s include: 16 (73%) with fatigue, 11 (50%) pain, 11 (50%) nausea, 6 (27%) with xerostomia (5 of 6 with prior 177Lu-PSMA), 3 (14%) AST elevation. With follow-up ongoing, 60% with any PSA decline, 35% with >50% PSA decline. Of 10 with detectable baseline and 12-week CTC counts (CellSearch), 8 declined (45-100% decline); 5 (50%) with CTC count conversion. While PSMA uptake was not a prerequisite for treatment, all had some PSMA uptake on 68Ga-PSMA11 PET/CT; 64% with SUVmax >5x liver SUV, 14% 2.5x – 5x liver, and 23% with SUVmax 0-2.5x liver SUV. Conclusions: PSMA-targeted alpha-emitter 225Ac utilizing intact Ab J591 is well tolerated with early evidence of clinical activity in a pre-treated population, including the majority with prior 177Lu-PSMA. Clinical trial information: NCT03276572.
A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).
Authors: Tran Phuoc T. , Phillips Ryan , Shi William , Lim Su Jin , Antonarakis Emmanuel S. , Rowe Steven P. , Ross Ashley , Gorin Michael A. , Deville Curtiland , Greco Stephen C. , Paller Channing Judith , DeWeese Theodore L. , Song Daniel Y. , Wang Hao , Carducci Michael Anthony , Pienta Kenneth J. , Pomper Martin , Dicker Adam P. , Eisenberger Mario A. , Diehn Maximilian
Published: February 2020

116

Background: Mounting evidence supports metastatic ablation for oligometastatic prostate cancer (OMPC). Importantly, biomarkers to determine patients who benefit most from complete ablation are unknown. We hypothesize that stereotactic ablative radiation (SABR) will improve oncologic outcomes in men with OMPC. Methods: In this phase II randomized trial, men with recurrent hormone-sensitive OMPC (1-3 radiation fields) were stratified by primary management (radiotherapy vs surgery), PSA doubling time, and prior androgen deprivation therapy and randomized 2:1 to SABR or observation (OBS). The primary endpoint was progression at 6 months by PSA (≥ 25% increase and ≥ nadir + 2 ng/mL), conventional imaging (RECIST 1.1 criteria or new lesion on bone scan), or symptomatic decline. Tissue, liquid and imaging correlatives were analyzed as biomarkers. Results: From 5/2016-3/2018, 54 patients were randomized. Progression at six months occurred in 19% of SABR patients and 61% of observation patients [p=0.005]. SABR improved median PFS (not reached vs 5.8 months, HR 0.30, p = 0.0023). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at six months (16% vs 63%, p = 0.006). No toxicity ≥ grade 3 was observed. T-cell receptor sequencing identified increased clonotypic expansion (p = 0.03) following SABR and correlation between baseline clonality and progression with SABR only. Analysis of circulating tumor DNA (ctDNA) and germline mutations identified a mutation profile that was associated with benefit from SABR. Conclusions: SABR for OMPC improves outcomes and is enhanced by total consolidation of disease identified by PSMA-targeted PET. SABR induces a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Clinical trial information: NCT02680587.
The tumor immune microenvironment of germline BRCA1/2 and sporadic prostate cancer.
Authors: Trigos Anna S. , Pasam Anupama , Banks Patricia Diana , Wallace Roslyn , Keam Simon P. , Thorne Heather , Mitchell Catherine , Clouston David , Murphy Declan G. , Lawrentschuk Nathan , Bolton Damien M. , Moon Daniel , Castro Elena , Olmos David , Darcy Phillip K. , Haupt Ygal , Williams Scott , Goode David L. , Neeson Paul J. , Sandhu Shahneen Kaur ,   kConFab
Published: February 2020

152

Background: Prostate cancer (PC) is considered an immunologically ‘cold’ tumor and therefore patients are generally not considered good candidates for immunotherapy. Tumors arising in germline (g) BRCA1/2 mutation carriers are associated with higher genomic instability and levels of immune infiltration in breast and ovarian cancer. We investigated how germline mutations in DNA repair genes affect the tumor immune microenvironment (TME) of PC. Methods: Archival primary tumor samples from 26 patients with g BRCA2 mutations, 5 with g BRCA1, 5 with mutations in other DNA repair genes ( ATM, CHEK2, FANCI, PALB2 or BRCA2+ MSH2), and 26 sporadic patients were analyzed. OPAL multiplex immunohistochemistry was used to detect 7 markers (CD3, CD4, CD8, FOXP3, PDL1, AMACR, DAPI) to identify immune subsets and provide the X,Y coordinates of single cells. We developed novel computational distance-based methods to characterize the spatial distribution of cells. Gene expression was evaluated with the Nanostring panel of 770 immune genes. Results: g BRCA1/2 carriers showed lower levels of T cells (9.73% of the tumor stroma) compared to sporadic tumors (14.8%). In in both cothors the T cell population was dominated by CD4+ cells (69.5%), with CD8+ cells representing only 25.6%. Sporadic PCs displayed aggregation of T cells into large clusters in the stroma dominated by CD4+ cells and few CD8+ cells, while 77% of high-grade g BRCA2 patients were enriched in high levels of free, non-aggregated CD8+ T-cells in the tumor area. HLA-A expression was 2.37 times higher in g BRCA2 patients ( p = 3.4x10−8), who also showed higher expression of genes associated with a present but suppressed immune system ( p = 1.4x10−4). gBRCA2 patients with larger T-cell aggregates had an overall poorer prognosis compared to patients without (time to metastasis 55.1 vs. 85.3 months, survival time 67.3 vs. 85.0 months). Conclusions: g BRCA2 carriers displayed higher levels of HLA-A, more free CD8+ T cells infiltrating tumor regions and higher inflammatory signatures, suggesting an immune system that could potentially be harnessed. The degree of clustering of T cells (free vs. aggregated) within the TME may provide valuable prognostic information that warrants further validation.
Comprehensive genomic profiling (CGP) in post-systemic treatment (Post) metastatic sites (MET) and pretreatment (Pre) primary tumors (PT) of metastatic prostate cancer (mPC).
Authors: Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Chung Jon , Alexander Brian Michael , Reddy Prasanth , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S.
Published: February 2020

175

Background: CGP was performed on Pre PT and Post MET including bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) mPC. Methods: 1,294 mPC underwent hybrid-capture based CGP. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: GA in AR were lowest in the Pre PT (2%) and highest in Post LU (24%) and LIV (50%). GA/tumor was significantly higher in BN (8.0) compared to PT (3.8). BR MET also featured higher PTEN GA than PT. BRCA2 GA varied from 0% in BR to 7-9% in PT, BO, LU, LN and ST to a high of 15% in LI MET. ATM GA were significantly higher in LU MET and RAD21 GA highest in LN MET. Potential predictors of IO drug response included high CDK12 GA in LU MET, MSI high status at 29% in BR MET associated with higher TMB levels, but virtual absence of high PD-L1 expression. ERBB2 GA appeared to be increased in the MET group compared with PT but BRAF GA were not. RB1 GA were significantly increased in LIV MET cases. Conclusions: CGP of mPC PT and MET demonstrates significant differences likely linked to exposure to systemic therapies. These findings suggest that, in the future, liquid biopsies may have advantages over individual MET site biopsies in their ability to capture the entire range of therapeutic opportunities for patients with advanced mPC.[Table: see text]
Does screening for frailty with the vulnerable elders survey (VES-13) identify older adults with GU malignancy who benefit most from a consultation in a geriatric oncology clinic?
Authors: AlQurini Naser M. KH. M. S , Timilshina Narhari , Jin Rana , Loucks Allison , Berger Arielle , Romanovsky Lindy , Puts Martine , Alibhai Shabbir M.H.
Published: February 2020

209

Background: The VES-13 is a well-studied brief frailty screening tool for ≥ 65 older adults (OAs) in the oncology setting. Vulnerable patients (scoring ≥ 3) are at higher risk for adverse outcomes and will benefit from a Comprehensive Geriatric assessment (CGA) and cancer treatment decision optimization. Whether the VES-13 is effective specifically in patients with Genitourinary (GU) malignancies remains to be established. Primary objective: to determine if the VES-13 can predict which OAs with GU cancer (Bladder, Prostate, Kidney) had subsequent treatment modification after CGA. Secondary objective: to investigate if there is any association between VES-13 score with comorbidity and chemotherapy toxicity prediction tool (CARG). Methods: The VES-13 was administered to consecutive patients referred to the geriatric oncology (GO) clinic from GU site at the Princess Margaret Cancer Centre, Canada. All patients underwent CGA. CGA assess 8 domains including cognition, comorbidities, function, falls risk. Among patients referred for pre-treatment assessment, we examined whether the VES-13 predicted changes in the final treatment plan after CGA. Descriptive statistics were used to describe the VES-13 scores and final treatment impact. Results: From July 2015-October 2019, 77 were included in this analysis. The VES-13 ≥ 3 group were 52/77 (67.5%), and significantly associated with higher comorbidities (P = 0.003) and worse CARG scores (P = 0.005). The final treatment plan was modified in 36/77 (47%). In univariate analysis, the odds ratio (OR) for VES-13 ≥3 was 1.92 (95% CI 0.72-5.12) for change in final treatment, which was not statistically significant likely due to modest sample size. Interestingly in the same univariate analysis, there was a strong association between final treatment plan with falls risk (OR 2.63, 95% CI 1.03-6.72), physical performance (OR 2.51, 95% CI 0.98-6.45) and cognition (OR 3.95, 95% CI 1.19-13.19). Conclusions: The VES-13 identified vulnerable GU patients who will benefit from CGA and may predict treatment optimization by identifying patients at higher risk of chemotherapy toxicity and higher comorbidity.
Treatment decision making in metastatic prostate cancer (mPC).
Authors: Morgans Alicia K. , Fought Angela , Lee Benjamin , VanderWeele David James , Hussain Maha H. A. , Moses Kelvin A. , Penson David F.
Published: February 2020

224

Background: Multiple treatments exist for mPC, and optimal treatment choice is not defined. Shared decision making (SDM) in which physicians communicate treatment purpose, risks, and benefits, and patients (pts) communicate values/preferences can be used to determine treatment. SDM is associated with superior health outcomes in non-cancer populations, but whether it is used in mPC is unknown. We assessed mPC pt and caregiver perceptions of decision locus of control (DLOC) (SDM vs physician (PD) or pt (PtD) directed decisions), and characteristics associated with DLOC. Methods: Between 12/16 and 11/17, mPC patients and caregivers completed surveys of decision making practices after a clinical encounter in which a decision occurred. To evaluate the relationship between pt perception of DLOC type and categorical variables we used Fisher’s exact test, and Kruskal-Wallis was used to evaluate the relationship between DLOC and age. Results: 50 pt/caregivers participated, with median pt age of 72 yo. Most pts were Caucasian (96%), married (90%), and reported good health or better (18% excellent, 58% good, 24% fair). 66% of pts reported SDM, 10% reported PD only, 12% reported PD considering patient’s preferences, and 12% reported PtD considering physician’s recommendation. Caregivers reported numerically lower rates of SDM (56%), PD only (6%), and PD considering patient’s preferences (8%), but greater PtD considering physician’s recommendation (30%), (p=0.28). Neither reported PtD without considering physician recommendations. There was no association between pt DLCO and age (p=0.70) or clinician type, (p=0.13). All pts reporting PtD considering physician’s recommendation saw medical oncologists rather than urologists. Conclusions: Both pts and caregivers perceived a majority of decisions as SDM, indicating a high level of patient engagement in mPC decision making, and clinician type and patient age were not associated with pt reported DLOC. Pts seen by medical oncology in this cohort reported directing treatment choice when considering physician’s recommendation. Efforts to assess and support decision making in more diverse patient populations and explore the association between SDM, pt satisfaction and quality of life are underway.
Quality of life of prostate cancer (PCa) patients with testosterone deficiency symptoms (TDS) before initiation of gonadotropin-releasing hormone (GnRH) agonist therapy: Subgroup analysis of EQUINOXE study.
Authors: Droupy Stephane , Colson Marie-Helene , Pello Leprince Ringuet Nathalie , Perrot Valérie , Descazeaud Aurelien
Published: February 2020

232

Background: Both PCa and TDS risk increase with age. Patients may therefore suffer from both conditions, and their quality of life (QoL) be reduced. Unexpectedly, multivariate analysis of the EQUINOXE study (NCT02630641) identified baseline TDS as a significant factor improving QoL after 6 months of GnRH agonist therapy. We therefore aim to analyze baseline parameters of this subgroup. Methods: EQUINOXE was a French prospective, multicenter, non-interventional study. Urologists recruited partner-patient couples with PCa for whom androgen deprivation therapy (ADT) was indicated. Data were collected at inclusion and after 6 months of treatment, on QoL (WHOQOL-BREF), perception of disease (B-IPQ), symptoms of the disease (QLQ-PR25) and perception of cohesion within the patient-partner relationship (dyadic adjustment, DAS-16). TDSat baseline, determined by QLQ-PR25 “treatment related symptoms” score ≥25/100, was the main parameter identified by multivariate analysis in improvement of QoL (OR [95% CI]: 3.0 [1.46, 6.17]. Post hoc subgroup analysis was made to compare baseline parameters of patients with and without TDS. Results: 487 patients were included in this analysis, 26% of whom had TDS at baseline. Symptoms were (quite a bit or very much): feeling of less masculinity (55.2%), hot flushes (41%), weight gain (40.1%) and enlarged nipples (23.1%). Patients with TDS were slightly older than those without TDS (75.3±8.3vs 73.8±8y.o), had significantly worse performance Status (0-1-2+ in 37.0-45.7-17.3% vs 52.8-36.4-10.8%, p=0.0153) and suffered more frequently from recurrent PCa (35.7% vs 24.7%, p=0.0175). Symptoms other than urinary and sexual (but including asthenia) were more frequent (p=0.0126). All dimensions of WHOQOL-BREF were rated significantly worse. Total score of illness (B-IPQ) was worse: 42.2±8.2 vs39.1±9.4, p=0.0040. Cohesion in the couple (DAS score) was worse: 98.6±22.3 vs107.3±20.9, p=0.0006. Conclusions: Patients with TDS experienced at baseline a worse cohesion of the couple and a lower QoL than patients without TDS but benefited relatively more from ADT in term of QoL. Clinical trial information: NCT02630641.
A phase IIa randomized placebo-controlled trial of pomegranate fruit extract/POMx in subjects with clinically localized prostate cancer undergoing active surveillance.
Authors: Jarrard David Frazier , Filon Miko , Huang Wei , Kim KyungMann , Havighurst Tom , Konety Badrinath R. , Saltzstein Daniel , Mukhtar Hasan , House Margaret , Suen Chen S. , Parnes Howard L. , Bailey Howard Harry
Published: February 2020

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Background: Due to its high prevalence and often indolent natural history, prostate cancer(PC) active surveillance(AS) is an ideal setting for chemoprevention. Studies assessing pomegranate and its extracts have shown promising anti-proliferative and pro-apoptotic effects in cell lines and animal models and a single-arm clinical trial of pomegranate fruit extract(PFE) reported an increase in PSA doubling time(PSADT) during AS. The primary objective of this trial was to assess the effect of PFE supplementation on plasma levels of Insulin-like Growth Factor-1(IGF-1). Secondary objectives addressed PSA doubling time(PSADT), tumor volume on end-of-study(EOS) biopsy and plasma and prostate tissue biomarkers. Methods: Men with organ-confined favorable-risk PC on AS were randomly assigned to receive PFE 1,000 mg(n=15) or placebo(n=15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the one-year intervention. Tissue biomarkers were assessed by immunohistochemistry(IHC) with automated quantitation. Results: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the one-year intervention. No differences in plasma IGF-1 levels(p=0.5), PSADT, or tissue biomarkers of apoptosis or proliferation were observed. A significant increase in urolithin A(a urinary metabolite of pomegranate) was observed in the PFE arm. IHC analyses of both tumor (Table) and normal-appearing tissue adjacent to tumor showed reductions from baseline in IGF-1, 8-OHdG(DNA damage marker), and androgen receptor expression associated with PFE treatment. A trend towards a reduction in the maximum percent of biopsy core tumor involvement was observed(p=0.06) in PFE. Conclusions: PFE administration for 12-months was not associated with a decrease in plasma IGF-1 levels nor an increase in PSADT. However, exploratory analyses suggest that PFE may contain bioactive compounds capable of altering biomarkers in PC and normal-appearing adjacent tissue providing a rationale for further investigation of PFE in the active surveillance population.
A comparison of sipuleucel-T (sip-T) product parameters from two phase III studies: PROVENT in active surveillance prostate cancer and IMPACT in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Ross Ashley , Armstrong Andrew J. , Pieczonka Christopher M , Bailen James L. , Tutrone Ronald F. , Cooperberg Matthew R. , Pavlovich Christian P. , Renzulli Joseph F. , Haynes Heather , Sheikh Nadeem Anwar , Shore Neal D.
Published: February 2020

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Background: Sip-T is an FDA approved, autologous cellular immunotherapy for mCRPC, manufactured by activating peripheral blood mononuclear cells collected by apheresis and culturing them with PA2024 (PAP fused to human GM-CSF). Overall survival (OS) in mCRPC is positively correlated with key product parameters of sip-T: CD54 upregulation; CD54+ cell count; and total nucleated cell (TNC) count. Product parameters were amplified in men with earlier stage prostate cancer vs mCRPC, including increased T cell trafficking to the prostate (Fong L, JNCI 2014) and greater CD54 upregulation and larger immune responses (Antonarakis ES, Clin Can Res 2017). Methods: ProVENT (NCT03686683) will evaluate sip-T in men with Gleason grade 1/2 prostate adenocarcinoma receiving active surveillance (target, 450 men; randomized 2:1 to receiving sip-T or not). We evaluated apheresis and final key product parameters (CD54 upregulation; CD54+ cell count; and TNC count) for each infused product as well as cumulative values while also comparing with IMPACT (NCT00065442) study results. Results: This preliminary analysis describes data from the first 184 sip-T men in ProVENT. CD54 upregulation profiles were consistent between IMPACT and ProVent, peaking in week 2 products; however, values at each treatment week, and subsequently cumulative CD54 upregulation, were statistically significantly higher for ProVENT (P<0.001 per comparison; Table). The number of CD54+ cells was significantly greater at each treatment for both incoming apheresis as well as the final product, including cumulative values, in ProVENT compared to IMPACT (P<0.001 per comparison) as was TNC count (P<0.001 per comparison). Conclusions: This preliminary analysis of product parameters in ProVENT suggest sip-T potency is higher in pts undergoing active surveillance. Clinical trial information: NCT03686683. [Table: see text]
Stereotactic pelvic radiotherapy with HDR boost for dose escalation in intermediate and high-risk prostate cancer (SPARE): Efficacy, survival, and late toxicity outcomes.
Authors: Loblaw Andrew , Musunuru Bindu , Cheung Patrick , Vesprini Danny , Liu Stanley K. , Chu William , Chung Hans T. , Morton Gerard , Deabreu Andrea , Davidson Melanie , Ravi Ananth , Helou Joelle , Ho Ling , Zhang Liying
Published: February 2020

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Background: The ASCO/CCO guidelines recommend brachytherapy boost for all eligible intermediate- or high-risk localized prostate cancer patients. We present efficacy, survival and late toxicity outcomes in patients treated on a prospective, single institutional protocol of MRI dose painted HDR brachytherapy boost (HDR-BT) followed by pelvic stereotactic body radiotherapy (SBRT) and androgen deprivation therapy (ADT). Methods: A phase I/II study was performed where intermediate (IR) or high-risk (HR) prostate cancer patients received HDR-BT 15Gy x 1 to the prostate and up to 22.5Gy to the MRI nodule and followed by gantry-based SBRT 25Gy in 5 weekly fractions delivered to pelvis, seminal vesicles and prostate. ADT was used for 6-18 months. CTCAEv3 was used to assess toxicities and was captured q6months x 5 years. Biochemical failure (BF; nadir + 2 definition), nadir PSA, proportion of patients with PSA < 0.4 ng/ml at 4 years (4yPSARR), incidence of salvage therapy, cause specific survival and overall survival were calculated. Day 0 was HDR-BT date for all time-to-event analyses. Results: Thirty-two patients (NCCN 3% favorable IR, 47% unfavorable IR and 50% HR) completed the planned treatment with a median follow-up of 50 months; 31 of these had an MRI nodule. Four patients had BF with actuarial 4-year BF rate of 11.5%; 3 of these received salvage ADT. Median nPSA was 0.02 ng/ml; 4yPSARR was 68.8%. One patient died (of prostate cancer) at 45 months. For late toxicities, grade 1, 2 and 3+ GU and GI toxicities were: 40.6%, 37.5%, 3% and 28.1%, 0%, 0%, respectively. Conclusions: This novel treatment protocol incorporating MRI-dose painted HDR brachytherapy boost and SBRT pelvic radiation for intermediate- and high-risk prostate cancer in combination with ADT is feasible, effective and well tolerated. Clinical trial information: 12345678. [Table: see text]
Phase II trial of neoadjuvant chemohormonal therapy (NAC) in prostate cancer (PC) with response assessment using PSMA PET/MRI.
Authors: Kyriakopoulos Christos , Johnson Brian , Heninger Erika , Khemees Tariq A. , Roldán-Alzate Alejandro , Huang Wei , Beebe David J. , Emamekhoo Hamid , Wells Shane A. , Jarrard David Frazier , Cho Steve Y. , Lang Joshua Michael
Published: February 2020

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Background: Previous studies have shown that addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival (PFS) and overall survival (OS) in men with metastatic hormone-sensitive PC. Removal of the primary may also improve outcomes by reducing tumor self-seeding. We are conducting a phase II trial in men with PC to examine the feasibility of NAC, response using PSMA PET/MRI imaging and molecular mechanisms of resistance. Methods: This is an open-label, single-arm trial. Thirty patients with newly diagnosed very high risk localized, locally advanced or oligometastatic PC will receive ADT/docetaxel for three cycles before prostatectomy. The primary endpoint is rate of complete pathologic response. Key secondary objectives include PSA recurrence at month 12 after surgery. Exploratory objectives include tumor response and response heterogeneity in primary and metastatic tumors before and after treatment assessed by PSMA PET/MRI and evaluation of gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells. Results: To date, 26 of 30 patients have enrolled and completed treatment. Mean age was 61 and mean PSA at time of diagnosis was 32.1 ng/dl. All patients had multi-focal prostate cancer with 23/26 patients with Gleason Grade Group 5. Metastatic disease by conventional imaging was identified in 6/26 patients (5 in lymph nodes [LN] and bone, 1 in LN only). Treatment was overall well tolerated. All patients had multi-focal primary prostate cancer detected on PSMA PET/MRI. All patients had a decline in PSMA PET SUVmax in at least one intraprostatic lesion. Two patients had an increase in SUVmax in at least one intraprostatic lesion that correlated with a resistant tumor focus on histopathology. Conclusions: NAC prior to surgery generates high rates of local tumor control with a heterogeneous response between foci. Primary resistance, identified by increasing PSMA PET SUVmax, is uncommon, however incomplete responses were observed in nearly all patients, suggesting that more cycles of treatment would improve response. PSMA PET/MRI can be used to monitor response and resistance in PC. Clinical trial information: NCT03358563.
Head-to-head comparison between decipher and prolaris tests: Two commercially available post-prostatectomy genomic tests.
Authors: Shahait Mohammed , Alshalalfa Mohammed , Schaeffer Edward M. , Huang Huei-Chung , Cronican Andrea , Nguyen Paul L. , el-Fahmawi Ayah , Lal Priti , Davicioni Elai , Lee David I.
Published: February 2020

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Background: Several post-prostatectomy genomic tests are available; which are used to improve prognostication and to guide additional treatment after radical prostatectomy (RP). There has been no head to head comparison between these tests. The objective of this study is to compare the performance of two genomic tests in predicting oncological outcomes. Methods: 16 patients who underwent RP at the University of Pennsylvania (UPenn) (2013-2018), had adverse pathology (margin, and/or pT3a/b) and had each been tested with both Decipher (D) and Prolaris (P). Pearson correlation was used to compare scores from D and P as well as CCP scores and microarray derived CCP (mCCP). The associations of D and P with biochemical recurrence (BCR) and metastasis (M) was evaluated in survival analysis in a large cohort of RP patients treated at Johns Hopkins University (1992-2010) (JHU). Results: The median follow-up of the UPenn cohort was 24 months. 6 patients developed BCR and two distant M. There was a significant correlation between the D and P score (r=0.67,p=0.004), and between the 10-year BCR risk reported by P and the 5-year M risk reported by D (r=0.69, p=0.003). Each test called 7 patients to be high risk; 5 were in common. Both tests correctly called the 2 M cases as high risk and 4/6 BCR patients to be high risk. A microarray-derived CCP (mCCP) was highly correlated to the CCP scores reported from P (r=0.88, p=6.7e-6) in the UPenn cohort. To compare the prognostic performance of mCCP to D for predicting BCR and M, we used Post-RP cohort from JHU (N=355). Both scores were correlated (r=0.36, p2e-12). D and mCCP were stratified into 5 groups of incremental 20%. When including mCCP groups, D groups, Gleason score, SVI, EPE, LNI, and PSA; D remained independent prognostic variable of BCR (HR 1.16, 95%CI [1.05-1.3], p=0.005) and M (HR 1.3, 95%CI [1.12-1.52], p=0.0005). However, mCCP was not prognostic of BCR (p=0.59) nor M (p=0.62). Conclusions: The findings from this study show that P and D scores post-RP were highly correlated and help in identifying patients who at high risk of progression in this small cohort with short follow up. However, D outperformed mCCP for predicting BCR and M in larger cohorts with longer follow up.
Stereotactic body radiotherapy boost toxicity for high and intermediate-risk prostate cancer: Report of a multi-institutional study.
Authors: Kaplan Irving D. , Appelbaum Limor , Aghdam Nima , Martin Jarad , Sidhom Mark , Pryor David , Aronovitz Joseph A. , Mahadevan Anand , Kennedy Kevin F. , Collins Sean P.
Published: February 2020

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Background: External beam radiation therapy (EBRT) with androgen suppression (AS) and low dose rate (LDR)brachytherapy boost has been shown to improve biochemical progression free survival in unfavorable intermediate risk and high-risk prostate cancer (PC) compared to EBRT and AS. Excellent rates of local control in locally advanced prostate cancer with EBRT with high dose rate brachytherapy (HDR) boost. Prostate Stereotactic Radiosurgery (SBRT) may be an alternative to brachytherapy in patients with unfavorable intermediate and high-risk PC. Here we report the toxicity of pelvic lymph node/prostate EBRT and SBRT as the radiation boost in a large retrospective cohort. Methods: 473 patients with intermediate or high-risk PC, from the Radiosurgery Society Registry, Beth Israel Deaconess Medical Center, Georgetown University, and 5 Australian centers, were included. Patients received treatment from 3/2004- 9/2018 were the basis of this IRB approved retrospective study. The prostate and pelvis nodes were treated with between 36-50.4 Gy in 1.8/2.0 Gy fractions of radiation therapy EBRT. Patients received a SBRT boost to the prostate. Boost dose was 19-19.5 Gy (range 19-36.25 Gy). 274 and 199 patients presented with unfavorable or high-risk disease. The median follow-up was 33 months (IQR:18-63). Results: 33 deaths of 473 patients occurred in this cohort, 8 of which were caused by PC. There were 13.9% (n=66) acute Grade 1 or 2 GI toxicities (11.8% grade 1, 2.1% grade 2). There were 27.7% (n=131) acute Grade 1 or 2 GU toxicities (19.2% grade 1, 8.5% grade 2). No severe acute GU or GI toxicities were reported. There were 32 (6.8%) Grade 1 and 3 (0.6%) Grade 2 late GI toxicities. There were 9 (1.9%) Grade 3 and 1 (0.2%) Grade 4 late GI toxicities. There were 60 (12.7%) Grade 1 and 23 (4.9%) Grade 2 late GU toxicities. 15 (3.2%) Grade 3, but no Grade 4 late GU toxicity were reported. Conclusions: In this large multi-institutional retrospective cohort SBRT boost to pelvic/prostate EBRT had acceptable acute and late toxicities. The high dose per fraction of SBRT is similar to the dose delivered with HDR. This data raises the hypothesis that SBRT boost should be evaluated in additional clinical trials.