bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of DNA damage repair and tolerance factors in patients with muscle-infiltrating urothelial carcinoma.
Authors: Palacka Patrik , Holickova Andrea , Roska Jan , Vallova Miroslava , Biro Csaba , Slopovsky Jan , Orasova Eveline , Mardiak Jozef , Kajo Karol , Chovanec Miroslav 
Published: June 2023

e16615 Background: Cisplatin (CDDP) is the key agent in treatment of muscle-infiltrating urothelial carcinomas (MIUCs). However, around a half of patients do not respond to combined chemotherapy based on this agent what might be caused by an increased capacity to repair CDDP-induced DNA damage. The objective of this study was to determine the levels of selected DNA repair and tolerance factors in patients with MIUC to reveal their potential prognostic value. Methods: We have evaluated the bladder tumors from 86 subjects reviewed by trained pathologists. Median age was 67 years (range 37-84 years), 75.6% were males. All patients had MIUCs. To detect the XPA, XPF, POLI, REV3L, and POLH levels in primary tumors, immunohistochemistry was used. Study population was divided into two groups by positivity defined as 76-100% (negative vs positive tumors). Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Results: At median follow-up of 20.6 months (1.0-212.5 months), 86.1% of patients died. Median OS of subjects with tumors stained negative for XPA, XPF, REV3L, and POLH did not differ significantly from patients with positive staining for these proteins, with hazard ratios (HRs) being 0.61, 0.62, 0.98, and 0.72, respectively. Patients with tumor negative for POLI expression had significantly ( p = 0.0334) better median OS of 23.5 months (range 17.3-47.3 months) compared to subjects with tumor stained positive for expression of this protein [median OS of 17.6 months (range 13.6-21.3 months)] (HR = 0.61, 95%, CI 0.39-0.97). Conclusions: In this study, we showed a clear correlation between higher POLI expression in primary tumor tissue and inferior outcome in MIUC patients. Hence, we believe that the expression level of POLI might represent a prognostic biomarker and potentially constitute promising therapeutic target.
Molecular and immune analysis of adrenocortical carcinoma (ACC): Implications for immune checkpoint inhibition (ICI).
Authors: Nazha Bassel , Gandhi Nishant , Naqash Abdul Rafeh , Hadfield Matthew James , Zhuang Tony , Brown Jacqueline T. , Carthon Bradley Curtis , Barata Pedro C. , Agarwal Neeraj , Soares Heloisa P. , Kucuk Omer , Goldman Jamie , Lou Emil , Abdulla Farah Rukshana , Oberley Matthew James , Farrell Alex Patrick , Master Viraj A. , Bilen Mehmet Asim 
Published: June 2023

e16617 Background: ACC is a rare and aggressive malignancy. Response rates to ICI are low with scarce yet promising durable responses. Molecular ACC subtypes have been reported based on The Cancer Genome Atlas (TCGA). Here we report the mutational and immune landscapes of ACC obtained from a real-world patient dataset. Methods: DNA (592-gene or whole exome; N=215) and RNA sequencing (whole transcriptome; N=121) were performed for ACC specimens submitted to Caris Life Sciences (Phoenix, AZ). PD-L1+ expression was tested by IHC (SP142; ≥1%). Hierarchical agglomerative clustering (HAC) analysis was performed on a pre-defined set of immune genes. Specimens grouped into immune-high/intermediate (IH) and immune-low (IL) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate immune cell infiltrates. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q<0.05). Results: Overall, the most frequent mutations were in TP53 (37%), CTNNB1 (18.7%), ATRX (12.1%), NF1 (9.6%), and RB1 (8.75%), consistent with previous reports. Further, 6.4% of tumors were PD-L1+, 6.1% TMB-high (≥ 10 mut/MB), and 5.9% dMMR/MSI-H. 38.2% of tumors were biopsied from metastatic sites (M). Compared to M, primary (P) specimens had a higher prevalence of TP53 (43.4 vs 26.9%, p<0.05) and TERT promoter mutations (11.1 vs 0%, p=0.08), and a lower prevalence of SMARCB1 (0 vs 3.7%, p=0.054) and BRCA2 (0 vs 3.8%, p=0.056) mutations. Interestingly, M lesions were enriched for HAVCR2 expression (1.3-fold, p<0.05), as well as infiltration of monocytes (1.8-fold, q<0.05) and endothelial cells (1.4-fold, q<0.05). HAC based segregation of tumors based on immune activity was corroborated by a general enrichment of immune cell infiltrates in the IH tumors. IH tumors were enriched for common immunotherapy-related biomarkers (TMB-high, dMMR/MSI-H and PD-L1 positivity), along with a higher prevalence of TP53 and ATRX mutations, while CTNNB1 mutation and CDK4 copy number amplification were less common in IH tumors. Conclusions: Querying a large real-world ACC patient dataset, we find somatic alterations and a low prevalence of ICI-related biomarkers (<10%), consistent with previous reports. Monocyte and endothelial cell infiltration in metastatic tumors suggests an immunosuppressive phenotype compared to primary tumors. Finally, identification of molecular alterations in tumors with distinct immune phenotypes may facilitate development of new therapeutic strategies in ACC. [Table: see text]
Intratumoral heterogeneity as a predictive biomarker in immunotherapy for advanced bladder cancer.
Authors: Chen Haige , Qian Lei 
Published: June 2023

e16619 Background: Previous studies have shown that intra-tumor heterogeneity (ITH) can lead to drug resistance to tumor therapy, which is associated with poor prognosis of solid tumors. However, studies on the correlation between ITH and immunotherapy efficacy in patients with advanced bladder cancer (BLCA) are still lacking. Methods: Bioconductor R package Maftools was used to analyze somatic variants of advanced BLCA from an independent cohort (Miao-249 study cohort, PMID: 30150660) with data from 27 patients who underwent whole-exome sequencing. The ITH score was measured using the mutant-allele tumor heterogeneity (MATH) algorithm to analyze the difference in the genetic profile between the ITH score high (ITH-H) and ITH score low (ITH-L) groups, its association with tumor mutational burden (TMB), and the effect of ITH on the prognosis of immunotherapy. Results: There were significant differences in gene mutation spectrum between ITH-H and ITH-L groups. The genes with the highest mutation frequency in ITH-H group were TP53 (57.14%), DNAH5 (38.1%), TNRC18 (38.1%), TTN (38.1%), CSMD3 (33.33%), MDN1 (33.33%), MRPL49 (33.33%), and MUC19 (33.33%), while the genes with the highest mutation frequency in ITH-L group were KDM6A (83.33%), TP53 (66.67%), CALN1 (50%), MICAL2 (50%), MTOR (50%), NINL (50%), PCDHA (50%), and RMIBP2 (50%). The objective response rate (ORR) of immunotherapy was 66.66% and 42.86% for the patients with ITH-L and ITH-H subgroup. The ITH-L patients had significantly improved median overall survival (mOS) than the ITH-H group (not reach versus 12.3 months, hazard ratio (HR) = 6.65, 95%CI 0.86−51.36, P = 0.037). There was no significant difference in median TMB levels between ITH-L and ITH-H groups (8 Muts/Mb versus 7.6 Muts/Mb, P = 0.97). The TMB high (TMB-H) patients had no significantly better mOS than the TMB low (TMB-L) group (not reach versus 9.07 months, HR = 0.33, 95%CI 0.07−1.49, P = 0.13). A pooled analysis of ITH and TMB show that mOS in the ITH-L+ TMB-H group was numerically better than that in the ITH-H+TMB-H, ITH-H+TMB-L, and ITH-L+TMB-L group (not reach versus 15.6 months versus 7.1 months versus not reach, HR-1.57, 95CI 0−Inf, P = 0.1). Conclusions: The results suggest that ITH may be independent of TMB and a positive predictor of immunotherapy in patients with advanced BLCA.
Incidence of other multiple primary malignancies in patients with adrenocortical carcinoma.
Authors: Koshiya Hiren , Pandav Vivek , Mosalem Osama M. , Inampudi Jyothik Varun , Patel Jaydeepbhai , Lou Yanyan , Manochakian Rami , Rao Sarika , Zhao Yujie 
Published: June 2023

e16621 Background: Adrenocortical carcinoma (ACC) is an exceedingly rare aggressive endocrine malignancy with about 1 new case per million people diagnosed annually in the US. Higher incidence of ACC has been reported in patients (pts) with inherited syndromes such as Lynch syndrome and Li-Fraumeni syndrome. However, the incidence rate of developing multiple primary cancers in this population is unknown. The aim of this study is to investigate the frequency of additional malignancies in ACC patients. Methods: Using the Mayo Clinic Cancer Registry, we identified 63 pts who were treated for ACC from 2010- 2018 with updated follow up data until 01/31/2023. Electronic medical records were reviewed. Results: Among the patient cohort, 22 pts were male. 18/63 (29%) pts were found to have at least one additional malignancy, including basal cell carcinoma (3/18, 17%), melanoma (3/18, 17%), thyroid cancer (3/18, 17%), prostate cancer (3/18, 17%), squamous cell carcinoma of skin (2/18, 11%), renal cell carcinoma (2/18, 11%), breast cancer (2/18, 11%), leukemia (2/18, 11%), lung cancer (1/18, 6%), transitional cell malignant neoplasm of kidney (1/18, 6%), squamous cell carcinoma of tonsil (1/18, 6%), ovarian cancer (1/18, 6%), seminoma (1/18, 6%) and bladder cancer (1/18, 6%). 8/18 (45%) pts had more than one (2-3) non-ACC malignancies. The median age at diagnosis of ACC was 56 years (02-83). The median age at diagnosis of non-ACC malignancies was 54 years (25-72). Most of the patients (13/18) were diagnosed with non-ACC malignancy within 5 years of diagnosis of ACC. Most pts (13/18, 72%) were diagnosed with non-ACC malignancy first. Germline mutation information was not available except for 2 pts with known family history (FH) of Lynch syndrome and 2 pt with a known FH of Li-Fraumeni syndrome. FH was available in 38 pts, out of which 29 pts had FH of cancer identified in first-degree relatives. Among the 18 pts with additional malignancies, 12 pts had FH of cancer in first-degree relatives. All except 2 pts underwent curative treatment for their non-ACC malignancies, and 14 pts had no evidence of disease at death or the time of last follow-up. Conclusions: The rate of other multiple primary malignancies in pts with ACC is high, indicating possible genetic predisposition associated with this disease; Early genetic consultation and evaluation for known and novel germline mutations may need to be considered for these pts to improve long-term outcomes.
Circulating levels of PCSK9, ANGPTL3, and other lipid-related factors in men with high-grade prostate cancer.
Authors: Joncas France-Hélène , Bergeron Ann-Charlotte , Wong Chong Emilie Yan Pin , Robitaille Karine , Fradet Vincent , Bergeron Alain , Calon Frédéric , Seidah Nabil Georges , Gangloff Anne 
Published: June 2023

e17001 Background: Cancer cells rely on abundant lipid supplies for growth and metastasis. Previous studies have shown that lipid-lowering drugs provide a protective effect against cancer progression, including prostate cancer. However, the role of hyperlipidemic factors has not yet been extensively studied. Here, we aimed to measure circulating levels of hyperlipidemic factors, such as PCSK9 and ANGPTL3, in a small cohort of men diagnosed with high-grade prostate cancer compared to men without cancer. Methods: Plasma samples and data were obtained from 70 consenting men treated at CHU de Québec-Université Laval. Thirty-five patients with high-grade prostate cancer (cases) were age and BMI-matched to 35 patients without cancer (controls). The circulating levels of various lipids, Apo B and Lp(a) were obtained with a Roche Modular analytical platform, whereas levels of PCSK9, ANGPTL3 and leptin were measured by ELISA. We performed group comparisons and correlations using R version 4.2.1. Results: As expected, Prostate-specific antigen (PSA) levels were significantly higher in the cancer group. The lipid profile as well as Lp(a) and leptin levels did not differ between groups. ANGPTL3 level tended to be lower in patients with prostate cancer without reaching statistical significance (mean 32.2 vs 36.3 ng/mL, p = 0.051). ANGPTL3 level also inversely correlated with leptin among the cases (rho = -0.44, p = 0.008). PCSK9 level was similar in both groups, but inversely correlated with PSA in the cancer group (rho = -0.39, p = 0.022). PSA level correlated with triglycerides, total cholesterol, Apo B, non-HDL-cholesterol and LDL in the control group (p < 0.05). Conclusions: None of the hyperlipidemic factors measured here was significantly different between high-grade prostate cancer patients and controls. However, the trend for lower ANGPTL3 levels in cancer, as well as the inverse correlations between PCSK9 and PSA and between ANGPTL3 and leptin levels in cancer patients, warrant further investigation in larger cohorts.
Comprehension characterization of prostate cancer cell lines identified JAK-STAT3 signaling in lineage-switched non-neuroendocrine cells.
Authors: Cheng Siyuan , Li Lin , Yu Xiuping 
Published: June 2023

e17005 Background: Prostate cancer (PCa) is the most diagnosed cancer type among American men. Androgen receptor (AR) targeted therapy as the gold standard of PCa has been challenged by treatment resistance. Lineage plasticity enables PCa cells to transit from prostate luminal epithelia to alternative lineages to bypass their dependency on AR signaling. Previously we established prostatic HOX code to study the prostatic lineage. We found that cells with neuroendocrine (NE) phenotype have a lineage switch. Besides, a subgroup of AR negative, NE negative samples also display lineage switch, among which is DU145, a human PCa cell line. Methods: RNA-seq data of PCa cell lines were obtained from GEO then aligned and quantified using human GRCh38 genome with STAR-Salmon pipeline. Downstream differential expression and enrichment analysis was performed with R. Immunohistochemistry (IHC) was used to assess protein levels on cell line derived xenografts. Results: 45 RNA-seq datasets of 6 prostate adenocarcinoma cell lines (VCaP, LNCaP, C4-2, 22RV1, PC3 and DU145) and 8 RNA-seq datasets of neuroendocrine prostate cancer cell line (H660) passed quality control. Principle component analysis indicates that samples from the same cell line had similar transcriptomes. Differential expression analysis followed by gene function enrichments analysis identified the marker genes and key signaling pathways of each cell line. HOX code analysis confirmed previous conclusion that all PCa cell lines but DU145 and H660 samples maintained prostatic HOX code. IHC staining on cell line-derived xenografts confirmed the protein expression of selected marker genes (TUBB2B for H660, HGF for VCaP and 22RV1, CXCL1 and KRT7 for DU145 and PC3). The three AR-negative PCa cell lines were further characterized in terms of AR/ NE activity scores, transcriptome identities, HOX codes. These analyses demonstrated that PC3 is a prostate progenitor like cell line, H660 is a lineage-switched NE cell line, and DU145 is a lineage-switched non-NE cell line. Further, signaling enrichment analysis revealed that DU145 cells had higher JAK-STAT3 signaling activity compared to other cell lines. IHC staining detected strong p-STAT3 signals on DU145-derived tumors but not on any other cell line-derived tumors. Conclusions: Human PCa cell lines were fully characterized based on their transcriptomes with high sample numbers. PC3 represents cells dedifferentiated into progenitor stage. DU145 and H660 represent cells that further trans-differentiate into alternative lineages. Neuron master regulators drive H660 cells into NE lineage and STAT3 drives DU145 cells into a non-NE lineage. DU145, representing a non-NE PCa class that have lost prostatic lineage, would be a suitable model system to study JAK-STAT targeting therapy.
Hyperinsulinemia and risk of lethal prostate cancer.
Authors: Tanawattanacharoen Veeraya Kate , Mucci Lorelei A , Giovannucci Edward L. 
Published: June 2023

e17008 Background: Epidemiologic studies have found that insulin-like growth factor (IGF)-1 causally increases prostate cancer incidence and mortality, but the effect of insulin is less clear. IGF-1 and insulin act as mitogens by binding non-selectively to their receptors. To this end, this study tests the hypothesis that high circulating insulin increases risk for lethal (fatal or metastatic) prostate cancer among men with non-metastatic prostate cancer. Methods: The study population was drawn from two U.S.-based longitudinal cohorts: the Health Professionals Follow-Up Study (HPFS) of 51,529 health professionals and the Physicians’ Health Study (PHS) of 29,067 physicians. Pre-diagnostic plasma concentration of C-peptide was used as a proxy for insulin and measured on blood collected in 1993-1995 (HPFS) or 1982 (PHS) and stratified into quartiles for analysis. The empiric lifestyle index (based on body mass index (BMI), physical activity, and diet) for hyperinsulinemia (ELIH) was calculated from questionnaire data. Covariates of interest (age and fasting status at blood draw, BMI, height, clinical stage, and tumor grade) were attained from questionnaires and medical records. We followed patients for development of metastasis or death (lethal) through 2019 (HPFS) and 2015 (PHS). SAS 9.4 and R Studio were used for analyses. Chi-squared tests and Mann Whitney U tests were used to compare differences between groups, and Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI. Results: The sample included 2,812 men with 353 lethal prostate cancer events and a mean follow-up of 164 months from diagnosis to death. The mean time from blood draw to cancer diagnosis was 8.1 years. Compared to men with non-lethal prostate cancer, those with lethal disease had significantly more severe clinical grade and stage at diagnosis, higher BMI (25.1 vs 24.6), older age at blood draw (64.5 vs 61.9 years), and higher ELIH index. There were no differences by other covariates. There was no association between pre-diagnostic c-peptide levels and cancer-specific survival in a multivariable model that included clinical stage and grade (HR, 95% CI for high vs. low quartiles: 1.17, 0.83, 1.67). High ELIH was positively associated with risk of lethal prostate cancer (HR, 95% CI: 2.41, 1.36, 4.28), even when controlling for C-peptide (HR, 95% CI: 2.18, 1.20, 3.96). Conclusions: C-peptide levels measured prior to cancer diagnosis were not associated with increased mortality from prostate cancer. Higher ELIH was associated with increased risk of lethal prostate cancer among those diagnosed with prostate cancer, which could be partly mediated by hyperinsulinemia, but other dietary, physical activity, or BMI mechanisms could contribute.
Defining the prevalence of inherited DNA damage repair genetic variants (DDRv) in men with prostate cancer (PCa) detected by PSMA PET.
Authors: Maldonado Edward , Hope Thomas A. , Aggarwal Rahul Raj , Kwon Daniel H , Zhang Li , Gordon Kelly , Tong Barry , Bailey Adina , Kumar Vipul , de Kouchkovsky Ivan , Koshkin Vadim S , Borno Hala , Chou Jonathan , Bose Rohit , Fong Lawrence , Desai Arpita , Friedlander Terence W. , Small Eric Jay 
Published: June 2023

e17010 Background: Approximately 12% of patients (pts) with metastatic PCa (mPCa) identified by conventional imaging harbor DDRv. The increased use of PSMA PET has identified a group of pts with extra-prostatic PCa which is not apparent on conventional imaging and for whom the frequency of germline DDRv testing remains unknown. Methods: A single-institution retrospective analysis of patients with PCa detected by PSMA PET who had also undergone germline genetic testing was undertaken. Data collected included PSA level at time of PSMA PET imaging, stage/Gleason score at diagnosis (dx), rationale for germline testing, castration status, and whether the metastatic disease identified on PSMA PET represented de novo or recurrent mPCa. Germline sequencing results were evaluated for 16 DNA damage repair genes: ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, GEN1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, and RAD51D. The frequency of DDRv was evaluated in groups defined by PSMA imaging results: localized (N0M0), Node-Positive (N+M0), metastatic (M+) PCa. Results: Of 795 PCa pts who underwent germline testing and 2101 PCa pts who underwent PSMA PET imaging, 386 had undergone both, and constitute the study cohort. In the study cohort the distribution of PCa extent identified by PSMA PET was: 81/386 (21.0%) N0M0; 76/386 (19.7%) N+M0; 229/386 (59.3%) M+. There were no statistically significant differences in the prevalence of DDRv with regards to age, Gleason score at dx, PSA at time of imaging, castration status at time of imaging, rationale for germline testing, or if metastatic, whether de novo or recurrent. The distribution of DDRv is shown in the table. There were no statistically significant differences between groups. Conclusions: The overall frequency of pathogenic germline DDRv in PCa pts who had undergone PSMA PET imaging was 4.66%, considerably lower than what has been reported in men with mPCa detected with conventional imaging. The presence or absence of extra-prostatic PCa detected by PSMA PET imaging did not appear to affect the frequency of DDRv. Validation of these findings in other cohorts will be important to guide recommendations for germline genetic testing in the growing group of PCa pts undergoing PSMA PET imaging. [Table: see text]
Patterns of recurrence post prostatectomy in the PSMA era: What lessons can we take to daily practice from a high-volume nuclear medicine center?
Authors: Lages Dr. Paulo Sergio , Monteiro do Prado Junior Luciano , Fonseca Monteiro do Prado Leonardo , Barbosa Michelle , Bergerot Paulo Gustavo , Muniz Pamela Carvalho , Lages Luciana , Rosa Diogo Augusto Rodrigues , Dias Mariane Fontes , Resende Cristiano Augusto Andrade de , Pinheiro Maria Fernanda Inocente Messias , Vargas Pivato de Almeida Daniel ,   Latin American Cooperative Oncology Group, LACOG
Published: June 2023

e17013 Background: PSMA has deeply modified the treatment of prostate cancer, mainly in the biochemical recurrence setting, where the therapeutic plan may be changed in up to two thirds of cases. Unfortunately, this diagnostic tool is still not fully available in many places over the world. Growing evidence from high-volume nuclear medicine centers may guide the development of adapted treatment plans based on sites of relapse according to wide available clinical information. Methods: We retrospectively reviewed 648 Ga68-PSMA-PET-CT scans in the biochemical relapse setting in patients initially treated with prostatectomy. Results were classified either as negative or positive if abnormal SUV uptake was detected in the prostate bed, pelvis, or distant organs. We then classified the patients with positive tests based on sites of relapse according to serum PSA level. Results: Among the 648 analyzed patients, there were 60, 63, and 61 recurrences in prostate bed, pelvis, or distant organs, respectively. For those with serum PSA ≤ 1.0 ng/mL, there was a higher chance of locoregional failure (prostate bed or pelvis), with less than 20% presenting distant metastasis. When assessing patients with serum PSA 1.1-2.0 ng/mL, the rate of distant metastasis increased to 22.7%, while it was found in 40.7% of patients with serum PSA between 2 and 5 ng/mL. Conclusions: PSMA-PET-CT scan is clearly modifying the therapeutic landscape of prostate cancer in different scenarios. Although it is not available in many regions due to high financial costs and logistic barriers, the emerging evidence arising from specialized cancer centers matching the clinical information with tests results may help doctors to make better treatment decisions even without PSMA-PET-CT scans. [Table: see text]