bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of androgen receptor variant (ARV) profiles in serial metastatic solid and liquid biopsies in metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate/ prednisone (AA/P).
Authors: Giridhar Karthik , Sosa Carlos , Sicotte Hugues , Wang Liewei , Wang Liguo , Sinnwell Jason P. , Tan Winston , Costello Brian Addis , Quevedo Fernando , Pitot Henry C. , Bryce Alan Haruo , Jimenez Rafael E. , Weinshilboum Richard M. , Dehm Scott , Kalari Krishna R. , Kohli Manish
Published: May 2019

e16559

Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]
Association of radiomic features from prostate bi-parametric MRI with Decipher risk categories to predict risk for biochemical recurrence post-prostatectomy.
Authors: Li Lin , Shiradkar Rakesh , Leo Patrick , Purysko Andrei , Algohary Ahmad , Klein Eric A. , Magi-Galluzzi Cristina , Madabhushi Anant
Published: May 2019

e16561

Background: Decipher test examines expression levels of 22 metastasis-related RNA sequences and provides a risk score (DS) for assessing metastasis risk within 5 years after radical prostatectomy (RP). Our previous work has shown that radiomics or computer extracted texture features are associated with DS on multiparametric MRI (mpMRI). DS associated radiomics (RDS) may capture signatures related to poor prognosis of prostate cancer (PCa) following RP. Thus, we sought to evaluate whether RDS were also able to predict the risk of biochemical recurrence (BCR), a surrogate clinical endpoint of metastasis, after RP. Methods: Two patient cohorts from two institutions who underwent 3T mpMRI prior to RP were used in this study - I1: 70 PCa patients who had a Decipher test following RP; I2: 120 PCa patients with at least 5-year follow-up after RP. I1 was investigated as a training set to identify RDS and develop a multivariate logistic regression model (CL). I2 was used as a testing set to validate CL for predicting BCR. A total of 150 radiomics were extracted within each lesion from T2-weighted MRI (T2WI) and apparent diffusion coefficient (ADC) maps. Area under the receiver operating characteristic curve (AUC) and Kaplan-Meier (KM) analysis were used to evaluate performance of CL. Results: Radiomics quantifying lesion spot and ripple texture patterns on ADC maps and T2WI intensity gradient changes were able to differentiate Decipher high and low/intermediate groups in I1 (AUC = 0.92). The same model CL was then applied to I2 resulting in a significant difference in BCR-free survival time between the predicted risk groups (p < 0.05, hazard ratio (HR) = 2.54) independent of Gleason Grade Group (GGG, p < 0.05, HR = 7.61) and PIRADS-v2 (p < 0.05, HR = 5.64) in multivariate testing. Especially, for patients with GGG > 2 (n = 57), CL predicted BCR risk groups shown HR = 3.1 (p < 0.05) while GGG alone was not prognostic (p > 0.05, HR = 1.93). Conclusions: Our radiomic model was able to predict DS and was found to also be prognostic of BCR-free survival. Further work will involve evaluating whether these radiomic features are predictive of PCa metastasis. [Table: see text]
MiR-1271-5p: An AR-modulatory microRNA with a distinct role in prostate cancer progression, through SND1 and MORF4L1 interaction.
Authors: Kalofonou Foteini , Leach Damien , Hamilton Mark , Mcguire Sean Eric , Fletcher Claire , Waxman Jonathan , Bevan Charlotte L
Published: May 2019

e16562

Background: Current screening methodologies for prostate cancer (PCa) are relatively insensitive and there is a need for new treatments for castrate resistant disease. MicroRNAs (miRs) are considered to be master regulators of the genome. We have investigated the role of miRs in modulating androgen receptor function and their potential as treatments of PCa. We report that the AR-modulatory miR-1271-5p also targets SND1 and MORF4L1 and may have a role in PCa progression and screening. Methods: AGO2-PAR-CLIP analysis was performed to ascertain miR-1271-5p target genes in human PCa cell lines. MiR-1271-5p levels were manipulated in cell lines by transfection with miR mimic and or antisense inhibitor. SND1 and MORF4L1 were confirmed as targets by real-time qPCR and western blotting. The functional role of miR-1271-5p and its target genes was assessed by SRB growth assays . Immunohistochemical detection of SND1 and MORF4L1 expression was studied in a cohort of 63 PCa patients and compared with normal controls. Results: MORF4L1 mRNA levels were significantly reduced with the use of miR-1271-5p mimic in 22RV1 cells (p = 0.001), while SND1 mRNA levels were significantly decreased with the use of miR-1271-5p inhibitor in C42 cells (p = 0.0014). Targeting SND1 or MORF4L1, in combination with miR inhibition, significantly reduced C42 (p = 0.0003) and 22RV1 (p = 0.0014) cell growth. MORF4L1 expression was higher in patients with Gleason score (GS) 4+3 relative to those with GS 3+4 and in PCa tissue, as compared with normal prostatic tissue, but did not reach significance. SND1 immunostaining was significantly higher in patients with GS 4+3 or GS 3+4 PCa, compared with normal prostatic tissue (p = 0.0211, p = 0.0007 respectively). SND1 staining was significantly higher in patients with GS 4+3, compared to GS 3+4 (p = 0.0431) or GS 3+3 (p = 0.0251). Conclusions: MiR-1271-5p is an AR-modulatory microRNA, which shows great potential as a biomarker and therapeutic target in PCa. The interaction of miR-1271-5p with its target genes SND1 and MORF4L1 could provide the basis for therapeutic advance in screening and in the treatment of castrate resistant PCa.
Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.
Authors: McBride Sean Matthew , Zelefsky Michael J. , Spratt Daniel Eidelberg , Paller Channing Judith , Kollmeier Marisa , Slovin Susan F. , Aghalar Jahan , Hearn Jason W.D. , Den Robert Benjamin , Deville Curtiland , Xiao Han , Abida Wassim , Scher Howard I. , Rathkopf Dana E.
Published: May 2019

e16563

Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or > 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( < 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.
Screening of BRCA2 mutated men for detection of prostate cancer: Preliminary results from a national high volume cancer center.
Authors: Zuradelli Monica , Buffi Nicolo' , Bianchi Paolo , Ripamonti Carla Barbara , Barile Monica , Casale Paolo , Saita Alberto , Lughezzani Giovanni , Hurle Rodolfo , Lo Iacono Nadia , Guazzoni Giorgio Ferruccio , Lazzeri Massimo , Santoro Armando
Published: May 2019

e16567

Background: Up to 10% of cases of Prostate Cancer (PCa) are hereditary. Germline pathogenic mutations in BRCA2 gene confer the highest risk (2.5 to 8.6 fold in men ≤ 65 yr). Beyond periodic Prostate Specific Antigen (PSA) dosage and digital rectal examination (DRE), a targeted screening for carriers is still undefined. Prostate Health Index (PHI), a combination of the tPSA, fPSA and proPSA tests, may be a more accurate biomarker than PSA only to detect PCa. We evaluated how to better screen BRCA2 mutated men for PCa. Methods: We reviewed the genealogical trees of all women tested positive for germline BRCA2 pathogenic mutation at our clinic. We offered targeted BRCA2 mutational analysis to all first/second degree relative men between 40 and 69 yr. A targeted screening program (annual PSA and PHI dosages and DRE) was proposed to all men tested positive. In case of PSA and/or PHI values out of range ( > 4ng/ml and > 20, respectively) we proceeded with a multiparametric Magnetic Resonance Imaging (mpMRI) and fusion biopsy of suspected lesions. Results: From June 2008 to October 2018 610 breast/ovarian cancer patients had BRCA test: 35 (5.7%) tested positive for BRCA1 pathogenic mutation, 32 (5.2%) for BRCA2 pathogenic mutation. From October 2017 90 relatives were checked for the familial mutation and 24 (27%) (12 women, 12 men) tested positive for BRCA2 mutation. All the 12 men (median age 48 yr, IQR 44 to 60) accepted to join our screening program. During the first year all men had negative DRE. Median PSA was 0.70 (IQR 0.43 to 1.02), median PHI was 17.56 (IQR 11.85 to 24.06). One patient with out of range PHI value already had mpMRI resulted negative. During the second year 4 men underwent screening so far: they had negative DRE. Median PSA was 0.57 (IQR 0.38-0.77), median PHI was 16.88 (IQR 11.87-21.90). Two men had PHI out of range and will undergo mpMRI. Conclusions: An accurate review of the genealogical trees of breast/ovarian cancer BRCA2 mutated patients allows to identify male relatives potentially carriers of the same mutation. These men have a high lifetime risk of PCa and require an appropriate screening, currently absent. Our approach may be leveraged as proof of concept of selection and screening program in carriers of BRCA2 mutations.
The effect of E2F7 expression in prostate cancer on apoptosis and cell cycle of prostate cancer cells.
Authors: Wang Ying
Published: May 2019

e16568

Background: Prostate cancer (PCa) is a leading cause of illness and death among men in the United States and Western Europe. However, the molecular mechanisms by which PCa developed has not been fully illustrated. Methods: Here, the expression of E2F7 in PCa was examined using IHC method and western blotting assay, and the expression of miR-30c was measured using qRT-PCR method. The cell cycle and apoptosis was determined by FACS. Cell Counting Kit-8 was used to testify cell proliferation. miR-30c mimics, miR-30c inhibitors and E2F7 siRNA transfections were performed to study the loss- and gain-function. Duel-luciferase reporter assay was performed to verify that E2F7 was one of the potential targets of miR-30c. Results: It was found that E2F7 was overexpressed in PCa cells and tissues compared with normal ones. Inhibition of E2F7 in PCa cells led to significant decreased proliferation rates, increased G1 phase percentage, and higher apoptosis rates of PCa. Duel-luciferase reporter assay showed that E2F7 was one of the targets of miR-30c. Moreover, introduction of miR-30c resulted in decreased proliferation rates, increased G1 phase percentage, and higher apoptosis rates of PCa cells while miR-30c inhibitor led to lower apoptosis rates of PCa cells. Conclusions: In conclusion, our study demonstrated that E2F7 may play a tumorigenesis promoting role of PCa cells, and that E2F7 was regulated via miR-30c, indicating that E2F7 and miR-30c might be viable therapeutic targets for PCa.
Determination of AR-V7 in plasma in patients with metastatic prostate cancer using capillary Nano-immunoassay.
Authors: Virseda Alvaro , Garcia Juan Luis , Marcos Asensio Sara , Garcia Garcia Javier , Herrero POLO Manuel , Cigarral Garcia Belen , Misiewicz-Krzeminska Irena , Gonzalez Rogelio , Garcia Rocio , Cruz-Hernández Juan J. , Veiga Francisco Gomez
Published: May 2019

e16574

Background: Liquid biopsy has the potential to provide information about cancers without invasive biopsy, using circulating biomarkers. The aim of present study was determinate the presence of androgen receptor splice variant 7 (AR-V7) in plasma using capillary nano-immunoassay in metastasis PCa and correlation with clinical and analytical data. Methods: Whole blood (10 ml) was collected and processed in EDTA tubes. Previously to determinate the presence of ARV-7 in plasma Capillary Electrophoresis Immunoassay or SimpleWestern analyses were performed using the WES™ machine. With this technique, proteins are separated by size, immobilised and probed with specific antibodies. The primary antibody used was Anti-Androgen Receptor antibody. Results: The study included 31 patients with diagnostic of PCa metatasic . Clinical characteristics of the patients were described in the table. AR-V7 signal was detected in 11 cases (36%). Twenty samples (64%) were considered as negative. The most of patients with expression positive for AR-V7, showed a Gleason score ≥ 8 (64% of cases). In AR-V7+, hemoglobine and dehydrogenase lactate levels were statistically significant (p < 0,05) respect to ARV7-. So, in AR-V7+ patients showed increased of FA and Albumin. Conclusions: Assessing the presence of AR-V7 in plasma from PC patients is feasible by a novel capillary nano-immunoassay. AR-V7 was observed in 36% of the PCA metastasic. These findings lay the foundations for liquid biopsy as a means of obtaining biological data in a more convenient way for the patient.[Table: see text]
Shared-decision making in prostate cancer with clinical decision-support.
Authors: Rocha Hermano Alexandre Lima , Dankwa-Mullan Irene , Juacaba Sergio Ferreira , Willis Van , Arriaga Yull Edwin , Jackson Gretchen Purcell , Meneleu Pedro
Published: May 2019

e16576

Background: Shared decision-making is the process of deliberately interacting with patients who wish to make informed value-based choices, when there are no indicated best treatment options. Given the wide variation in prostate cancer treatment options, clinical decision-support systems (CDSS) may effectively support treatment decisions for patients with challenging risk-benefit profiles. However, limited data are available regarding CDSS in shared decision making. This study aimed to assess the alignment of CDSS therapeutic options with treatment received through a shared decision process. Methods: We identified patients with prostate cancer (Gleason Groups 1-5) who were engaged in shared treatment decision making, (from August–September 2018) at the Instituto do Câncer do Ceará, Brazil. IBM Watson for Oncology (WfO), a CDSS was used for the study. Treatment decisions were compared with WfO options (active surveillance, clinical trial, chemotherapy [CT], hormone therapy [HT], radiation [RT], brachytherapy [brachy], surgery and systemic therapy with GnRH suppression) and categorized as concordant (equivalent), partially concordant (a partial match), or discordant. Results: Concordance between WfO and shared treatment decisions was observed in 54% (26/48) of patients, partial concordance in 15% (7/48) and discordance in 31% (15/48). Most frequent treatments were RT+HT combination therapy (25%) and prostatectomy (21%). 8/15 (53%) discordant cases were due to patient preference for treatment over active surveillance. Patient preference for treatment over active surveillance was the most common reason (53%) for discordance. Conclusions: Variation in prostate cancer treatment exists. CDSS therapy options may be useful in quantifying and modifying unwarranted variations in prostate cancer treatment. Future studies are important for understanding reasons for variations. [Table: see text]
Longitudinal prostate cancer outcomes in a racially diverse cohort of military heath care beneficiaries: 1990-2017.
Authors: Cullen Jennifer , Oehrlein Nathan , Streicher Samantha , Kuo Huai-Ching , Chen Yongmei , Rice Kevin R. , Lu-Yao Grace L. , Rosner Inger L.
Published: May 2019

e16581

Background: Prostate cancer (PCa) incidence and mortality disproportionately burden African American (AA) men compared to Caucasian American (CA) men. An interplay of biological, social, and health care factors is blamed for this disparity. However, a recent multi-center study of the Veterans Affairs population found no differences in cancer progression, disease specific survival, or overall survival for AA versus CA men. This study examines a large, racially diverse military health care beneficiary cohort, enrolled over 25+ years, to examine the roles of race and comorbidity on metastasis-free and overall survival. Methods: The Center for Prostate Disease Research (CPDR) multi-center national database was the source of study subjects. Eligible patients included all men who underwent radical prostatectomy (RP) as primary treatment for PCa between January 1, 1990 to December 31, 2017. Comprehensive demographic, clinical, treatment, and outcomes data were collected on all enrollees. Unadjusted Kaplan-Meier estimation curves and multivariable Cox proportional hazards analysis with adjustment for key clinical and pathologic factors were used to examine BCR-free, metastasis-free, and overall survival as a function of patient self-reported race (AA vs. CA). Results: There were 7,135 eligible men, among whom 22% self-reported as AA. Median age at RP and follow-up were 62 and 6.9 years, respectively. A total of 1521 BCR events, 210 metastasis events, and 879 deaths occurred. Compared to CA men, AA men were younger at diagnosis (59.4 vs. 62.7 years, p < 0.05) with higher median PSA (5.8 vs. 5.5 ng/mL, p < 0.05); however, NCCN risk strata, as well as clinical and pathologic stage and grade were distributed comparably across race. Despite slightly poorer BCR-free survival for AA men in both unadjusted and adjusted analysis, there were no statistically significant differences in 5-, 10-, and 15-year probabilities for metastasis-free or overall survival. Conclusions: In this racially diverse equal-access health care setting, this longitudinal cohort study revealed no differences in distant metastasis or overall survival between AA and CA men. Future work will examine molecular signatures of metastatic cancer.
Cancer driver genes in prostate cancer from young men.
Authors: Maistro Simone , Xavier Camila dos Santos , Serio Pedro Adolpho MP , Katayama Maria Lucia Hirata , Roela Rosimeire Aparecida , Koike Folgueira Maria A. A.
Published: May 2019

e16586

Background: Although prostate carcinoma is the most frequent cancer in older man, it is a rare disease in young adults. Search for global knowledge of the cancer genome is of great importance for diagnosis and/or treatment of these patients. Our goal was to identify the mutation profile of prostate carcinoma from young adults aged ≤49 years, using in silico tools. Methods: In silico analysis of somatic variants derived from exome or genome sequencing, deposited in the COSMIC or CBIOPORTAL database or in published manuscripts was performed. Data was searched for cancer driver genes catalogued in Cancer Gene Census (CGC) or Candidate Cancer Gene Database rank A or B (CCGD) and DNA repair genes. Results: 46 prostate adenocarcinoma samples from patients aged between 23-49 years (median 44.5) were included. A median of 15 variants per patient (minimum: 2 and maximum: 343) was detected. The most frequent events were C to T transitions, representing a median percentage of 39% of the substitutions. A total of 160 genes were affected by pathogenic mutations (splice site, nonsense, frame shift ins, frame shift del, nonstop, in frame del). Ten tumors presented pathogenic variants in at least one cancer driver (CGC); 3 tumors presented SNVs in two CGC. The most frequently altered cancer causing genes (CGC) were MUC16 (17%); TP53 (8%), SPOP (8%), XPC, SYNE1, IDH1, CDMD3, ANAPC1, AHNAK (6%). Seven tumors presented pathogenic variants in at least one in driver candidate from CCGD rank A, and 3 tumors in CCGD rank B. Single nucleotide variants affecting genes involved in DNA repair were found in 35% samples and one tumor presented variants in genes involved in BER, NER, FA, DDC and HRR. Variants in TP53 and XPC wer3e detected in 3 tumors. Conclusions: In prostate carcinoma from young men a wide range of cancer causing genes may be altered, including MUC16 and TP53. Variants in DNA repair genes may be found in 35% of the samples.
The impact of simultaneous dose escalation VMAT to the focal lesion micro boost of localized prostate cancer.
Authors: Ahmed Radwa Fawzy Saleh , Abdel Malek Raafat Ragaie , Metwaly Mohamed , Abdel Aziz Omar , Al sirafy Samy , Seleem Ahmed
Published: May 2019

e16592

Background: Dose Escalation to the prostate is showing promising results of increasing local control. The study aims to assess biochemical failure free survival (BFF) after dose escalation to the prostate 78Gy with simultaneous integrated boost (SIB) 87Gy to the focal lesion. Genito-urinary (GU) & gastro-intestinal (GI) toxicity was assessed by comparing investigational toxicity score & patient outcome reports. Methods: Thirty intermediate & high risk localized prostate cancer patients were treated with dose escalated VMAT protocol of 78 Gy/35 fractions to prostate & 87Gy boost to focal lesion detected by baseline multi-parametric MRI & TRUS as well. Neo-adjuvant, Concurrent & adjuvant hormonal therapy was applied. Risk structures dose statistics were matched to modified Quantec with EQD2 equation. For each patient, daily online fiducial markers image guided verification was done. Toxicity profile was assessed by RTOG for subjective assessment and FACIT quality of life protocol for objective assessment during the radiotherapy course & follow up period. Results: About 80% of patients received the pre-determined protocol, however three patients received 76Gy to prostate & 84Gy to the focal lesion to comply with the risk structure constrains. At median follow up period of 18 months-BFF was 93.3 %. By the end of radiotherapy, 80% developed G3 GU toxicity while 30% developed G2 GI toxicity. Correlation between bladder V40 (≥or≤ 40%) & GU toxicity (≤ G3 vs G3) was of border line statistical significance (P = 0.05). After radiotherapy, GU toxicity dropped to 17.2% G2 & 13% G3 at the 3rd month while 0 % G3 afterwards. Three patients developed G4 rectal toxicity (bleeding per rectum); one at 9th month of ending treatment & two at 12th month; two of them needed cautery for angio-dysplasia as post radiation sequelae confirmed by colonoscopy. However, the correlation between V40 of the rectum ≥ 40% was significant with rectal toxicity (G0 vs G4) (P = 0.02). Comparing FACIT assessment during radiotherapy or in follow up showed no significant difference affecting the quality of life. Conclusions: Dose Escalation with SIB should be done using advanced technique like VMAT with image guidance. Re-validation of risk structure & rectal dose constrains should be considered especially for dose escalation ≥ 72Gy. Clinical trial information: NCT03384199.
Prostate image-guided transperineal elastic-registration biopsy, a new diagnostic tool to refine the risk-stratification of prostate cancer and improve therapeutic decisions.
Authors: Graff-Cailleaud Pierre , Covin Bertrand , Portalez Daniel , Aziza Richard , Khalifa Jonathan , Roumiguié Mathieu , Malavaud Bernard
Published: May 2019

e16595

Background: To evaluate image-guided Transperineal Elastic-Registration biopsy (TPER-B) in the risk-stratification of low-to-intermediate risk prostate cancer detected by Transrectal-ultrasound biopsy (TRUS-B) when estimates of cancer grade and volume discorded with multiparametric Magnetic Resonance Imaging (MRI). Methods: All patients referred for active surveillance or organ-conservative management were collegially reviewed for consistency between TRUS-B results and MRI. Image-guided TPER-B of the index target (IT) defined as the largest Prostate Imaging-Reporting Data System-v2 ≥3 abnormality were organized for discordant cases. Pathology reported Gleason grade, maximum cancer core length (MCCL) and total CCL (TCCL). Results: Of 237 prostate cancer patients (1-7/2018), 42 required TPER-B for risk-stratification. Eight cores were obtained [Median&IQR: 8 (6-10)] including five (IQR: 4-6) in the IT. TPER-B of the IT yielded longer MCCL [Mean&(95%CI): 5.4(3.9-6.9) vs. 2.5mm(1.9-3.1), p = 0.002] and TCCL [16.7(10.6-22.8) vs. 3.9mm(3.1-4.8), p = 0.0001] than TRUS-B of the gland. On TPER-B cores, longer TCCL [Mean&(95%CI): 28.9mm(19.1-38.7) vs. 12.3mm(4.8-19.7), p = 0.02] were measured in Gleason score-7 than score-6 cancers (no cancers detected on IT TPER-B in 11 patients, all but one score 6 < 4mm on TRUS-B). TPER-B cores of the IT upgraded 16/42(38.1%) patients. 21/42(50.0%) met University College London-definition 1 (Gleason score≥4+3 and/or MCL≥6mm) and 27/42(64.3%) definition 2 (Gleason score≥3+4 and/or MCL≥4mm), which correlate to clinically significant cancers > 0.5mL and > 0.2mL, respectively. Allocation to higher risk groups than anticipated from TRUS-B spurred adaptation of treatment protocols (active surveillance n = 15, prostatectomy n = 11, ionizing radiation n = 13, pending n = 3). Conclusions: Image-guided TPER-B of the index target provided more cancer material for pathology. Subsequent re-evaluation of cancer volume and grade switched a majority of patients towards higher risk groups and treatments with curative intent.
Ten year treatment complication outcomes of radical prostatectomy versus external beam radiation therapy versus brachytherapy for 1,503 patients with intermediate risk prostate cancer.
Authors: Goy Barry W. , Burchette Raoul J.
Published: May 2019

e16599

Background: To compare 10 year treatment complication outcomes of radical prostatectomy(RP) vs external beam radiation therapy(EBRT) vs brachytherapy(BT) for patients with intermediate risk prostate cancer(IRPC). Methods: A retrospective analysis was performed on 1,503 IRPC patients who underwent treatment from 2004 to 2007, using univariate comparisons. 819 underwent RP, 574 underwent EBRT, and 110 underwent BT using iodine-125. Urinary and rectal complications for RP were graded as severe if patients required ≥ 3 pads/diapers per day, required chronic use of condom catheter or penile clamp, daily self-catheterization, placement of sling or artificial urinary sphincter, or developed rectal fistula/incontinence. Complications for EBRT and BT were graded as severe if they were classified as grade 3 or 4 on the Radiation Therapy Oncology Group grading system for late effects. For erectile dysfunction, the prevalence of patients requiring injections, pumps or penile implants were calculated after a minimum of 1 year of follow up. Results: Median follow up was 10.0 years for RP, 9.6 for EBRT, and 9.8 for BT. Neoadjuvant androgen deprivation therapy was given in 0.6% for RP patients vs 58.9% of EBRT vs 12.7% of BT, p < 0.0001. Median age for RP vs EBRT vs BT was 62.1, 70.8, 65.3, p < 0.0001. The 10-year prevalence of severe urinary complications for RP vs EBRT vs BT was 10.1%, 12.5%, 4.6%, p = 0.04. The percentage of patients having a pre-treatment American Urological Association(AUA) urinary score for RP vs EBRT vs BT was 7.3%, 11.5%, 97.3%, p < 0.0001. The 10-year prevalence of severe rectal complications for RP vs EBRT vs BT was 0.5%, 1.6%, 0.0%, p = 0.06. The 10-year prevalence of erectile dysfunction devices for RP vs EBRT vs BT was 24.3%, 6.6%, 8.2%, p < 0.0001. Conclusions: After 10 years of follow-up, BT had the lowest rate of severe urinary complications, which may due to using the AUA score to avoid implanting those who had significant baseline obstructive voiding symptoms. EBRT had a higher rate of severe rectal complications. RP had the highest probability of undergoing treatment using erectile dysfunction devices, despite having younger patients.
Deep learning hybrid 3D/2D convolutional neural network for prostate MRI recognition.
Authors: Van Jasper , Yoon Choongheon , Glavis-Bloom Justin , Bardis Michelle , Ushinsky Alexander , Chow Daniel S. , Chang Peter , Houshyar Roozbeh , Chantaduly Chanon , Grant William A. , Fujimoto Dylann
Published: May 2019

e16600

Background: Prostate cancer is the most common cancer of men in the United States, with over 200,000 new cases diagnosed in 2018. Multiparametric MRI of the prostate (mpMRI) has emerged as valuable adjunct for the detection and characterization of prostate cancer as well as for guidance of prostate biopsy. As mpMRI progresses towards widespread clinical use, major challenges have been identified, arising from the need to increase accuracy of mpMRI localization of prostate lesions, improve in lesion categorization, and decrease the time and technical complexity of mpMRI evaluation by radiologists or urologists. Deep learning convolutional neural networks (CNN) for image recognition are becoming a more common method of machine learning and show promise in evaluation of complex medical imaging. In this study we describe a deep learning approach for automatic localization and segmentation of prostates organ on clinically acquired mpMRIs. Methods: This IRB approved retrospective review included patients who had a prostate MRI between September 2014 and August 2018 and an MR-guided transrectal biopsy. For each mpMRI the prostate was manually segmented by a board-certified abdominal radiologist on T2 weighted sequence. A hybrid 3D/2D CNN based on U-Net architecture was developed and trained using these manually segmented images to perform automated organ segmentation. After training, the CNN was used to produce prostate segmentations autonomously on clinical mpMRI. Accuracy of the CNN was assessed by Sørensen–Dice coefficient and Pearson coefficient. Five-fold validation was performed. Results: The CNN was successfully trained and five-fold validation performed on 411 prostate mpMRIs. The Sørensen–Dice coefficient from the five-fold cross validation was 0.87 and the Pearson correlation coefficient for segmented volume was 0.99. Conclusions: These results demonstrate that a CNN can be developed and trained to automatically localize and volumetrically segment the prostate on clinical mpMRI with high accuracy. This study supports the potential for developing an automated deep learning CNN for organ segmentation to replace clinical manual segmentation. Future studies will look towards prostate lesion localization and categorization on mpMRI.
Shifting patterns of care in localized prostate cancer: Impact on patient reported outcome measures (PROMs).
Authors: Connell Brendan James , Patel Rima , Chang Hong , Luongo Tony , Zhuang Liyan , DiPetrillo Thomas A. , Mignano John , Carpinito Gennaro , Mathew Paul
Published: May 2019

e16603

Background: In localized prostate cancer (LPC), evolving therapeutic techniques and patterns of care including the use of active surveillance (AS) are expected to have had a positive effect on quality of life. A longitudinal assessment of changes in disease presentations and patterns of care in LPC correlated to PROMs is required. Methods: All cases of LPC (T1-T4, N0-N1) at a tertiary care institution were identified between 2005 and 2015. Two cohorts (C1: 2005-10, C2: 2010-15) with a minimum of 2-years follow-up, were identified. Demographics, disease characteristics and management strategies were compared across cohorts. To assess PROMs, a one-time questionnaire including EPIC-26 and Clark’s Quality of Life was administered. Domain summary scores were compared across cohorts. Results: 873 patients met criteria [C1: 422, C2: 535]. Demographics were well balanced (p = 0.10): overall 64.1% white, 12.7% AA, 12.7% Asian. D’Amico risk scores increased over time (p = 0.001): fewer low-risk cases [C1: 49.2%, C2: 43.7%], higher intermediate-risk disease [C1: 34.6%, C2: 40.3%], and stable high-risk proportions [C1: 15.7%, C2: 14.9%]. Patterns of care shifted significantly (p = 0.005) with a marked decrease in radiation therapy [C1: 25.7%, C2: 15.4%], unchanged radical prostatectomy rates [C1: 47.9%, C2: 51.0%], a shift to robotic surgery [C1: 23.8%, C2: 90.3%], and an increase in AS [C1: 21.8%, C2: 30.8%], particularly in low-risk disease [C1: 32.4%, C2: 53.5%]. Questionnaire response rate was 45.1%. Using multivariate regression, C2 demonstrated an improvement in bowel function (p = 0.031) but not in urinary, sexual, or psychometric scores. Conclusions: Notwithstanding an increase in AS utilization for low-risk disease, an improvement in bowel function and lack of improvement in urinary/sexual PROMs in LPC across time-cohorts was noted. This may be accounted for by increased presentations of higher-risk disease managed with robotic surgeries at the expense of radiation therapy. Although time-length bias can influence comparisons, given national trends with a similar shift in presentation and care patterns, these PROM correlations are likely generalizable to the U.S. population.
The relative contributions of the Genomic Prostate Score and comorbidity profile in predicting outcomes in surgically treated men with clinically low and intermediate-risk prostate cancer.
Authors: Cullen Jennifer , Pierre-Victor Dudith , Lawrence H. Jeffrey , Kuo Huai-Ching , Sesterhenn Isabell , Rosner Inger L.
Published: May 2019

e16607

Background: The 17-gene Oncotype Dx Genomic Prostate Score® (GPS™) assay has been validated as a predictor of aggressive prostate cancer (PCa) in men treated with radical prostatectomy (RP) for clinically low and intermediate risk PCa. This study examined the performance of the GPS assay as a predictor of adverse pathology (AP) and biochemical recurrence (BCR)-free survival (BRFS), after adjusting for the presence of major comorbidities commonly seen in older men. Methods: Additional analyses were performed using data from a prior clinical validation study of the GPS assay. GPS values (scaled 0-100), determined from diagnostic biopsy tissue, were categorized into 3 levels: lowest quartile (Q1), middle quartiles (combined Q2-Q3) versus the highest quartile (Q4). Major comorbidities included heart disease, stroke, COPD, and other cancers. The associations between GPS result and the presence of ≥1 major comorbidity and outcomes were examined. AP was defined as high-grade (Gleason Score ≥ 4+3) and/or pT3 tumor. BCR was defined as 2 successive PSA levels > 0.2 ng/mL. Logistic regression analysis was used to examine AP; Cox proportional hazards analysis was used to model BRFS. Results: Among 389 eligible men, median age at diagnosis and follow-up time was 62 and 5.6 years, respectively. The prevalence of ≥1 major comorbidity differed significantly across GPS category, rising from 10.2% to 19.7% to 25.5% for GPS Quartiles 1, 2-3, and 4, respectively (p = 0.0024). However, presence of ≥1 major comorbidity was not a significant predictor of AP or BCR in multivariable models with GPS, age, race, and NCCN risk stratum. Men whose GPS result was in the highest quartile had 4-fold higher odds of AP (OR: 4.1; 95% CI = 2.1-7.99, p < 0.0001) at RP and a 3.5 times higher risk of BCR (HR = 3.49; 95% CI = 1.59-7.64, p = 0.002) compared to men in the lowest GPS quartile (Table 1). Conclusions: A high GPS result remains the strongest predictor of BCR and AP in this cohort of low and intermediate risk PCa men, after adjusting for the presence of major comorbidities. Further work will explore the relationships between specific comorbidities and metabolic syndrome, with GPS testing and PCa outcomes.
Weighted gene co-expression network analysis combined with machine learning to identify prognostic biomarkers for cervical squamous cell carcinoma.
Authors: Li Yimin , Lan Mei , Peng Xinhao , Zhang Zijian , Lang Jin Yi
Published: May 2019

e17000

Background: Cervical cancer represents the fourth most frequently diagnosed malignancy affecting women all over the world. However, effective prognostic biomarkers are still limited for accurate identifying high-risk patients. Here, we provide a co-expression network and machine learning-based signature to predict the survival of cervical cancer. Methods: Utilizing expression profiles of The Cancer Genome Atlas datasets, we identified differentially expressed genes (DEGs) and the most significantly module by differential expression analysis and Weighted Gene Co-expression Network Analysis, respectively. The candidate genes was obtained by combining the both results. Then the prognostic classifier was constructed by LASSO COX regression analysis and validated in testing set. Finally, survival receiver operating characteristic and Cox proportional hazards analysis was used to assess the performance of prognostic prediction. Results: We identified 190 differentially expressed genes (DEGs) between cervical squamous cell cancer(CSCC) and normal samples in purple module. Next we built a 8-mRNA-based signature, and determined a optimal cutoff value with sensitivity of 0.889 and specificity of 0.785. Patients were classified into high-risk and low-risk group with significantly different overall survival(training set: p < 0.0001; testing set: p = 0.039). Furthermore, the prognostic classifier was an independent and powerful prognostic biomarker for OS (HR = 7.05, 95% CI: 2.52-19.71, p < 0.001). Conclusions: The prognostic classifier is a promising predictor of CSCC patients, the novel co-expression network and machine learning-based strategy described in the study may have a broad application in precision medicine.
Survival of patients with cervical cancer and diabetes: An exploratory study.
Authors: Romero Maria Luisa , Gonzalez Vela Jose Luis , Hernandez Barajas David , Velazquez-Pacheco Ascary , Hernández Abrham Josafath , Villarreal Ondarza Irma Anaid , Escobedo Rodriguez Roberto Alejandro , Vidal-Gutiérrez Oscar
Published: May 2019

e17008

Background: Mexico is the sixth country with the highest number of diabetics, this being the second cause of death. Between 8-18% of cancer patients have Diabetes (DM) as comorbidity. Studies have reported DM has worst prognosis in Overall Survival (OS) and Progression Free Survival (PFS) in patients with Cervical Cancer (CC). Aim: to compare OS in patients (pt) with a diagnosis of CC and DM, and to evaluate this outcome in relation to the clinical stage and the glycemic level at diagnosis of CC. Methods: data was obtained from pt treated for invasive CC between 2006 and 2016. Pt aged ≥20 years, with squamous, adenocarcinoma or adenosquamous histology. 59 pt with CC and DM in group 1 (G1), and 118 pt with CC without DM in group 2 (G2), paired 1:2 according to clinical stage, age and comorbidities. Results: Prevalence of DM in pt with CC was 16%. Follow-up of 142.2 months (median of 40.4 months), lower OS for G1 was seen (74.6% vs 77.1%), without statistical significance (p.803). PFS was similar for both groups (67.8% G1 vs 66.9% G2, p .608). In patients with locally advanced and metastatic disease, a lower OS and PFS were found in G1, without statistical significance. 42.4% diabetic pt had glycemic level < 130 mg / dL). OS was lower in pt with higher glycemic level (70.6% vs 80%), not being statistically significant (p .32). PFS was similar in both groups (G1: 68% vs G2: 67.6%, p.852). Analysis for influence of metformin treatment, evidenced a higher OS among pt receiving metformin (84.8% vs 61.5%), without statistical significance (p 0.65). PFS was higher in the metformin group (78.8 vs 53.8%), with a trend towards statistical significance (p .052). Conclusions: Pt diagnosed with CC and DM do not have different OS compared to those without DM. There was a tendency towards the improvement of PFS in pt with CC and DM, who received metformin.
Revised FIGO staging shows dramatic survival differences in cervical cancer patients with positive lymph nodes in Louisiana.
Authors: Nair Navya , Zhang Lu , Kuan-Celarier Anna , Wu Xiao-cheng , Jernigan Amelia
Published: May 2019

e17010

Background: With revisions to FIGO cervical cancer staging system in 2018, patients with positive pelvic or para-aortic lymph nodes (LN) are now classified as stage IIIC. Rationale for this change is based on data published in 1990. Methods for work up and treatment of cervical cancer have advanced since then. We aim to determine if updated FIGO staging reflects contemporary survival differences in women with cervical cancer in Louisiana. Methods: Women with FIGO stage I-III cervical cancer diagnosed between 2010 and 2016 were identified from the Louisiana Tumor Registry. Those with < 30 days follow up were excluded. Patients were classified into 3 groups: true stage I & II (LN negative), revised stage IIIC (old stage I or II but positive LN), previous stage III (old FIGO stage IIIA or IIIB). Cox proportional hazards were used to estimate differences in overall and (OS) cause-specific survival (CSS). Covariates of age, race, insurance, census-tract poverty level, and marital status were controlled. Results: 740 patients were included with a median follow up of 40.6 months. Patients in revised stage IIIC group were younger than the others (45.9 yrs vs 47.9 yrs in true stage I&II vs 55yrs in previous stage III, p < 0.0001). True stage I&II patients were more likely to be privately insured (48.9% vs 32.1% revised stage IIIC vs 27.7% previous stage III, p < 0.0001). The groups did not differ by race, poverty level, or marital status. Revised stage IIIC and previous stage III patients had significantly worse survival outcomes compared to true stage I & II in both OS [revised stage IIIC HR 1.93 (1.20-3.11); previous stage III 5.92 (4.27, 8.22)] and CSS [revised stage IIIC HR 2.54 (1.45-4.44); previous stage III HR 7.95 (5.29, 11.94)]. Kaplan-Meier survival curves demonstrate significant differences in both OS and CSS (p < 0.0001) with best outcomes in true stage I&II and worst in previous stage III patients. Conclusions: LN status is an important prognostic indicator for contemporary cervical cancer patients in Louisiana. This analysis provides recent data to support the revised FIGO staging system in upstaging patients with positive LN to stage IIIC as they have significantly worse survival than the true stage I & II patients. Importantly, revised stage IIIC patients who would have previously been stage I & II have strikingly better survival outcomes than women with stage IIIA and IIIB disease. If staging is to be intuitive, the stage III subcategories may need to be redefined.
Value of adjuvant chemotherapy using paclitaxel plus carboplatin after radical surgery with or without radiotherapy in stage IB-iia cervical adenocarcinoma with risk factors.
Authors: Wu You , Nan Li , An Jusheng , Huang Manni , Ma Shaokang , Wu Lingying
Published: May 2019

e17016

Background: The aim of this study was to evaluate the efficacy and safety of paclitaxel/carboplatin as an adjuvant systemic chemotherapy for stage IB-IIA cervical adenocarcinoma patients after radical hysterectomy and pelvic lymphadenectomy with or without radiotherapy(RT). Methods: The cases of all patients (n = 152) with FIGO IB-IIA cervical adenocarcinoma who were treated by radical hysterectomy and pelvic lymphadenectomy with or without RT at Chinese academy of medical sciences cancer institute and hospital between January 2008 and January 2017 were reviewed. Of these, 35 patients displayed high-risk prognostic factors (high-risk group), 65 displayed intermediate-risk prognostic factors meeting sedlis criteria(intermediate-risk group),and 54 cases presented poorly differentiated status or LVSI, without other risk factors. In the high-risk group,18 patients received adjuvant radiotherapy and concurrent cisplatin chemoradiotherapy(RT-CCRT ) and 17 received adjuvant radiotherapy plus systemic chemotherapy using Paclitaxel Plus Carboplatin (RT-CT ). In the intermediate-risk group, 47 patients were treated with RT-CCRT and 16 were treated with RT-CT ,among the patients with poorly differentiated status or LVSI ,20 were treated with adjuvant chemotherapy using Paclitaxel Plus Carboplatin (CT ) and 34 received no further treatment (NFT). Results: In the high-risk group, adjuvant RT-CT was significantly superior to RT-CCRT with regard to median PFS and 2-year PFS rate(93.07months vs 52,44months, 94.1% vs 72.2%), but the recurrence rate and survival rate showed no significantly difference(11.8% vs 33.3%,100% vs 83.3%) . In the intermediate-risk group, Patients receiving RT-CT showed a better 2-year PFS rate and recurrence rate compared to those with RT-CCRT (100% vs 90.7%, 6.3% vs 12.6%), but the differences were not statistically significant. Among the patients with poorly differentiated status or LVSI, addition of adjuvant systemic chemotherapy resulted in significantly improved 2-year PFS rate compared with the NFT group (95% vs. 75.2%,p = 0.032). Conclusions: Adjuvant systemic chemotherapy using Paclitaxel Plus Carboplatin improved the prognosis of FIGO stage IB-IIA cervical adenocarcinoma patients in the high-risk group and patients who presented 2 or more intermediate-risk factors. Early cervical adenocarcinoma patients with low differentiation or LVSI can also benefit from postoperative adjuvant TC chemotherapy.