bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of DNA damage repair (DDR) mutations (mts) and clinical outcomes in CALGB 90601 (Alliance).
Authors: Iyer Gopa , Halabi Susan , Luo Bin , Rosenberg Jonathan E. , Choi Woonyoung , Al-Ahmadie Hikmat A. , Mountain Jack , Regazzi Ashley Marie , Fong Megan , Mouw Kent William , Van Allen Eliezer Mendel , McConkey David James , Wen Yujia , McCart Linda , Ballman Karla V. , Beltran Himisha , Morris Michael J. 
Published: June 2022

4521 Background: Platinum-based chemotherapy is the standard 1st-line therapy for metastatic urothelial cancer (mUC). C90601 was a randomized phase III trial testing gemcitabine and cisplatin (GC) with bevacizumab (B) or placebo (P) in patients (pts) with untreated mUC. Median overall survival (OS) for GCB vs GCP was 14.5 months (mo) vs 14.3 mo (p=0.14) and median progression-free survival (PFS) was 8 vs 6.7 mo, respectively. DDR mts have been implicated in response and survival in mUC and were investigated in this negative trial. Methods: C90601 enrolled 506 pts randomized 1:1 to GCB or GCP from 7/15/09-12/2/14, with stratification for prior chemotherapy and visceral metastases. Consenting pts submitted archival FFPE tumor specimens and blood for matched germline (g)DNA. Tumor and gDNA were sequenced by MSK-IMPACT, a 468-gene exon capture assay, to detect mts in select DDR genes. The proportional hazards model was used to correlate mts in the DNA helicase ERCC2 (pre-specified hypothesis) and additional DDR gene panels being explored in prospective trials in muscle-invasive disease with OS and PFS, adjusting for tumor mt burden and stratification factors. Mts were categorized as deleterious (del) or non-del using pre-defined published criteria. Results: 208 pts underwent DNA sequencing. Clinical features and PFS/OS were comparable to the 506-pt cohort. Median sequencing coverage was 497X. Median mutation count was 13.2 and 8.8 for DDR mt and wild-type tumors, respectively. A non-significant improvement in OS and PFS was seen in pts with ERCC2 mts (HR 0.70), but the 5.3% frequency of ERCC2 mts was lower than in historical series. Neither del mts (table) nor any mts in DDR genes were associated with PFS/OS. Conclusions: DDR mts were not associated with improved outcomes in C90601. The reliance on archival specimens, lower-than-expected ERCC2 mt frequency, small sample sizes, and tumor genomic heterogeneity may have influenced the predictive capacity of DDR mts in this cohort. Similar analyses are underway in pts who received neoadjuvant chemotherapy prior to cystectomy from completed prospective trials. Support: U10CA180821, U10CA180882, Genentech.[Table: see text]
Progression-free survival after second line of therapy (PFS-2) for metastatic clear cell renal cell carcinoma (ccRCC) in patients treated with first-line immunotherapy combinations.
Authors: Fitzgerald Kelly N. , Duzgol Cihan , Knezevic Andrea , Shapnik Natalie , Kotecha Ritesh , Aggen David Henry , Carlo Maria Isabel , Shah Neil J. , Voss Martin H , Feldman Darren R. , Motzer Robert J. , Lee Chung-Han 
Published: June 2022

4536 Background: Front-line therapy with immunotherapy combinations is standard of care for metastatic ccRCC, with ipilimumab/nivolumab (IO/IO) and several combinations of a VEGFR-targeted tyrosine kinase inhibitor with a PD-1 inhibitor (TKI/IO) showing superior efficacy to TKI monotherapy. PFS-2 evaluates the ability to be salvaged by 2nd line therapy and is a surrogate for overall survival (OS). PFS-2 was compared in patients receiving 1st line IO/IO vs TKI/IO for metastatic ccRCC. Methods: A retrospective analysis was performed on patients with ccRCC treated at Memorial Sloan Kettering Cancer Center between 1/1/2014 and 12/30/2020, in cohorts defined by 1st line: IO/IO or TKI/IO. PFS-2 is defined as time from start of 1st line to progression on next therapy, or death. Patients without a PFS-2 event were censored at a prespecified cutoff date. Objective response rate to 1st (ORR1st) and 2nd (ORR2nd) line are compared with the Fisher’s exact test. OS, PFS-2, and time on therapy are estimated with the Kaplan-Meier method and compared with the log-rank test. Results: One hundred seventy-three patients received 1st line IO/IO (N = 90) or 1st line TKI/IO (N = 83); respectively, 52 and 40 patients had a PFS-2 event. 1st line TKI/IO regimens included: 34% axitinib/pembrolizumab, 29% lenvatinib/pembrolizumab, 25% axitinib/avelumab, 11% other. More IO/IO patients had brain metastases and intermediate/poor MSKCC risk category (respectively p = 0.007, p < 0.001). ORR1st and median months on 1st line were higher with TKI/IO vs IO/IO (65% vs 39%, p < 0.001; 16.1 vs 5.1, p < 0.001). ORR2nd was higher with IO/IO vs TKI/IO (47% vs 13%, p < 0.001), and median months on 2nd line was not significantly different (7.7 vs 7.1, p = 0.30). Median PFS-2 for TKI/IO was 44 months (95% CI: 27, 53) vs 23 months (95% CI: 16, 47) for IO/IO, p = 0.13. For TKI/IO and IO/IO groups, respective PFS-2 at 12 months was 86% (95% CI 77, 92) and 74% (95% CI 63, 82); PFS-2 at 36 months was 51% (95% CI 39, 63) and 42% (95% CI 30, 53). OS was not significantly different (p = 0.32; 3 year OS: IO/IO 60%, 95% CI 47, 71; TKI/IO 62%, 95% CI 49, 73). (Table) Conclusions: In patients receiving 1st line IO/IO or TKI/IO, ORR2nd was higher with IO/IO and median PFS-2 was numerically higher with TKI/IO, but no statistically significant difference in PFS-2 or OS was seen. These findings suggest that IO/IO and TKI/O are both acceptable 1st line treatment strategies in ccRCC. [Table: see text]
Prognostic factors for patients with advanced renal cell carcinoma (aRCC) in the era of first-line (1L) treatment with immune checkpoint inhibitors (ICIs).
Authors: Mantia Charlene , Jegede Opeyemi , Regan Meredith M. , Atkins Michael B. , McDermott David F. 
Published: June 2022

4544 Background: The most commonly used prognostic models in aRCC, the Memorial Sloan-Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, were developed when cytokines and VEGF targeted monotherapies were standard of care, respectively. aRCC 1L treatment now includes combination therapy with 2 ICIs or ICI+VEGF receptor inhibitor. Re-evaluation of the MSKCC and IMDC prognostic models in the era of ICI therapy and identification of additional prognostic factors are overdue. Methods: Data from 1052 patients with aRCC treated on the CheckMate-214 (CM214) clinical trial with 1L nivolumab/ipilimumab (NIVO/IPI) or sunitinib (SUN) were analyzed retrospectively at median follow-up 5 yrs. For each treatment group, multivariable Cox model hazard ratios (HR) were compared to the published MSKCC and IMDC model HRs. Discrimination (c index) was assessed based upon the continuous scores obtained as the weighted combination of regression parameters from the published MSKCC & IMDC models. Results: KPS < 80% remained highly prognostic in both treatment groups (HRs > 2.5). With the exception of high calcium, the other factors of time from dx to treatment < 1 yr, hemoglobin < lower limit of normal (LLN), neutrophils > upper limit of normal (ULN), platelets > ULN and LDH > 1.5xULN consistently retained prognostic value for SUN (HRs ≥ published model HRs) but had diminished prognostic value for NIVO/IPI (each HR < published model HR). High calcium had diminished prognostic value for SUN and retained prognostic value for NIVO/IPI. The c-indices for discrimination were 0.61 and 0.64 for the MSKCC model in the NIVO/IPI and SUN treatment groups, respectively, and were 0.63 and 0.67 for the IMDC model in the NIVO/IPI and SUN treatment groups compared to reported IMDC c-index of 0.73 (Heng 2009). (Table) Conclusions: The prognostic ability of the MSKCC and IMDC risk models is reduced with combination ICI treatment. Evaluation of additional prognostic factors and development of new risk scores are needed and this work is ongoing. [Table: see text]
Artificial intelligence algorithms for the diagnosis of urothelial carcinoma based on urine cytology: A noninvasive and efficient diagnostic approach.
Authors: Shen Chong , Wang HaiTao , Hu Hailong , Niu Yuanjie , Tian Dawei , Huang Shiwang , Zhao Gangjian , Huang Chuanyi , Wu Zhouliang , Zhang Zhe 
Published: June 2022

4590 Background: Urine cytology is a noninvasive and relatively inexpensive approach that plays an important role in both screening/initial diagnosis of urothelial carcinoma, and surveillance of tumor recurrence; However, interpretation of urine cytology is labor-intensive and time-consuming. Artificial intelligence (AI) has been widely used in the field of medically assisted diagnosis, but it is almost blank in the field of urothelial carcinoma diagnosis based on urine cytology. In this study, artificial intelligence (AI) algorithms have been developed to efficiently and automatically analyze urinary cytological specimens stained with Acridine orange fluorescence for screening and diagnosis of urothelial carcinoma with a good clinical application prospect. Methods: To develop the algorithms, images of urinary cytological specimens with Acridine orange Fluorescence staining were collected from patients who underwent examination, surgery, or both at the Second Hospital of Tianjin Medical University from August 2015 to August 2021. To standardize the urine cytological determination, the images were determined by 3 certified and experienced cytopathologists in this hospital. Images were collected to establish a dataset containing two major categories: Malignant (Defined as images containing malignant cells) and Benign (Defined as images containing malignant cells). From the acquired database, 2794 malignant and 2787 benign eligible images were selected for AI training/validation/testing. Inception V3, a specific type of neural network optimized for image classification called a deep convolutional neural network was trained based on the database. To prevent the model from over-fitting during training, data augmentation methods, such as rotation and flipping were adopted. The diagnosing performance of the binary classification model was analyzed using accuracy, F1 score, operating characteristic (ROC), and the area under the curve (AUC) generated from the sensitivity and specificity to evaluate. Results: A total of 21022 slides of urine cytological specimens with Acridine orange Fluorescence staining were collected. The AI algorithms achieved excellent performance, which showed the best prediction with an accuracy of 92.25%, a sensitivity of 98.50% along with a specificity of 86.00%, the F1score was 0.9271, and the area under the ROC curve was 0.96. Conclusions: Our novel artificial intelligence algorithms could accurately classify urine specimens as malignant or benign efficiently and automatically. The use of AI during cytopathology screening provides a new strategy and technical support for the diagnosis and screen of urothelial carcinoma. [Table: see text]
Prognostic factors and clinical outcomes in patients with upper tract urothelial carcinoma undergoing surgery: The Cleveland Clinic experience.
Authors: Ahmed Ramsha , Sheu Michael , Wei Wei , Ornstein Moshe Chaim , Gilligan Timothy D. , Dima Danai , Campbell Steven , Lee Byron H , Weight Christopher , Wee Christopher Eing , Mian Omar Y. , Kaouk Jihad , Haber Georges-Pascal , Gupta Shilpa 
Published: June 2022

4593 Background: Upper tract urothelial carcinoma (UTUC) is a rare and heterogeneous disease accounting for approximately 5-10% of UC. While tumor grade and stage are known prognostic factors, data on other factors affecting outcomes in UTUC patients (pts) undergoing surgery is scant. We studied effect of various clinical factors and treatment on outcomes in UTUC. Methods: This is a single-institution retrospective study of 607 pts with UTUC undergoing surgery (nephroureterectomy (NU) or ureterectomy (U)) between Jan 2000 and Dec 2020. We studied effect of demographics, clinicopathological features, tumor location, preoperative Neutrophil-to-Lymphocyte ratio (NLR) and Albumin-to-Globulin ratio (AGR) and use of neoadjuvant or adjuvant chemotherapy on overall survival (OS) and recurrence free survival (RFS). Results: Of the 607 pts 401 (66.06%) were males and 355 (58.48%) were > 70 yrs; 232 pts (38.22%) had UTUC of renal pelvis, 242 (39.87%) of ureter and 133 (21.91%) of both. 542 pts (89.29%) underwent radical NU and 65 (10.71%) segmental U; 328 patients (54.04%) were diagnosed with muscle invasive UC (MIUC) ( > / = pT2) and 276 (45.47%) with non-MIUC ( < / = pT2). Only 51 (8.4%) pts had lymph node positive (N+) disease. Lymphovascular invasion (LVI) was identified in 163 (26.85%) and carcinoma- in-situ (CIS) in 163 (26.85%) pts. Surgical margins were positive in 92 pts (15.16%). Median NLR cutoff was 3.25 and AGR cutoff was 1.25 (dichotomized based on literature). 44 pts (7.2%) received Neoadjuvant chemotherapy and 49 pts (8%) received adjuvant chemotherapy. Tumor recurrence occurred in 216 pts (35.58%) of which 65% were at urothelial and 35% at non-urothelial sites. With median follow up of 35.2 mos, median OS was 82.69 mos and 5-yr OS rate was 60%; median RFS was 29.47 mos and 5-yr RFS rate was 40%. High grade, age > / = 70 yrs, high NLR, low AGR, presence of LVI, positive margins, CIS, MIUC, N+ disease were associated with worse outcomes. Pts with only renal pelvis involvement had better OS. Conclusions: In this large, long term follow-up series of UTUC pts, we identified several prognostic factors besides grade and stage that impact outcomes. These findings warrant further validation for use in clinical practice. [Table: see text]
Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Halabi Susan , Roy Akash , Rydzewska Larysa , Godolphin Peter , Parmar Mahesh K. B. , Hussain Maha H. A. , Tangen Catherine , Thompson Ian , Xie Wanling , Carducci Michael Anthony , Smith Matthew Raymond , Morris Michael J. , Gravis Gwenaelle , Dearnaley David P. , Verhagen Paul , Goto Takayuki , James Nicholas D. , Buyse Marc E. , Tierney Jayne F. , Sweeney Christopher 
Published: June 2022

5006 Background: We hypothesized that radiographic progression free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite phase 3 clinical trials. This hypothesis was investigated by the STOPCAP M1 Collaboration. Methods: We obtained individual patient data (IPD) from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC. We evaluated the surrogacy of rPFS and cPFS as potential ICEs. rPFS was defined as time from randomization to radiographic progression (defined per protocol) or death from any cause whichever occurred first; cPFS was defined as time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. OS was defined as time from randomization to death from any cause, if patients had not died they were censored at the date of last follow-up. We implemented a two-stage meta-analytic validation model where conditions of trial level and patient level surrogacy had to be met. We computed the surrogate threshold effect (STE), which is the minimum ICE treatment effect necessary to estimate a non-zero effect on OS. Results: IPD from 8592 patients randomized from 1994-2012 from 13 trials were pooled for a stratified analysis. There were 5377 deaths, of which 3971 (74%) were due to prostate cancer. The median follow-up for surviving patients was 75.6 months. In addition, there were 6227 rPFS and 6314 cPFS events. The median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively. The STE was 0.82 for rPFS and 0.84 for cPFS. Conclusions: Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned. Clinical trial information: Several. [Table: see text]
Biomarker-directed therapy in black and white men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hwang Clara , Henderson Nicholas , Cackowski Frank Cameron , Pilling Amanda , Jang Albert , Rothstein Shoshana , Labriola Matthew , Park Joseph J. , Ghose Alyssa , Bilen Mehmet Asim , Kilari Deepak , Tripathi Abhishek , Garje Rohan , Koshkin Vadim S , Schweizer Michael Thomas , Armstrong Andrew J. , McKay Rana R. , Dorff Tanya B. , Alva Ajjai Shivaram , Barata Pedro C. 
Published: June 2022

5013 Background: Black men have been underrepresented in large-scale molecular prostate cancer (PC) surveys, despite having higher PC incidence and mortality. Since molecular profiling to guide the use of targeted agents is increasingly important in mCRPC, we compared precision medicine data and utilization in a cohort of black and white men with mCRPC. Methods: The PROMISE precision medicine database is an academic collaboration to compile clinical and genomic data from men with PC. All patients have had germline and/or somatic genetic testing performed. Eligibility criteria for this analysis included a diagnosis of mCRPC with available race and biomarker data. The primary outcome was the proportion of non-Hispanic black (NHB) and non-Hispanic white (NHW) men with actionable molecular data, defined as the presence of mismatch repair deficiency (MMRd/MSI-H), homologous recombination repair deficiency (HRRd), tumor mutational burden (TMB) ≥ 10 mut/MB, or AR-V7. Secondary outcomes included the proportion of NHB and NHW men with other alterations, the type and timing of genomic testing performed, and the use of targeted therapy. Results: A total of 962 mCRPC patients (21.2% NHB; 78.8% NHW) met inclusion criteria of 1619 in the overall database. Median age (NHB/NHW) was 61/63; 77.5/68.8% had Gleason 8-10; 52.5/56.7% presented with de novo metastatic disease (33.8/29.9% LN, 36.2/32.2% bone and 8.3/6.1% viscera). The median time from diagnosis to first molecular result was 56.3 mo for NHB v 58.7 mo for NHW (p = 0.45). Use of blood-based molecular testing was more common in NHB men (48.7% v 36.4%, p < 0.001). Overall, 32.8% of NHB men harbored actionable molecular data compared to 30.3% of NHW men (Table). MMRd/MSI-H was more common in NHB men (9.1 v 4.9%, p = 0.04). Other than PTEN (12.7/23.8% NHB/NHW, p = 0.0001), no significant differences were seen in the 15 most frequently mutated genes, including TP53, AR, CDK12, RB1, and PIK3CA. Tumor suppressor co-mutations (PTEN/TP53/RB1) were found in 13.1% of NHB and 18.0% NHW (p = 0.13). Delivery of targeted therapy was reported in 19.6% of NHB and 23.7% of NHW men (p = 0.25) after a median of 2 CRPC lines. Median OS from development of mCRPC was 41.5 mo (95% CI, 34.7-51.3) and 44.7 mo (95% CI, 41.1-51.5) for NHB and NHW men, respectively (p = 0.14). Conclusions: In a real-world mCRPC molecular profiling cohort, we found similar overall rates of actionable molecular alterations in NHB and NHW men, but higher rates of MMRd/MSI-H and lower frequency of PTEN alterations in NHB men. We did not find differences in delivery of targeted therapy. [Table: see text]
Long-term predictive value of serum PSA values obtained in clinical practice: Results from the Norwegian Prostate Cancer Consortium (NPCC).
Authors: Oldenburg Jan , Bjerner Johan Lars , Lilja Hans , Aas Kirsti , Fossa Sophie D. , Mueller Christoph , Mueller Stig , Thomas Owen , Stensvold Andreas , Walz Jochen , Røe Oluf D. , Bratt Ola , Carlsson Sigrid V. 
Published: June 2022

5021 Background: A baseline prostate-specific antigen (PSA) level in midlife is strongly associated with risk of lethal prostate cancer several decades later. In most prior studies, PSA was measured in archived blood from men participating in cohort studies unrelated to prostate cancer. In clinical practice, however, men commonly obtain a PSA test because of lower urinary tract symptoms. Here, we study the association between PSA values when a first PSA test was obtained as part of clinical care – and subsequent risks of prostate cancer diagnosis and death. Methods: The NPCC database contained laboratory results from 1995-2006 of the first (“baseline”) PSA test below 4.0 ng/mL in 157,836 men aged 40-69 years without prior prostate cancer (PCa) diagnosis. PSA strata were pre-defined: < 1, 1-1.99, 2-2.99, 3-3.99 ng/ml and analyses were split in two age groups based on a prior risk: 40-54 (“younger”) and 55-69 (“older”). Predictive accuracy was assessed with Harrell’s concordance (C) index. The Kaplan-Meier method was used to visualize risk of PCa death as reported on the death certificate by PSA strata for the two age groups. Results: Among 157,836 men with a PSA below 4.0 ng/mL, 83% had < 2.0 ng/mL. Risk of prostate cancer and death from prostate cancer were strongly associated with PSA-levels and age: Harrell’s C-index 0.75 and 0.72 for diagnosis of younger and older group, respectively and 0.72 for PCa death for both age groups. In the younger age group 196 deaths among 75,446 men (0.26%) were registered, in the older 943 deaths among 82,390 men (1.14%). The risk of PCa death in lowest (< 1) and highest (3-3.99) strata were 0.23% and 3.22%, respectively (189 deaths among 81,982 vs. 274 deaths among 8517 men). Conclusions: This population-based NPCC study shows as strong predictive impact of the different strata of the initial PSA measurement in routine clinical care as prior studies based on cryopreserved blood samples. [Table: see text]