bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of microbial metabolism of tryptophan with resistance to immune checkpoint (ICB) therapy in renal cell cancer (RCC).
Authors: Bari Shahla , Manley Brandon J. , Muzaffar Jameel , Sarfraz Humaira , Armstrong Andrew J. , Tannir Nizar M. , George Daniel J. , Conejo-Garcia Jose 
Published: January 2024

452 Background: Metastatic RCC has a poor prognosis. Despite improvement in treatment outcomes with ICB and targeted therapy, many patients fail to respond to first line therapy and durable responses remain elusive. The tryptophan metabolite kynurenine, an agonist of the immunosuppressive aryl hydrocarbon receptor (AhR), is associated with resistance to ICB. However, IDO (Indole 2,3 dioxygenase) blockers which inhibit tryptophan metabolism to kynurenine failed to show benefit in clinical trials, suggesting the presence of alternate AhR activation. We hypothesize that microbial metabolism of tryptophan to indole metabolites may be associated with AhR activation and ICB resistance. Methods: We prospectively collected paired stool and blood samples of treatment naïve metastatic RCC patients, treated with ICB +/- Tyrosine kinase inhibitors (TKI) at treatment initiation and at time of first response assessment (12+/-3 weeks). We evaluated stool metagenomics and untargeted stool and plasma metabolomics among responders (R) and non-responders (NR). We focused on kynurenine/tryptophan and indoles/tryptophan ratio to evaluate differential host and microbial metabolism of tryptophan. A responder was classified as progression free survival (PFS) greater than 6 months. We also performed global metabolomics on tumor and plasma of germ-free (GF) & specific pathogen free (SPF) mice to identify microbial & host metabolites. Results: Among 120 patients accrued, baseline paired samples were analyzed from 99 patients, 39 were treated with combination ICB, while 60 patients were treated with ICB + TKI. Median follow up was 15 months. 65% of patients had PFS > 6 months. Using unpaired t test comparing baseline relative abundance of metabolites between R vs NR - plasma Kynurenine/tryptophan ratio was significantly higher in NR vs R, at baseline and at 3 months (baseline-0.042 vs 0.01, p=0.01, 3 months-0.058 vs 0.02, p=0.02). Microbial metabolites of Tryptophan -Indole pyruvic acid (IPA), Indole carboxylic acid (IcA), and Indole acetaldehyde (IAAld) were differentially associated with ICB resistance and was significantly higher in NR (IcA: 8.0 vs 5.2, p=0.03; IPA: 82.4 vs 64.9, p=0.01; IAAld: 78.7 vs 64.6, p=0.03). We also noted differential enrichment of microbial KEGG enzymes associated with IPA, IAAld and IcA production in the stool of NR patients compared to R. Microbial origin of these metablites was confirmed by its absence in tumor of GF mice. Conclusions: This is first study in metastatic RCC which shows the association of indoles (microbial metabolites of tryptophan) with resistance to ICB. These indoles are known to be potent AhR agonists and are associated with immunosuppression suggesting that microbial metabolism of tryptophan may represent a novel pathway for ICB resistance in RCC patients.
Endogenous retrovirus expression and its impact on tumor-infiltrating immune cells in papillary renal cell carcinoma.
Authors: Vento Joseph , Brewer Jared , Reddy Anupama , De Cubas Aguirre , Beckermann Katy , Rini Brian I. , Rathmell W. Kimryn , Haake Scott Mattox 
Published: January 2024

453 Background: Endogenous retroviruses (ERVs) represent 5-8% of the human genome, and their expression in cancer cells correlates with response to immunotherapy in clear cell renal cell carcinoma (ccRCC). Whether this association also exists in papillary renal cell carcinoma (PRCC) is unknown. Studying ERV expression in PRCC and its impact on the tumor microenvironment (TME) may help elucidate its role in PRCC response to immunotherapy. Methods: We quantified ERV expression on human PRCC tissue samples using real-time quantitative PCR (RT-qPCR). ERV4700 was selected due its correlation with response to immunotherapy when expressed in ccRCC. In addition, we stained matched human FFPE tissue with 31 antibodies using multiplex immunohistochemistry (mxIHC) to investigate the TME. Using mxIHC protein expression levels, we generated a probabilistic cell classification algorithm to quantify immune cells. We investigated associations between ERV expression data, clinicopathologic variables, and immune cell proportions in the tumor samples using linear regression. Results: We performed ERV expression and mxIHC analysis on 104 PRCC nephrectomy samples from 1997-2016. After quality control, 78 unique patient tumor samples had results from both pipelines. Median patient age was 65 (IQR 56-71), 74.4% were male, and Fuhrman grade was 1 in 3.9%, 2 in 5.9%, 3 in 50.0%, and 4 in 9.0% of patients. Over a median follow-up of 3.03 years (IQR 0.61-6.99 years), 11.5% had recurrence after definitive local therapy, and 7.7% had an RCC-related death. Increased ERV expression correlated with increasing Fuhrman grade (r = 0.057, p <0.001), but not with disease recurrence or RCC-related death. Increased ERV expression was also associated with an increased TME proportion of cytotoxic T cells, memory T cells, and CD20+ B cells, and with a decreased TME proportion of macrophages (see Table 1). Conclusions: Higher expression of ERV4700 correlates with increased proportions of cytotoxic T cells in the TME of PRCC samples. Given its association with immunotherapy response in ccRCC, further studies are warranted to study ERV expression as a prognostic and predictive biomarker in PRCC. [Table: see text]
Tumor characteristics associated with detectable circulating tumor DNA preoperatively in patients with renal masses suspicious for RCC.
Authors: Ben-David Reuben , Alerasool Parissa , Kalola Hitasha , Tillu Neeraja , Tsao Kai , Galsky Matt D. , Attalla Kyrollis , Sfakianos John P. , Wiklund Peter , Waingankar Nikhil , Mehrazin Reza 
Published: January 2024

461 Background: Understanding the specific tumor characteristics associated with detectable ctDNA in the blood of patients with renal cell carcinoma (RCC) is critical to informing future studies seeking to establish the clinical utility of such testing. We characterized pathological and clinical characteristics associated with ctDNA detected preoperatively in patients with renal masses suspicious of RCC. Methods: Using our single institution prospectively maintained database, we identified consecutive patients who underwent partial or radical nephrectomy for non-metastatic suspected RCC (stages cT1b-cT3) during 2022-2023. Included were patients who had undergone tumor-informed ctDNA testing using the commercial Signatera assay (Natera). Baseline characteristics, pathology results, imaging study results, and oncological treatment and follow-up data were collected from the electronic medical records. ctDNA results were collected through the Natera portal. Study findings were reported using descriptive statistics. A p-value of <0.05 was considered statistically significant. R programming language version 4.3 was used for all statistical analyses. Results: A total of 54 patients with a median age of 63 years (IQR 51-71) were included in the study. Twenty-one (39%) were women. The median follow-up time was 4 months (range: 1-21 months). Among the 54 patients, 27 (50%) had detectable ctDNA pre-operatively Post-operative results were available for 33 patients, and 3 (9%) had detectable tDNA (of those 2 had Inferior vena cava involvement). The first patient developed metastatic disease. The two other patients are receiving adjuvant immunotherapy. Analysis of 50 patients with solely malignant RCC revealed that patients with detectable versus undetectable ctDNA were older 67 vs. 54 years (p=0.03), had a higher pathological stage (p= 0.002), larger tumors (7.2 vs. 4.7 cm, p = 0.004), and higher pathological grade (grade 3-4 vs. grade 1-2; p=0.035) (Table 1). All the patients with renal vein or inferior vena cava involvement had detectable ctDNA (n=8). Conclusions: In our cohort, preoperative ctDNA was detectable in 50% of patients with suspected clinically localized RCC. Detectable ctDNA preoperatively correlated with clinically relevant features. The ability of preoperative ctDNA to predict recurrence and survival in patients with clinically localized RCC warrants further evaluation. [Table: see text]
Diversity among editorial boards of genitourinary oncology journals.
Authors: Arter Zhaohui , Mar Nataliya , Rezazadeh Arash , Benjamin David Joseph 
Published: January 2024

481 Background: Several studies have evaluated the ethnic and gender diversity among editorial boards of academic journals in science and medicine, and revealed disparities among representation of historically underrepresented groups. However, the diversity among editorial boards in the field of genitourinary oncology remains unclear. Methods: Using the master journal list from Clarivate, we identified academic journals with a dedicated or primary focus in genitourinary cancers. We then identified the list of editorial board members on each journal’s website. We evaluated economic diversity based off each editor’s country of origin, and classified countries as high income based off World Bank listing for the 2024 fiscal year. We confirmed gender from each editor’s self-reported gender on his or her academic profile. Results: We identified 7 journals with a focus in genitourinary cancers. Among these journals, a total of 485 editor positions were identified, with 397 men (81.86%) and 80 women (16.49%). The gender of 8 individuals (1.65%) could not be confirmed. 28 editors (5.77%) were from countries not identified as high-income countries per World Bank criteria. Conclusions: There are disparities in country of origin among editors of genitourinary oncology journals, with a small proportion of editors originating from countries classified as middle- or low-income. [Table: see text]
Using automated machine learning to detect kidney anomalies.
Authors: Rawal Rushil , Heard John , Castaneda Peris , Davood Joshua , Ahdoot Michael 
Published: January 2024

483 Background: Artificial Intelligence (AI) in Urology has been used for many conditions including benign prostatic hyperplasia (BPH), urological oncology, and kidney transplant. Many computer models use algorithms that may be intricate for urologists to implement, but automated machine learning (AML) can be used to create simple models. Here we expand the use of AI and AML in image detection of kidney tumors, stones, and unremarkable kidney from computed tomography (CT) using Google Vertex AI, a machine learning platform that allows for the building, training, and deployment of models. Methods: Google Vertex AI machine learning system was trained to perform image detection. CT Kidney images were taken from publicly available data from Kaggle, an online database and machine learning platform. Images are from multiple hospitals in Dhaka, Bangladesh. 300 CT Kidney Images were uploaded on Google Vertex AI: 100 tumors, 100 stone, and 100 normal. 240 images were used to train the model, 30 for validation, and a final 30 images for assessing the accuracy of predictions after the training phase. To comprehensively evaluate our model, CT kidney images from the Cedars Sinai Medical Center were employed for further testing. All training images lacked annotations and were solely classified as normal, stone, or tumor. Results: True positivity rate for image detection during model training was 100% for tumors, stones, and normal CTs. We further tested accuracy using Cedars Sinai patient images, using 10 tumors, 10 stones, and 5 normal. The accuracy of the AI prediction was 80%, 70%, and 100%, respectively. Conclusions: Artificial Intelligence can be useful in interpreting urological imaging even in a minimally trained system. A model such as ours may allow for rapid identification and labeling of renal masses, kidney stones, and normal studies with moderate fidelity. Further training of this model may increase accuracy.
Survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC): A real-world analysis.
Authors: Zhang Hanbo , Graham Jeffrey , Czaykowski Piotr , Gingerich Joel Roger , Bybel Bohdan , Dawe David E 
Published: January 2024

50 Background: Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant metastatic castrate-resistant prostate cancer (mCRPC). It accumulates at sites of high bone turnover with emerging evidence suggesting use of radium-223 increases risk of pathologic fractures. Bone-protective agents (BPAs) reduce skeletal-related events including pathologic fractures in men with mCRPC. We evaluated real-world outcomes of patients treated with radium-223, including the effect of BPA use on pathologic fracture risk. Methods: This was a single institution retrospective cohort study that included patients with mCRPC treated with radium-223 in Manitoba, Canada from 2014 to 2021. Outcomes of interest included incidence of pathologic fracture, pain response, alkaline phosphatase (ALP) response, and overall survival. Kaplan-Meier method was used for time to event outcomes and multivariable Cox regression models were used to adjust for covariates. Results: We identified 92 patients who received radium-223 for mCRPC (Table). Thirty patients (33%) completed 6 cycles of radium-223. Documented pain relief occurred in 39% of patients. For those with elevated ALP at baseline (n = 46), 57% had at least 30% reduction in total ALP. PSA reduction occurred in 29% with 11% having at least 30% reduction in PSA. Median overall survival (OS) was 9.4 months (95% CI 5.8 to 15.9). Of those who did not receive concurrent BPA, 26% developed a pathologic fracture, compared to 3% who received concurrent BPA during a median follow up of 8.1 months. BPA use was associated with significant delay in time to pathologic fracture (median not reached vs. 15.9 months; HR = 0.20, 95% CI: 0.05 – 0.76, p < 0.05) after adjusting for number of bone metastases and corticosteroid use. Conclusions: In this real-world study, concurrent BPA use was associated with significant reduction in risk of pathologic fractures in mCRPC patients receiving radium-223. BPA administration should be considered for patients receiving radium-223. [Table: see text]
North American patterns of care in clinical stage I testicular cancer from SWOG S1823.
Authors: Morin Coulombe Antoine , Colby Sarah , King Jennifer , Neuhouser Marian L. , Arun Banu , Daneshmand Siamak , Harzstark Andrea , Arnold Kathryn B. , Nichols Craig R. , Nappi Lucia 
Published: January 2024

509 Background: SWOG/CCTG S1823/GCC-001 is a non-interventional translational prospective cohort investigation with a primary endpoint of defining pre-treatment operational characteristics of the liquid germ cell cancer biomarker microRNA 371a-3p in predicting the presence of active germ cell malignancy. Opened in June 2020, 813 of the projected 956 patients have been registered with anticipated completion of accrual in early 2024. While analysis of the final endpoint awaits complete accrual and sufficient follow-up, S1823 creates a rich template of baseline clinical information and real-world treatment. Herein, we report baseline patterns of care in modern day real-world care delivery for Clinical Stage I (CSI) germ cell tumors across academic and community practices in North America. Methods: Data is obtained from case report forms and source documents for 547 S1823 enrollees with CSI seminoma or nonseminoma. Aggregate baseline clinical data unrelated to the primary endpoint are described to understand baseline clinical characteristics and management recommendations for CSI germ cell tumors. Results: Clinical characteristics and management recommendations for CSI are described in the table. The leading contributor to date is the Kaiser Permanente NCI NCORP followed by Canadian Institutions which together make up 38% of accruals from top level institutions. The majority of these largely young males were overweight or obese (67%). S1823 did not stipulate management which was at the discretion of local institutions/investigators. Active surveillance is the dominant strategy in both CSI seminoma and nonseminoma (85% overall). In CSI seminoma, adjuvant treatment with radiation is very rare (1/547) and adjuvant treatment with single agent carboplatin (1 or 2 cycles) is uncommon (4%). In CSI nonseminoma, adjuvant retroperitoneal lymph node dissection is also uncommon (3%) as is adjuvant chemotherapy with BEP X 1 or 2 (6%). Conclusions: In this large prospective multi-institutional observational cohort, surveillance appears to be the predominant management strategy for CSI germ cell tumors with very limited use of adjuvant chemotherapy or RPLND and virtual elimination of recommendation for radiation therapy for seminoma. Clinical trial information: NCT04435756 .[Table: see text]
Safety of pegfilgrastim in patients with metastatic germ-cell tumor receiving combination chemotherapy containing bleomycin.
Authors: King Jennifer , Hassoun Rebecca , Althouse Sandra K. , Schneck Stephanie , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: January 2024

513 Background: There are conflicting reports on the impact of growth factor support in combination with bleomycin on the development of bleomycin associated lung toxicity in various malignancies. In addition, theories remain surrounding the possibility of worsened hematologic toxicity when receiving pegfilgrastim too close to the time of subsequent chemotherapy that is given in consecutive weeks. Here, we aim to evaluate the safety of the use of pegfilgrastim in patients with germ-cell tumor (GCT) undergoing combination chemotherapy containing bleomycin. Methods: The prospectively maintained Indiana University testicular cancer database was queried for patients with metastatic GCT treated between 2010-2023 at Indiana University with chemotherapy containing bleomycin. Safety in patients who received at least one dose of pegfilgrastim were compared to patients who did not receive any doses. Bleomycin lung toxicity was per the discretion of treating physician. Comparison between groups was done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Results: 196 patients met eligibility. Median age at diagnosis was 26.7 (range, 20.2-50). Primary site was testis in 95.4%, retroperitoneum in 2.6%, and mediastinum in 2%. 79% of patients included had nonseminomatous germ-cell tumor (NSGCT). IGCCCG risk was good in 146, intermediate in 19, and poor in 31 patients. First-line chemo was BEPX3 in 71% of patients, BEPX3 with EPX1 in 9% of pts, BEPX4 in 10% of patients, and other in 10% of patients. There were 49 patients (25%) who received at least one dose of pegfilgrastim with chemotherapy. There was no statistically significant difference in the type of chemotherapy received, metastatic sites of disease at time of diagnosis, or IGCCCG risk in patients who received pegfilgrastim vs. those who did not. The median number of pegfilgrastim doses received was 2. The median number of doses of bleomycin received was 9 for both patients who received pegfilgrastim and those who did not. In those who received pegfilgrastim, 4 patients developed bleomycin lung toxicity vs. 13 patients who did not receive pegfilgrastim (p=1.000). Of these 17 pts, 9 were diagnosed on symptoms and exam alone, 2 by imaging with symptoms, 2 by imaging without symptoms, 3 on PFTs ordered because of symptoms, and 1 on PFTs alone without symptoms. 3 patients required steroids. There were no fatalities related to pulmonary toxicity. Median nadir ANC in those who received pegfilgrastim was 3350 vs. 800 in those who did not (p<0.0001). Conclusions: The administration of pegfilgrastim with combination chemotherapy containing bleomycin for metastatic GCT did not increase the risk for bleomycin associated lung toxicity. Hematologic toxicity, demonstrated by nadir ANC, was worse in pts who did not receive pegfilgrastim.
Single-stage retrocrural and retroperitoneal lymph node dissection for metastatic germ cell tumor: The University of Southern California experience.
Authors: Ghoreifi Alireza , Alsyouf Muhannad , Djaladat Hooman , Schuckman Anne K. , Daneshmand Siamak 
Published: January 2024

515 Background: Resection of retrocrural disease in patients with metastatic germ cell tumors is a surgical challenge, especially in the post-chemotherapy setting. Herein, we present our experience with single-stage retrocrural metastasectomy and retroperitoneal lymph node dissection (RPLND). Methods: Using our IRB-approved testicular cancer database we identified patients who underwent one-stage retrocrural and retroperitoneal mass resection between September 1997 and December 2022. Clinical characteristics, surgical approach, peri-operative complications, and oncological outcomes of these patients were reviewed. Results: Among 400 patients who underwent RPLND for testicular cancer over the study interval, concurrent retrocrural resection was performed in 23 cases. Demographics and clinical features of the patients are shown in the table. All surgeries were performed in the post-chemotherapy setting, except one who underwent primary RPLND for seminoma. Surgical approach has evolved over time, including thoracoabdominal (TA) in 6 (all before 2010) and midline transabdominal (MA) in 17, including 3 midline extraperitoneal. There were 9 (39%) patients who required adjunctive procedures. Histology of retrocrural masses revealed viable tumor in 2 (embryonal carcinoma and seminoma), teratoma in 18 (including one with malignant transformation), and necrosis/fibrosis in 3. Pathologic concordance rate between retrocrural and retroperitoneal pathology was 83%. Median length of hospital stay was 5 days (9 vs. 3.5 for TA and MA, respectively). The 90-day complication rate was 43% (Clavien 3=17%), with a lower rate in patients undergoing MA vs. TA incisions (35% vs. 67%). With a median (IQR) follow-up of 24 (6-90) months, only one patient had retrocrural recurrence requiring re-resection, and no mortality was reported. Conclusions: The midline transabdominal is an effective approach for the concurrent retrocrural and retroperitoneal lymph node dissection in select patients with metastatic germ cell tumors. It is associated with a lower perioperative complication rate compared to the traditional thoracoabdominal approach.[Table: see text]