bluuebunny/crossref_metadata_2025_split huggingface dataset:
First assessment of the stool mycobiome in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving targeted therapy (TT) or immunotherapy (IO).
Authors: Dizman Nazli , Hsu Joann , Gillece John D , Folkerts Megan , Reining Lauren J , Bergerot Paulo Gustavo , Meza Luis A , Zengin Zeynep Busra , Muddasani Ramya , Chawla Neal , Karimi Misagh , Trent Jeffrey M. , Highlander Sarah K , Pal Sumanta K. 
Published: March 2021

337 Background: Previous studies have associated specific stool bacterial species with response to both targeted therapy and immunotherapy (Routy et al Science 2018; Dizman et al Cancer Med 2020). Abundant fungal elements also constitute the human microbiome (the so-called “mycobiome”); we explore whether these could be related to clinical benefit (CB) from TT. Methods: Pts from 2 simultaneously conducted studies were included in the analysis. Both studies enrolled patients with histologically confirmed RCC with metastatic disease; in one study, pts received standard of care (SOC) TT, while in the other pts received SOC IO. In both studies, stool was collected at baseline and at multiple timepoints thereafter. Whole metagenome sequencing was performed for fungal microbiome composition (TGen North, AZ). Linear discriminant analysis (LDA) effect size (LEfSe) was used for comparison of the gut mycobiome in patients who obtained clinical benefit (CB; complete response, partial response or stable disease > 6mos) versus no clinical benefit (NCB; progressive disease or stable disease ≤6mos) from TT or IO. Results: A total of 50 samples from 24 pts (19:5 M:F) were included in the analysis. The majority of pts (19; 79%) had clear cell histology. 15 pts received TT while 9 pts received IO. The fungal genera demonstrating the highest abundance was Saccharomyces with a median relative abundance of 86.9% (range, 11%-99%). LEfSe performed in different taxonomic levels revealed Malassezia globosa (LDA = 4.93; P = 0.038) and Alternaria infectoria (LDA 4.94; P = 0.018) as gut mycobiome components associated with NCB, and order Russulales associated with CB from TT (LDA = 4.93; P = 0.018). In contrast, no association was identified between mycobiome profile and CB in the IO-treated group. The presence of several pathogenic fungi such as Candida albicans and Aspergillus fumigatus was noted in a minority of pts and did not have any bearing on clinical outcome. In pts with serial samples, a trend towards decreasing Saccharomyces spp. (the most abundant species) and increasing fungal diversity was noted. Conclusions: Our study is the first to highlight potential associations between the mycobiome and CB with TT. Our finding of Malassezia spp resulting in lack of CB with TT bolsters findings from Aykut et al (Nature 2019), implicating the same genera in progression of pancreatic cancer. Confirmation of these findings in larger series is underway.
Plasma exosome microRNAs in patients with advanced renal cell carcinoma treated with nivolumab and ipilimumab: Potential biomarkers of response to therapy.
Authors: Soleimani Maryam , Thi Marisa , Saxena Neetu , Khalaf Daniel Joseph , Eigl Bernhard J. , Chi Kim N. , Kollmannsberger Christian K. , Nappi Lucia 
Published: March 2021

338 Background: There is a critical unmet need for predictive biomarkers in the management of metastatic renal cell carcinoma (mRCC). We sought to quantify plasma exosome microRNAs (miRNAs) and correlate with response to first line nivolumab and ipilimumab (N/I) to potentially serve as such a biomarker. Methods: We evaluated the expression of 11 miRNAs in 19 patients with mRCC (prior to initiation of N/I) and in 32 healthy volunteers. Exosomes were extracted from 500 uL of plasma (qEV original, Izon Science) and once confirmed, were used for miRNAs extraction. MiRNAs expression was evaluated by real time polymerase chain reaction using a TaqMan miRNA assay (Applied Biosystems). The relative quantity of each miRNA in patients was compared to healthy volunteers. The expression of each miRNA was correlated to the best response to N/I, categorizing patients as either responders or non-responders. Results: Clinical characteristics are summarized in the table below. Median age at the start of systemic therapy was 64.3 years. MiR200b demonstrated a significantly higher expression in mRCC patients than in healthy volunteers (unpaired t-test; p=0.04). We observed a variable pattern of miRNA expression based on response to N/I. Although not statistically significant, 4 miRNA (miR138, 155, 200b, 221) were upregulated in non-responders, while two (miR200a and 497) were upregulated in responders. Of note, the only patient to achieve a complete response had the lowest expression of miR138 and the highest expression of miR497. Conclusions: Although preliminary and limited by a small number of patients, these initial observational results are promising and suggest a potential role for miRNAs as predictive biomarkers in mRCC. MiR138 and 497 are known to regulate CTLA-4 and PD-L1, respectively. We speculate that these miRNA are potentially involved in response to immune checkpoint therapy. Ongoing work in evaluating expression of these and other miRNAs in blood and in tissue along with clinical correlation continues. [Table: see text]
The very favorable metastatic renal cell carcinoma (mRCC) risk group: Data from the International Metastatic RCC Database Consortium (IMDC).
Authors: Schmidt Andrew Lachlan , Xie Wanling , Gan Chun Loo , Wells Connor , Dudani Shaan , Donskov Frede , Porta Camillo , Suarez Cristina , Szabados Bernadett , Wood Lori , Ruiz Morales Jose Manuel , Tran Ben , Bjarnason Georg A. , Yuasa Takeshi , Beuselinck Benoit , Hansen Aaron Richard , Agarwal Neeraj , Bakouny Ziad , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: March 2021

339 Background: The IMDC criteria have been used as a prognostic tool for patients with mRCC receiving single agent VEGF-targeted drugs, and more recently combination immuno-oncology (IO) +/- VEGF-targeted agents, which improve outcomes over VEGF TKI monotherapy. We sought to identify a subset of patients with very favorable outcomes, for which less intensive therapy might be considered. Methods: Utilizing the IMDC dataset, 1638 patients with IMDC favorable risk disease received first-line systemic therapy. Patients were randomly selected in a 2:1 ratio to the training and testing sets, stratified by year of systemic therapy initiation. Multivariable Cox regression estimated prognostic factors for overall survival (OS). Results: Median age was 63 (range 21-95) years and 98% had received prior nephrectomy. First-line systemic therapy consisted of targeted therapy (91%), IO-combination regimens (8%), or other (1%). From the training data, three variables (primary diagnosis to systemic therapy <3 vs ≥3yr; Karnofsky Performance Status 80 vs >80; presence of brain, liver, or bone metastasis) significantly predicted for OS in the multivariable model (hazard ratio 1.4~1.5, p-values<0.05). The model had similar performance in the test dataset (C-index=0.64). Using the 3 included risk factors, patients were classified to very favorable risk (0 risk factors, 29% of patients) or favorable risk disease (≥1 risk factors, 71% of patients). Clinical outcomes for the two risk groups are presented in the table below. Conclusions: We identified a very favorable risk group in the IMDC criteria in RCC patients treated with first-line therapy. External validation including populations receiving IO containing therapies is ongoing. [Table: see text]
Associations between plasma cytokine levels and gut microbiota composition in metastatic renal cell carcinoma (mRCC).
Authors: Chehrazi-Raffle Alex , Dizman Nazli , Bergerot Paulo Gustavo , Karimi Misagh , Hsu Joann , Gillece John D , Folkerts Megan , Reining Lauren J , Highlander Sarah K , Pal Sumanta K. 
Published: March 2021

351 Background: Plasma cytokines and the gut microbiome have been shown separately to influence the response to systemic therapy in mRCC. We sought associations between serum cytokines and gut microbial composition in patients (pts) with mRCC. Methods: Eligibility requirements included histologically proven mRCC and an intent to receive either vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Blood samples were collected prior to treatment initiation and immunologic profiles were evaluated using a Human Cytokine 30-plex protein assay (Invitrogen). Stool was collected at baseline and shotgun metagenomic sequencing was performed to quantify gut microbial populations using previously published methods (Salgia et al Eur Urol 2020). Results: A total of 50 pts were studied (36:14 M:F) with a median age of 67 (range, 32-85). Twenty pts and 30 pts had subsequent initiation of VEGF-TKI and ICI therapy, respectively. Levels of Akkermansia spp were significantly higher in pts who were IL-6 low (P = 0.023). In contrast, pts who were IL-6 high had higher levels of enteric pathogens, including Salmonella spp and Enterococcus spp. Both Akkermansia spp and Bacteroides spp levels were higher in pts who were IL-8 low. Associations between cytokine levels, microbiome composition, and treatment response will be presented. Conclusions: Given studies suggesting the role of Akkermansia spp in enhancing ICI response (Routy et al Science 2018), our data provide a critical link between the gut microbiome and systemic immunomodulation.
18F-DCFPyL PSMA PET imaging compared to conventional imaging in the detection of pelvic nodal metastases in patients with locally advanced or oligometastatic prostate cancer.
Authors: Esdaille Ashanda Rosetta Patrice , Lawrence Edward , Kyriakopoulos Christos , Johnson Brian , Roldán-Alzate Alejandro , Huang Wei , Beebe David J. , Emamekhoo Hamid , Wells Shane , Lang Joshua Michael , Cho Steve Y. , Jarrard David Frazier 
Published: March 2021

36 Background: Interest has arisen in the use of prostate specific membrane antigen (PSMA) PET/CT imaging to detect prostate cancer at metastatic sites using different tracers. Here, we examined the ability of 18F-DCFPyL (DCFPyL) PSMA-based PET imaging to detect nodal disease in comparison to conventional imaging in a cohort of men with locally advanced or oligometastatic prostate cancer (PC). Methods: UW17009 is an IRB-approved open-label, single-arm trial that enrolled 26 patients with newly diagnosed advanced PC. Patients received androgen deprivation therapy and docetaxel for 3 months followed by radical prostatectomy (RP) and pelvic lymph node dissection (PLND). Exploratory interventions include PSMA PET/CT and MRI imaging as a method for determining treatment response and heterogeneity in primary PC and metastatic lesions performed before and after chemohormonal therapy. Prior to randomization, patients received DCFPyL PET/CT and PET/MR imaging as well as CTs and Bone Scans. A mean dose of 7.86 mCi DCFPyL was administered. Whole-body PET/CT images were acquired starting at approximately 60 minutes after radiotracer injection followed by dedicated pelvic PET/MR and whole-body PET/MR. PET imaging findings were compared to conventional dedicated CT imaging and were correlated to the results of final pathologic examination of each pelvic nodal dissection. Results: 26 patients underwent conventional and exploratory imaging with subsequent neoadjuvant treatment, RP and PLND. The mean diagnostic PSA was 32.1 ng/dl and 88.5% had Gleason 9 PCa. Using conventional imaging, pelvic nodal disease was identified in 6/26 patients. Pelvic lymph node uptake was identified in 12/26 patients using DCFPyL-based PSMA PET. Initial correlation of the pathologic specimens with pretreatment PSMA PET imaging revealed pelvic nodal metastatic PC in 10/12(83%) patients. On a per-lymph node packet basis (6 per patient), there were 156 evaluable regions, including 65 from patients with positive nodes. PSMA detected 14 packets that were positive for PC and 102 packets that were negative on imaging and final pathology. PC was missed in 5 packets. The mean tumor size in the missed nodes was 2.3 mm(range 1-4 mm). Calculated sensitivity was 73.7%(95% CI [48.8, 90.8]), 85.7 % specificity(95% CI[78.1, 91.4]), and 95.3 % negative predictive value(95% CI[90.5, 97.7]). Conclusions: In comparison to conventional imaging, in this cohort, DCFPyL PSMA-based PET imaging identified nodal positive disease at twice the rate and when evaluating on a per-packet basis, there was high negative predictive value. Ongoing analysis of post-chemohormonal therapy PET imaging may provide more information regarding tumor response in this cohort.
Australia and New Zealand (ANZ) outcomes of high-dose chemotherapy and stem cell transplantation for relapsed or refractory germ cell tumors (GCT) from 1999 to 2019: Multicenter registry-based study with ABMTRR.
Authors: Connolly Elizabeth Anne , Weickhardt Andrew James , Grimison Peter S. , Heller Gillian , Lewin Jeremy Howard , Liow Elizabeth Chien Hern , Tung Iris , Tran Ben , Hill Sean , Walpole Euan Thomas , McKenzie Jane , Kuchel Anna , Forgeson Garry , Tan Alvin Boon Tee , Joshi Abhishek , Wickham Alistair , Tan Thean Hsiang , Wang Yang , Hamad Nada , Wong Vanessa ,   Australasian Bone Marrow Transplant Recipient Registry
Published: March 2021

382 Background: High dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) is effective in advanced germ cell tumours (GCT) that are refractory to, or progress after, first-line therapies. Five-year overall survival in North American and European series range from 48-60%1,2,3. This study aimed to assess ANZ outcomes for quality assurance. Methods: Retrospective multi-centre audit of all male patients with GCT who underwent HDCT and ASCT from 1999-2019. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. Primary outcomes included overall and progression- free survival (OS, PFS). Results: 111 patients were identified at 13 centres, each treating a median (range) of 7 (1-27) patients. Median (range) age was 30 (14-68) years. 88 (79%) had testicular primary. 16% were pure seminoma. Median time from first diagnosis to first stem cell cycle was 11 months (range 3 months-38 years). Prior to ASCT, 35% had primary refractory disease and 65% had relapsed. IPFSG risk score was very low in 5%, low in 13%, intermediate in 36%, high in 25%, and very high in 21%. HDCT regimen was CE in 78% (as part of TI-CE regimen in 38%), Carbop-EC-T in 6%, ICE in 6%, CEC in 5% and other in 4%. 89% completed all planned HDCT and ASCT cycles. Five treatment related deaths occurred. Progressive disease on treatment occurred in 14%. At median follow-up time 4.4 years (95% CI: 2.9 to 6.0), 51% were disease-free, 13% alive with disease, 34% deceased. 3 patients displayed late progression over 2 years after ASCT. The estimated 1, 2 and 5-year PFS rates were 62%, 57% and 52% respectively and OS rates were 73%, 65% and 61%. Survival by IPFSG and IGCCG risk categories are displayed in the table below. Conclusions: This is the first registry-based audit of HDCT for metastatic GCT from ANZ, which has demonstrated our outcomes are comparable with best international practice. References: Gossi Bone Marrow Transplant 2018;53:820-825. Adra J Clin Onc 2017; 35(10):1096-1102. Feldman J Clin Onc 2010; 28(10):1706-13. [Table: see text]
Real-world application of pre-orchiectomy miR-371a-3p test in testicular germ cell tumor (GCT) management.
Authors: Badia Rohit R , Abe Dreaux , Wong Daniel , Singla Nirmish , Savelyeva Anna , Chertack Nathan , Jia Liwei , Kapur Payal , Murray Matthew , Amatruda James F. , Lafin John T. , Bagrodia Aditya 
Published: March 2021

387 Background: Current serum tumor markers (STMs) for testicular germ cell tumor (GCT) are limited by low sensitivity. Growing evidence supports the use of circulating miR-371a-3p as a superior marker for malignant (viable) GCT management. We evaluated the real-world application of serum miR-371a-3p levels in detecting viable GCT among patients undergoing partial or radical orchiectomy. Methods: Serum samples were collected from 69 consecutive patients pre-orchiectomy. Performance characteristics of serum miR-371a-3p were compared with conventional STMs (AFP/β-hCG/LDH) between viable GCT patients and those without viable GCT on orchiectomy pathology. Relative miR-371a-3p levels were correlated with clinical course. Kruskal-Wallis test and linear and ordinal regression models were used for analysis. Results: For detecting viable GCT, combined conventional STMs had a specificity of 100%, sensitivity of 58%, and area under the curve (AUC) of 0.79 (Table). The miR-371a-3p test showed a specificity of 100%, sensitivity of 93%, and AUC of 0.978. Median relative expression of miR-371a-3p in viable GCT patients was >6,800-fold higher than in patients lacking viable GCT. MiR-371a-3p levels correlated with composite stage (CS) (p=0.006), and, among CS I patients, independently associated with embryonal carcinoma percentage (p=0.0012) and tumor diameter (p<0.0001). Six patients received orchiectomy after chemotherapy and were correctly predicted to have presence or absence of viable GCT by the miR-371a-3p test. Conclusions: If validated, the miR-371a-3p test can be used in conjunction with conventional STMs to aid clinical decision-making. A positive miR-371a-3p test in patients after preoperative chemotherapy or with solitary testes could potentially guide subsequent orchiectomy or observation. [Table: see text]
Socio-environmental conditions associated with geospatial clusters of urothelial carcinoma: A multi-institutional analysis.
Authors: Edwards Daniel C. , Yankelevich Gabrielle R , Dreher Paulette C , Narowska Gabriela , Kim Daniel , Taylor Zachariah , Larson Sharon H , Buckley Meghan , Belkoff Laurence H , Bernstein Guy T 
Published: March 2021

392 Background: Industrial byproducts and environmental pollutants (IBP/EP) are associated with the development of urothelial carcinoma (UC). While tobacco exposure (TE) is the major risk factor for UC, the interaction between sources of IBP/EP and incidence of UC in surrounding communities has been infrequently explored. We seek to identify high-density microregions of UC prevalence and spatially-related industrial and environmental risk factors. Methods: We queried a multi-institutional database for patients diagnosed with UC between 2008-2018. Geocoded addresses and ArcGIS software were used to calculate the Getis-Ord-Gi* statistic and perform hotspot analysis on the census-block level to identify UC hotspots. Demographics, clinicopathologic disease characteristics, and proximity to sources of IBP/EP were compared using Pearson’s chi-square and Student’s T-test. Univariate analyses and multivariable multilevel logistic random-intercept regression models were fitted to test the association between patient and census block-level factors and living in a UC hot spot. Results: Of 5,080 patients meeting inclusion/exclusion criteria, 148 patients (2.9%) were associated with one of three UC hotspots. In univariate analyses, hotspot patients were less likely to be tobacco users (OR 0.24, p=0.004) or of white race (OR 0.10, p<0.001) and less likely to have higher income (OR 0.73, p=0.005). They were more likely to be associated with IBP/EP exposure (OR 8.24, p=0.001) (Table). Multivariable analysis confirmed increased likelihood of residing in a UC hotspot and proximity to high-traffic density (OR >999, p=<0.001) and sites of IBP/EP contamination (OR 106.90, p=0.009), with decreased likelihood of tobacco use (OR 0.11, p=0.045) and white race (OR 0.02, p=0.004). Conclusions: Patients residing in geospatial hotspots of UC prevalence are less likely to be white, higher income or tobacco users and more likely to reside in proximity to sources of IBP/EP. Further research is necessary to investigate the interplay between socioeconomic status, race and environmental risk factors in order to better identify at-risk populations and improve screening, referral, diagnosis and timely intervention. [Table: see text]
Cost-effectiveness analysis of pembrolizumab for BCG-unresponsive carcinoma in situ of the bladder.
Authors: Sharma Vidit , Wymer Kevin , Saigal Christopher , Chamie Karim , Litwin Mark S. , Packiam Vignesh T. , Mossanen Matthew , Pagliaro Lance C. , Borah Bijan J , Boorjian Stephen A. 
Published: March 2021

395 Background: Patients with BCG-unresponsive carcinoma in situ (CIS) are treated with radical cystectomy (RCx) or salvage intravesical chemotherapy (SIC). Recently, the FDA approved pembrolizumab for BCG-unresponsive CIS +/- papillary tumors. Given the costs and toxicities of pembrolizumab, it remains unclear whether its benefits are sufficient to warrant widespread use for BCG-unresponsive CIS. To that end, we conducted a cost-effectiveness analysis comparing pembrolizumab with RCx and SIC (using gemcitabine-docetaxel as the prototypical regimen) for patients with BCG-unresponsive CIS. Methods: A decision-analytic Markov model compared pembrolizumab, SIC (with gemcitabine-docetaxel), and RCx for patients with BCG-unresponsive CIS +/- papillary tumors who are RCx candidates (index patient 1) or are unwilling/unable to undergo RCx (index patient 2). Each treatment option was a Markov node containing distinct variations of the following health states: surveillance, recurrence, progression to MIBC, progression to metastasis, treatment toxicity, and death. Incremental Cost-Effectiveness Ratios (ICERs) were compared using a willingness-to-pay threshold of $100,000/Quality-adjusted life year (QALY). The model used a US Medicare perspective with a 5-year time horizon for the base case. One-way and probabilistic sensitivity analyses were performed for all model parameters. Results: For index patient 1, pembrolizumab was not cost-effective vs. RCx (ICER $1,403,008) or SIC (ICER $2,011,923). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to RCx with a > 93% price reduction. Relative to RCx, SIC was cost-effective for time horizons < 5 years and nearly cost-effective at 5 years (ICER $118,324). One-way sensitivity analysis revealed that SIC became cost-effective relative to RCx if its risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required > 90% price reduction to be cost-effective vs. RCx (ICER $1,073,240). Probabilistic sensitivity analyses revealed that pembrolizumab was unlikely to be cost-effective even at high willingness-to-pay thresholds. Further sensitivity analyses found that no two-way combination of extrapolated values resulted in pembrolizumab being favored over RCx or SIC for either index patient. Conclusions: Based on decision-analytic Markov modeling of treatment options for patients with BCG-unresponsive CIS, pembrolizumab was unlikely to be cost-effective without a > 90% price reduction. While both RCx and SIC were more cost-effective than pembrolizumab, further studies may validate the cost-effectiveness of gemcitabine-docetaxel relative to RCx if the recurrence and metastasis thresholds are met. Overall, our model supports the preferential use of RCx and SIC over pembrolizumab for BCG-unresponsive CIS.