bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Bacillus Calmette-Guerin (BCG) exposure on severity of COVID-19 infection: A COVID-19 and Cancer Consortium (CCC19) study.
Authors: Schmidt Andrew Lachlan , Bakouny Ziad , Labaki Chris , Bashir Babar , Clement Jessica M. , Edwin Natasha Catherine , Flora Daniel Blake , Girard Jennifer , Gulati Shuchi , Hwang Clara , Jani Chinmay , Lopes Gilberto , Mesa Ruben A. , Redelman-Sidi Gil , Mishra Sanjay , Warner Jeremy Lyle , Choueiri Toni K. 
Published: June 2021

4529 Background: Oncology patients experience more severe disease outcomes from COVID-19 infection than the general population. BCG is a live bovine tuberculosis bacillus with immunotherapeutic effects in urothelial cancers; it is also used as vaccination against Mycobacterium tuberculosis in parts of the world. As BCG vaccination has been associated with broad protection against viral pathogens, BCG exposure through vaccination or intravesical therapy may modulate host immunity and reduce the severity of COVID-19 infection. We report the effect of BCG exposure on COVID-19 severity in oncology patients from the CCC19 registry. Methods: The CCC19 registry (NCT04354701) was used to identify patients with prior BCG exposure. Cohort A received intravesical treatment for bladder carcinoma, and cohort B received prior BCG vaccination. Each cohort was matched 3:1 to non-BCG-exposed controls by age, sex, race, primary cancer type, cancer status, ECOG performance status (PS) and calendar time of COVID-19 infection. The primary endpoint was COVID-19 severity reported on an ordinal scale (uncomplicated, hospitalized, admitted to ICU +/- ventilated, died within 30 days) of patients exposed to prior BCG compared to matched non-exposed controls. 2-sided Wilcoxon rank-sum tests were used. Results: As of 6-Feb-2021 we included 124 patients with BCG exposure, 68 patients with bladder carcinoma who had received intravesical BCG (Cohort A), and 64 cancer patients with prior BCG vaccination (Cohort B). Median age was 76 years, IQR 69-83 (Cohort A) and 67 years, IQR 62-74 (Cohort B). Bladder cancer pts were predominately male (78%) vs 55% for Cohort B. Patients with PS 2+ were uncommon, 18% in Cohort A and 16% in Cohort B. COVID-19 illness severity was no different in patients exposed to prior intravesicular BCG (p=0.87). COVID-19 illness severity was no different in patients exposed to prior intradermal BCG vaccination (p=0.60). Conclusions: Despite this being the largest such cohort reported to date, we failed to demonstrate an association of prior BCG exposure with modulation of severity of COVID-19 illness. Prospective trials evaluating the protective effect of BCG vaccination are ongoing and will add further insight into the effect of BCG on COVID-19 illness.[Table: see text]
Genomic predictors of response to PD-1 axis inhibitors in metastatic urothelial cancer (mUC) patients using machine learning analysis of tissue comprehensive genomic profiling (CGP).
Authors: Reisinger Raquel , Sacristan Santos Victor , Nussenzveig Roberto , Wesolowski Sergiusz , Hernandez Edgar Javier , Henrie Alexander Ryan , Maughan Benjamin L. , Swami Umang , Yandell Mark , Grivas Petros , Agarwal Neeraj 
Published: June 2021

4542 Background: Immune check point inhibitors (ICI), specifically PD-1 axis inhibitors, are an established treatment for mUC patients (pts), though molecular markers of response are not well-established. Probabilistic Graphical Models (PGMs) are artificial intelligence (AI) algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that machine learning analysis can reveal biomarkers of response to ICI beyond Tumor Mutational Burden (TMB) and PD-L1 expression. Methods: Pts with mUC receiving systemic therapy and available tumor CGP were included in the analysis. CGP was performed by a CLIA validated NGS panel (Foundation Medicine). 17 clinically relevant variables were included in the analyses. Multilevel molecular and clinical interdependencies between ICI response were assessed using a Bayesian network (BN) machine learning approach. To account for high computational cost of the BN dependence structure discovery, variables were selected based on primary and secondary dependencies to ICI Objective Response Rate (ORR) via Hill Climbing Algorithm. Genes selected for analysis included those present in > 5% of the cohort . All variants of unknown significance were removed. Kaplan-Meyer (KM) survival analysis was also performed. Results: 174 pts were eligible and included: median age was 67 (33 – 86), 54.6% were smokers, 27.6% male, 14.4% had upper tract disease at diagnosis and 77 pts were treated with an approved ICI. Results from BN analysis revealed strong positive interdependencies between ICI ORR and TMB ≥ 10 or mutated PIK3CA gene. KM analysis was in agreement with BN results, a low TMB ( < 10 muts/MB) and wild-type PIK3CA were predictive of poor PFS (Table). PGMs will be presented at the meeting. Conclusions: BN and KM survival analysis supported TMB ≥ 10 as a biomarker of improved outcomes to ICI. Moreover, these results reveal mutated PIK3CA as a novel biomarker of improved outcomes to ICI. Study has limitations as expected in a retrospective analysis. These hypothesis-generating data require external validation.[Table: see text]
Programmed death ligand-1 (PD-L1) expression in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in NIVES study.
Authors: Masini Cristina , Carlinfante Gabriele , Iotti Cinzia , De Giorgi Ugo , Bellia Roberto Salvatore , Buti Sebastiano , Salaroli Francesco , Zampiva Ilaria , Mazzarotto Renzo , Mucciarini Claudia , Vitale Maria Giuseppa , Bruni Alessio , Procopio Giuseppe , Kinspergher Stefania , Vanoni Valentina , Nole Franco , Morelli Franco , Baier Susanne , Buttigliero Consuelo , Pinto Carmine 
Published: June 2021

4558 Background: The NIVES study represents the first prospective trial with NIVO in combination with SBRT in pre-treated mRCC patients. This study did not meet the primary endpoint in terms of objective response rate (ORR) as previously reported. However this combination showed a faster time to treatment response, a long progression free survival and median duration of response without increasing toxicities. Here we have tested with an exploratory analysis the correlation between PD-L1 expression and clinical outcomes in pts treated with NIVO plus SBRT. Methods: PD-L1 expression was assessed in archival collected tumour samples in our central laboratory using 4 commercial kits for immunoistochemical (ICH) analysis (clone 22C3 pharm DX Dako Agilent, 28.8 Abcam and SP142 and SP263 Ventana Medical System). A tumor cell was considered positive if any membranous staining was found regardless of the intensity. In particular the immunostaining was scored 0 when all tumor cells were unstained (PD-L1-negative), 1+ when < 1% positive tumor cells were counted, 2+ when the percentage was between 1% and 50%,3+ when the number of stained cells was more than 50%. ORR and overall survival (OS) were correlated with PD-L1 staining. Results: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 44 of 69 pts enrolled in the NIVES study. Twenty-two pts of 44 (50%) were considered PD-L1-negative using all the 4 commercial kits for ICH analysis, while 14 of 44 pts (31,8%) were defined PD-L1 weakly positive (positive tumor cells < 1% at least in one kit for ICH). Eight of 44 pts (18.1%) were defined PD-L1 strong positive when at least one kit for ICH scored 2+ or 3+. About the correlation between ORR and PDL1 staining in the 42 pts (2/44 pts are not evaluable for ORR), ORR was 18.2% (95% CI, 5.2% to 40.3%) in the PD-L1-negative group vs 20% (95% CI, 5.7% to 43.7%) in weakly/strongly PD-L1 positive (p = 1.00). Among the 44 pts in the intention-to-treat population with available PD-L1 status, median OS was not significantly different between pts with PD-L1 negative (20.56 months, 95% CI, 7.16 to NR) and PD-L1 positive (18.33 months, 95% CI, 6.83 to NR) (p = 0.56). Conclusions: For the first time four commercial kits for ICH analysis were used to test PD-L1 expression in pretreated mRCC pts. Data from these small sample size seem to confirm that PD-L1 in pre-treated mRCC cancer is not a predictive biomarker for selecting pts to receive NIVO-based treatment. Clinical trial information: NCT03469713.
Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).
Authors: Shah Amishi Yogesh , Motzer Robert J. , Apolo Andrea B. , Powles Thomas , Escudier Bernard , Zhang Joshua , Scheffold Christian , Karumanchi Sravan , Nguyen Linh Thuy , Choueiri Toni K. 
Published: June 2021

4561 Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.
Outcomes with novel combinations in non-clear cell renal cell carcinoma(nccRCC): ORACLE study.
Authors: Kilari Deepak , Szabo Aniko , Ghatalia Pooja , Rose Tracy L , Weise Nicole , Tucker Matthew D. , Nelson Ariel Ann , Dong Huaying , Hester Danubia , Acharya Luna , Jain Rohit K. , Maughan Benjamin L. , Alva Ajjai Shivaram , Tripathi Abhishek , Basu Arnab , Koshkin Vadim S , Emamekhoo Hamid , Davis Nancy B. , Desai Arpita , McKay Rana R. 
Published: June 2021

4580 Background: Despite advances in the treatment of clear cell RCC, there is a paucity of data to guide management of nccRCC due to the heterogeneity and rarity of these tumors. The clinical activity of new combination therapies (including immunotherapy (IO), anti-vascular endothelial growth factor inhibitors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors) in metastatic nccRCC is not known. Methods: In this multicenter retrospective analysis, we explored the efficacy of combination systemic therapies in patients with nccRCC. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate (ORR) assessed by investigator review. Secondary endpoints include progression- free survival (PFS), disease control rate (DCR), median duration of response (DOR), overall survival (OS), and biomarker correlates. Results: Among 66 included patients, median age was 59 yr; 60% were male and 62% white. Histologies included papillary (38%), chromophobe (17%), unclassified (24%), translocation (12%), and other (9 %). Sarcomatoid and/or rhabdoid differentiation was present in 18%, 70% had prior nephrectomy, 86% were IMDC intermediate/poor risk, 29% and 32% had liver and bone metastasis respectively. 67% received combination treatment in the first line. Comparison of outcomes based on treatment regimen is shown in the table. Conclusions: Antitumor activity was observed with novel combinations in nccRCC which warrants further prospective studies. Response rates and survival with combination therapy in this dataset remain inferior to rates seen in clear cell RCC.[Table: see text]
Immunity to childhood vaccines following high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for germ cell tumors (GCT) with comparison to Hodgkin lymphoma (HL).
Authors: Feldman Darren R. , Lewis Akeem Ronell , Knezevic Andrea , Ali David , Bromberg Maria , Aronson Julia , Funt Samuel Aaron , McHugh Deaglan Joseph , Motzer Robert J. , Bajorin Dean F. , Patil Sujata , Shah Gunjan L. , Shah Monika , Seo Susan , Kamboj Mini , Perales Miguel-Angel , Papanicolaou Genofeva 
Published: June 2021

5017 Background: HDCT/ASCT represents a curative salvage treatment for patients with GCT but is rarely used for other solid tumors. Patients undergoing HDCT/ASCT for hematologic neoplasms require revaccination for their childhood immunizations. Whether this is necessary in patients with GCT is unknown. Methods: In this prospective longitudinal study, patients with GCT undergoing HDCT-ASCT from 11/2010 to 5/2018 had serologies for Measles, Mumps, Rubella, Diphtheria, Tetanus, Polio, and Varicella Zoster measured before HDCT and at 3, 6, and in a subset, 12+ months after the last HDCT with results at these timepoints compared using descriptive statistics. In addition, titer levels at ≥6 months post-transplant were matched 1:1 for age and gender with HL patients who underwent HDCT/ASCT during the same time period. Immunity was compared between cohorts using the Cochran-Mantel-Haenszel test. Results: Of 80 patients with GCT (median age 30, 84% nonseminoma), 91% received 3 sequential transplants and 68 had repeat titers at ≥6 months. Immunity at baseline was >95% for Diphtheria, Tetanus and Polio and 89% for Varicella Zoster but lower for Measles (74%), Mumps (85%), and Rubella (83%) (Table). Compared to baseline, proportional immunity for all infections was similar at 3, 6, and 12 months post-transplant in the GCT population (≥6 months shown in Table). Matching resulted in 58 GCT-HL pairs. One-year immunity was numerically lower for most infections in the HL vs. GCT patients and significantly decreased for Measles and Rubella (Table). Conclusions: To our knowledge, this is the first study to assess vaccine titers following HDCT/ASCT for GCT. We demonstrate that HDCT/ASCT does not result in loss of immunity to childhood vaccines and that GCT patients retain protective titers more frequently than those with HL. However, 15-31% of GCT patients lack MMR immunity at baseline and at 1-year post-ASCT. Therefore, we recommend checking MMR titers at 1-year post-ASCT with revaccination of those lacking immunity. Titer evaluation and revaccination is not necessary for other childhood immunizations.[Table: see text]
Very late recurrence in germ cell tumor of the testis: Lessons and implications.
Authors: Moore Joseph A , Tidwell Rebecca , Campbell Matthew T , Shah Amishi Yogesh , Zhang Miao , Guo Charles , Ward John Francis , Karam Jose A. , Wood Christopher G. , Logothetis Christopher , Pisters Louis L. , Tu Shi-Ming 
Published: June 2021

5030 Background: Up to 30% of patients with germ cell tumor of the testis (TGCT) develop recurrent disease after initial treatment. The majority of recurrences occur in the first 2 years after treatment. Very late recurrence (LR), i.e. > 5 years after initial presentation, occurs in about 1% of patients with TGCT and is associated with poor prognosis. Current guideline does not require follow-up after 5 years to detect LR, except in those presenting with metastatic NSGCT. Methods: We retrospectively reviewed the records of patients from the Genitourinary Medical Oncology clinic at the M. D. Anderson Cancer Center, who developed recurrent disease > 5 years after their initial diagnosis of TGCT. Specifically, we examined the pathology and location of their primary and recurrent tumors, treatments rendered (e.g., surgery, radiotherapy, chemotherapy), and overall survival after LR. Overall survival from the time of LR was estimated using Kaplan-Meier estimates and compared for patient subgroups with log rank tests. Fisher’s exact test was used to compare proportions in patient subgroups. Results: We identified 25 patients who developed LR between July 2007 and August 2020. Age at time of LR: median 46 years (range, 29-61); time of late LR: median 16.1 years (range, 6.8-33.1 years) after diagnosis. Stage at time of diagnosis: I – 5, II-IIIA – 13, IIIB-C – 7. Pathology of primary: nonseminoma with yolk sac tumor or teratoma – 15, nonseminoma without yolk sac tumor or teratoma – 1, not available – 9. Pathology of LR: somatic transformation to carcinoma – 9, somatic transformation to sarcoma – 2, nonseminoma with yolk sac tumor or teratoma – 10, nonseminoma without yolk sac tumor or teratoma – 2, not available – 2. Overall, 5 patients (20%) had LR in retroperitoneum alone, 6 patients (24%) had non-retroperitoneal nodal or pulmonary metastases, and 14 patients (56%) had non-pulmonary visceral metastases. Nine patients (36%) are deceased, ten patients (40%) are alive without evidence of disease (NED), and 6 patients are alive with disease (24%). With a median follow-up of 42 months, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery have longer survival, 80% vs. 53% at 3 years, respectively (p = 0.01). Additionally, at their last follow-up 9/12 vs. 1/13 patients were NED with vs. without prior post-chemotherapy consolidation surgery, respectively (p = 0.001). Conclusions: Patients with LR > 5 years after initial presentation tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR. Further investigation into rates of LR among all patients may be warranted given the poor survival after LR.
Biomarker analysis of phase (Ph) IB trial of radium-223 (Rad) and niraparib (Nira) in patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) (NiraRad).
Authors: Yang Eddy Shih-Hsin , Leiby Benjamin , Sonpavde Guru P. , Einstein David Johnson , Quinn Zachary L. , Szmulewitz Russell Zelig , Sartor A. Oliver , Kelly William Kevin 
Published: June 2021

5036 Background: Rad is an alpha particle emitter that causes DNA double strand breaks and has been FDA-approved for use in mCRPC pts with bone metastases. PARP-1 activity critically supports androgen receptor (AR) activity in mCRPC and potentiates AR-dependent DNA damage response pathways that promote prostate cancer cell survival. Nira is a potent and selective PARP-1/2 inhibitor that has shown single agent clinical activity in mCRPC. We previously reported the safety of targeting the PARP-1/AR axis with Nira in combination with Rad. Herein we describe the results of an exploratory biomarker analysis. Methods: The primary objective of NiraRad is to determine the optimum Ph II dose of Nira plus Rad (55 kBq/kg of body weight IV every 4 weeks (wks) x 6) in pts with and without prior chemotherapy (docetaxel). Pts were enrolled to one of three dose levels of Nira (100, 200, or 300 mg PO daily). All cohorts were combined for exploratory biomarker analysis using Nanostring PanCancer Driver and Immune Pathways panels and the nSolver Advanced analysis module was performed on blood obtained from 23 pts at baseline, cycle (C) 1 day (D) 15, and C3D15. A favorable response was defined as any PSA reduction at week 12 or treatment (tx) duration > 18 wks, the median time on tx in the cohort of pts analyzed. A threshold of > 2 fold (X) differentially expressed genes was used. Results: Of the 23 pts with biomarker data, 7 (30%) experienced PSA reductions and 11 (48%) received tx for > 18 wks, 6 of which also had PSA reductions. Exploratory analysis revealed that the PI3K/Ras, MAPK, and transcriptional misregulation pathways were differentially regulated in pts who had favorable responses. The top downregulated gene, PAX5, which has been shown to promote prostate cancer growth, was decreased at C1D15 (2.7X, p < 0.01) and C3D15 (4.8X, p < 0.001) in pts with tx duration > 18 wks and at baseline in pts who had PSA reductions (3.1X, p < 0.05). Immune pathways analysis suggested downregulation of immunosuppressive B-cell (plasma cell) and upregulation of NK and T cell pathways in pts with tx duration > 18 wks. Conclusions: Previously Nira and Rad have been shown to have acceptable tolerability in mCRPC pts. This exploratory analysis suggests potential response biomarkers that warrant further investigation. Managed by: the Prostate Cancer Clinical Trials Consortium; Funded by: Janssen Pharmaceuticals and Bayer Healthcare Pharmaceuticals, Inc. Clinical trial information: NCT03076203.