bluuebunny/crossref_metadata_2025 huggingface dataset:
The HOLA COVID-19 study: Evaluating the impact of caring for patients with COVID-19 on cancer care delivery in Latin America.
Authors: Bernabe Ramirez Carolina , Velazquez Manana Ana I. , Olazagasti Coral , Bergerot Cristiane Decat , Soto Perez De Celis Enrique , Corona-Cruz Jose Francisco , Riano Ivy , Adaniel Christina , Ramirez Francisca , Anampa Mesias Jesus Del Santo , Cajina Carmen , Mena Evelin , Gracia Elias , Menendez Alvaro G. , Idrobo Henry , Bezares Raimundo , Castillo Fernandez Omar Orlando , Duque Duran Liseth , Bergerot Paulo Gustavo , Duma Narjust
Published: June 2021

1537

Background: The severe acute respiratory syndrome 2 (SARS-cov-2) virus causing COVID-19 has brought great challenges to global health services affecting cancer care delivery, outcomes, and increasing the burden in oncology providers (OP). Our study aimed to describe the challenges that OP faced while delivering cancer care in Latin America. Methods: We conducted an international cross-sectional study using an anonymous online survey in Spanish, Portuguese, and English. The questionnaire included 43 multiple choice questions. The sample was stratified by OP who have treated patients with COVID-19 versus those who have not treated patients with COVID-19. Data was analyzed with descriptive statistics and Chi-square tests. Results: A total of 704 OP from 20 Latin American countries completed the survey (77% of 913 who started the survey). Oncologists represented 46% of respondents, followed by 25% surgical-oncologists. Of the respondents, 56% treated patients with COVID-19. A significant proportion of OP reported newly adopting telemedicine during COVID-19 (14% vs 72%, p=0.001). More than half (58%) of OP reported making changes to the treatments they offered to patients with cancer. As shown in the table, caring for patients with COVID-19 significantly influenced practice patterns of OP. Access to specialty services and procedures was significantly reduced: 40% noted significantly decreased or no access to imaging, 20% significantly decreased or no access to biopsies, 65% reported delays in surgical oncology referrals, and 49% in radiation oncology referrals. A vast majority (82%) reported oncologic surgeries were delayed or cancelled, which was heightened among those treating patients with COVID-19 (87% vs 77%, p=0.001). Conclusions: The COVID-19 pandemic has significantly affected the way cancer care is delivered in globally. Although changes to healthcare delivery are necessary as a response to this global crisis, our study highlights the significant disruption and possible undertreatment of patients with cancer in Latin America that results from COVID-19.[Table: see text]
Bridging the gaps between tertiary and community care networks: Results from a southern California survey research analysis.
Authors: Chehrazi-Raffle Alex , Salgia Nicholas , Hsu Joann , Zengin Zeynep Busra , Salgia Sabrina , Chawla Neal , Malhotra Jasnoor , Dizman Nazli , Muddasani Ramya , Meza Luis A , Cianfrocca Mary E. , Gong Jun , Anand Sidharth , Chiu Victor Yundeh , Yeh James Jen-Chi , Pal Sumanta K.
Published: June 2021

1538

Background: Although many tertiary cancer centers offer access to myriad research protocols, the majority of patients nevertheless receive treatment at community practices. We sought to examine the barriers that hamper clinical collaboration between tertiary and community practice environments in Southern California. Methods: A 31-item survey was distributed to community and tertiary oncologists using REDCap, a browser-based electronic data capture system. Survey questions assessed the following attributes: demographics and features of clinical practice, referral patterns, availability and knowledge pertaining to clinical trials, strategies for knowledge acquisition, and integration of community and tertiary practices. Results: The survey was distributed to 98 oncologists, 85 (87%) of whom completed it in full. The most common institutional affiliations were City of Hope Comprehensive Cancer Center (58%), University of California, Los Angeles (10%), and Cedars Sinai Medical Center (8%). In total, 52 (61%) respondents were community practitioners and 33 (38%) were tertiary oncologists. A majority (56%) of community oncologists defined themselves as general oncologists whereas almost all (97%) tertiary oncologists reported a subspecialty. Clinical trial availability was the most common reason for pt referrals to tertiary centers (73%). The most frequent barrier to tertiary referral was financial considerations (59%). Clinical trials were offered by 97% of tertiary practitioners as compared to 67% of community oncologists (p = 0.001). Of note, while a majority of tertiary center providers (52%) described the primary value of community practices to be a source of referrals for clinical trials, most community oncologists (82%) reported only a minimal-to-moderate understanding of clinical trials available at regional tertiary centers. Conclusions: Community oncologists refer patients to tertiary centers primarily with the intent of clinical trial enrollment; however, significant gaps exist in their knowledge of trial availability. Our results identify the need for enhanced communication and collaboration between community and tertiary providers to expand patients’ access to clinical trials.
Dedicated clinical trial tissue tracking database to improve turn-around time at high-volume center.
Authors: Blankenship Peter , DeLaRosa David , Burris Marc , Cusson Steven , Hendricks Kayla , Earwood Christopher , Jones Suzanne Fields , Hamilton Erika P. , Johnson Melissa Lynne , Burris III Howard A. , Bendell Johanna C. , McKean Meredith
Published: June 2021

1543

Background: Tissue requirements in oncology clinical trials are increasingly complex due to prescreening protocols for patient selection and serial biopsies to understand molecular-level treatment effects. Novel solutions for tissue processing are necessary for timely tissue procurement. Based on these needs, we developed a Tissue Tracker (TT), a comprehensive database for study-related tissue tasks at our high-volume clinical trial center. Methods: In this Microsoft Access database, patients are assigned an ID within the TT that is associated with their name, medical record number, and study that follows their request to external users: pathology departments, clinical trial coordinators and data team members. To complete tasks in the TT, relevant information is required to update the status. Due to the high number of archival tissue requests from unique pathology labs, the TT has a “Follow-Up Dashboard” that organizes information needed to conduct follow-up on all archival samples with the status “Requested”. This results in an autogenerated email and pdf report sent to necessary teams. The TT also includes a kit inventory system and a real-time read only version formatted for interdepartmental communication, metric reporting, and other data-driven efforts. The primary outcome in this study was to evaluate our average turnaround time (ATAT: average time from request to shipment) for archival and fresh tissue samples before and after TT development. Results: Before implementing the TT, between March 2016 and March 2018, we processed 2676 archival requests from 235 unique source labs resulting in 2040 shipments with an ATAT of 19.29 days. We also processed 1099 fresh biopsies resulting in 944 shipments with an ATAT of 7.72 days. After TT implementation, between April 2018 and April 2020, we processed 2664 archival requests from 204 unique source labs resulting in 2506 shipments (+28.0%) with an ATAT of 14.78 days (-23.4%). During that same period, we processed 1795 fresh biopsies (+63.3%) resulting in 2006 shipments (+112.5%) with an ATAT of 6.85 days (-11.3%). Conclusions: Oncology clinical trials continue to evolve toward more extensive tissue requirements for prescreening and scientific exploration of on-treatment molecular profiling. Timely results are required to optimize patient trial participation. During the intervention period, our tissue sample volume and shipments increased, but the development and implementation of an automated tracking system allowed improvement in ATAT of both archival and fresh tissue. This automation not only improves end-user expectations and experiences for patients and trial sponsors but this allows our team to adapt to the increasing interest in tissue exploration.
Oncology patient and provider preferences regarding rapid radiology result release to online portals.
Authors: Bleeker Jonathan , Wernisch Jan , Tronier Shawn , Terstriep Shelby A.
Published: June 2021

1544

Background: Spurred by changes in legislation and technology, rapid patient access to medical results has never been higher. Many health systems now release results of radiology tests within 24 hours of completion, meaning patients may see results before being able to discuss them with the ordering provider. Generally, surveys have demonstrated that patients are in favor of rapid result availability, but research on rapid result release to oncology patients with distinct concerns is scant. Methods: Starting in February 2020, oncology providers throughout Sanford Health, a multi-site primarily rural integrated practice in the upper Midwest were invited to complete an online survey regarding their opinions on rapid result release. Starting in February 2020, oncology patients were invited to complete a similar survey. This survey was open until August 2020, when 100 patients had completed the survey; both surveys contained both categorical and narrative results. Results: Oncology providers had a generally more negative opinion of rapid radiology result release to online portals compared to patients. 65% of patients believed radiology results should be released within 24 hours of resulting; only 12% of providers shared this view. 66% of providers shared that they did not feel comfortable with patients’ ability to interpret radiology results and only 13% felt that “normal” results should be released immediately to an online portal; this number decreased to 3% when results were “abnormal”. Patient opinions on appropriate result release were impacted by test results as well. For “normal” radiology results, 50% of patients favored initial communication be via online portal without discussion with a provider; for “abnormal” results, this number decreased to 28%. 43% of patients had learned of an “abnormal” result via online portal before discussion with a provider; 66% of these patients felt that this was a positive which allowed them to process information prior to the visit; 33% felt that it created undue anxiety. 94% of providers reported having a patient contact them regarding a test result prior to a planned visit, with 60% providers sharing this happens at least once weekly. When asked what improvements could be made to the system currently in place at Sanford, 80% of providers suggested holding radiology results until direct communication with the provider can occur; only 8% of patients suggested the same intervention. Conclusions: Rapid result release is generally a patient satisfier, although oncology patients do distinguish abnormal from normal results in terms of rapid release. It is a dissatisfier for providers both due to concerns regarding patients’ ability to interpret results and due to excess work created by rapid release. Ongoing work should focus on ways to allow patients to access resources to make medical results more interpretable if reviewed prior to provider visits.
Predicting disease progression and mortality in metastatic colorectal cancer patients (mCRC) through an artificial intelligence-based analytical tool.
Authors: Galmarini Carlos Maria , Lucius Maximiliano
Published: June 2021

1549

Background: Predicting the clinical course of metastatic disease remains a key challenge in CRC. Estimating prognosis of these late-stage patients can avoid undertreatment or overtreatment and also guide the follow-up intensity. This study has investigated the ability of an artificial intelligence-based analytical tool to identify those mCRC patients with high risk of disease progression and mortality based on their clinical parameters. Methods: Through www.projectdatasphere.org we accessed datasets of two randomised phase III trials including chemo-naïve (NCT00364013, n = 1183 patients) and chemo-refractory (NCT00113763, N = 483) mCRC patients. We generated synthetic fingerprints (SF) for each patient through the integration of 44 clinical features (demographics, anthropometrics, medical history, blood tests and treatment characteristics) collected, respectively, during the screening phase and the first month of inclusion in each trial. These SF were then input into a deep learning framework (DLF) to identify subgroup of patients based on their similarities. The resultant clusters were correlated with progression-free survival (PFS) and overall survival (OS). Results: After discarding missing data, 861 chemo-naïve and 341 chemo-resistant mCRC patients were eligible for the study. In the chemo-naïve cohort, the SF/DLF system was able to detect two different clusters: C0 (n = 31) and C1 (n = 830). Patients in C0 had a higher risk of progression (median PFS 6.2 months vs. 9.1 months; hazard ratio 1.83, 95% CI 1.16-2.88; p = 0.008) and death (median OS 13.2 months vs. 20.1 months; hazard ratio 2.84, 95% CI 1.68-4.80; p < 0.001) compared to patients in C1. When applied to the chemo-resistant cohort, the SF/DLF system was again able to identify two different clusters: P0 (n = 159) and P1 (n = 182). Patients in P0 had a higher risk of progression (median PFS 1.7 months vs. 1.8 months; hazard ratio 1.32, 95% CI 1.05-1.67; p < 0.001) and death (median OS 6.1 months vs. 6.8 months; hazard ratio 1.34, 95% CI 1.07-1.68; p = 0.01) compared to patients in P1. In both cases, feature contribution analysis showed that major differences between clusters were related to clinical status, anthropometrics and haematological and biochemistry tests. Conclusions: Our SF/DLF system can identify mCRC subtypes based on distinct clinical features that correlate with higher risk of progression and death. Further work is required to validate this approach as a novel prognostic biomarker tool for monitoring mCRC patients.
Efficacy analysis of a remote symptom management platform.
Authors: Kosmidis Paris A. , Lagogianni Christie , Kosmidis Thanos
Published: June 2021

1566

Background: Quality of life of cancer patients is a critical part of cancer care. Symptom management is evolving as a multidisciplinary approach, and is increasingly delivered through a combination of physical and remote interactions. CareAcross is an online platform offering personalized, guidelines-based support to cancer patients, that complements physicians’ support and enables remote monitoring. This analysis investigated the improvement in the quality of life of cancer patients delivered through such remote support. Methods: Patients engage with an online interactive platform to receive personalized support based on a variety of parameters, through algorithms incorporating their exact diagnoses, treatments and comorbidities, and more. For symptom management, patients report the presence of specific side-effects via brief questionnaires; for each side-effect reported, they receive tailored support (text and multimedia) to help overcome it. These online questionnaires are repeated periodically to capture the outcome of the supportive process, and provide additional support as necessary. A retrospective analysis evaluated the efficacy of the personalized support: each patient’s reported side-effects were compared before versus after receiving the support, hence calculating the reduced incidence. Results: 2203 patients from 8 countries, with breast, lung, prostate or colorectal cancer (1563, 404, 159 and 77, respectively) reported side-effects, received support, and updated their reports at least once. The median follow-up period was 4.9 months. The patient-reported outcomes on their quality of life revealed substantial improvement, regardless of cancer type (lowest recorded improvement = 25.7%). Commonly reported side-effects included sleep problems, dry mouth, constipation, changes in food taste, and more (see Table). Side-effects reported in specific cancer types also showed substantial improvement, including hot flushes (breast; 32.0% improvement), dyspnea (lung; 38.1%), bowel dysfunction (prostate; 80%) and others. The efficacy of the support to breast, prostate or colorectal cancer patients was similar; support to lung cancer patients exhibited the lowest efficacy (p < 0.05). Fatigue was the most common side-effect. It was also the most resistant to improvement compared to all others (p < 0.05). Conclusions: Digital remote support of cancer patients is a realistic option to improve quality of life. Randomized controlled trials can help quantify its impact on health economics, hospital admissions, resource utilization, and other aspects.[Table: see text]
Risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from solid tumors: A real-world machine learning approach.
Authors: Stopeck Alison , Higano Celestia S. , Henry David H. , Bachmann Basia A. , Rehn Marko , Jacobson Dionna , Cadieux Benoit
Published: June 2021

1567

Background: The anti-RANKL monoclonal antibody denosumab has been shown to be superior to the bisphosphonate zoledronate for the prevention of skeletal-related events (SREs) in patients with incident bone metastases (BM) from solid tumors (ST). Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥ 2 years. However, real-world treatment patterns in the U.S. suggest that the denosumab treatment duration is often < 1 year. Applying a machine learning approach, we sought to identify risk factors associated with SRE incidence following cessation of denosumab to help inform optimal clinical SRE prevention strategies. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BM from a primary ST between 1 Jan 2007 and 1 Sep 2019 were evaluated for inclusion in the study. Eligible patients had to receive ≥ 2 consecutive 120 mg denosumab doses on an every 4-week (± 14 days) schedule and have a minimum follow-up ≥ 1 year after the last denosumab dose or an SRE occurring between days 84 and 365 after denosumab cessation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Impact and relative importance of available medical, clinical, and treatment factors on SRE risk following denosumab cessation were extracted from the model using Shapley additive explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 patients (breast, n = 563 [40%]; prostate, 421 [30%]; lung, 180 [13%]; other cancers, 250 [17%]) met inclusion criteria, with a median of 253 (min, 88; max, 2726) days of denosumab treatment; 490 (35%) experienced ≥ 1 SRE following denosumab cessation. With a meaningful model performance based on an area under the receiver operating characteristic (AUROC) score of 77%, SHAP identified several significant factors that predicted an increased SRE risk following denosumab cessation, including prior SREs, shorter denosumab treatment duration, and a higher number of clinic visits as the top-ranked factors (Table). Conclusions: A machine learning approach to SRE risk factor identification may help clinicians better assess the individualized patient’s need for denosumab treatment persistence and improve patient outcomes. Results from tumor-specific groups will be presented at the meeting.[Table: see text]
A Phase 0 ‘trigger’ trial of CDK4/6 plus ERK1/2 inhibitors in recurrent glioblastoma.
Authors: Sanai Nader , Chang Yu-Wei , Margaryan Tigran , DeSantis Anita , Elliott Mackenna , Pennington-Krygier Chelsea , Hook Garry , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: June 2021

2005

Background: The RB-CDK4/6 and MAPK signaling pathways are dysregulated in glioblastoma (GBM). Our recent phase 0 study of ribociclib in recurrent GBM patients suggested that CDK4/6 inhibitor monotherapy is not durable. In this ongoing, dual-drug phase 0 study (NCT04391595), we evaluate the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, a selective ERK1/2 inhibitor, in recurrent GBM patients. Methods: Adult patients eligible for this open-label, multi-center phase 0 protocol had recurrent GBM with (1) intact RB expression, (2) >30% pERK expression, and (3) CDKN2A/B deletion or CDK4/6 amplification. Prior to a planned resection, patients received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD). In a Time-Escalation Arm, ten patients were assigned to 3-5 hour or 7-9 hour intervals from final drug dose to tumor removal. Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ ( i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy. Results: In this interim analysis, no dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib (including its equipotent M2 and M20 metabolites) were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort). In the same tissue, median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Gd-enhancing tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase. Conclusion: Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB pathway and tumor proliferation. Following 6 days of presurgical drug exposure, the Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI. Clinical trial information: NCT04391595.
Comparison of immune microenvironment between primary lung tumors and paired brain metastatic tumors.
Authors: Chen Likun , Wu Lihong , Li Meichen , Chen Huan , Wu Lijia , Hao Pei , He Ji
Published: June 2021

2020

Background: Lung cancer is one of the most common causes of brain metastases (BMs) and is always associated with poor prognosis. To evaluate the characteristics of the tumor immune microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and paired brain metastases. Methods: Forty-three Chinese patients with NSCLC who had BMs at presentation or during the course of their disease were admitted to the Sun Yat-Sen University Cancer Center (Guangzhou, China) from 2000 to 2019. RNA sequencing (RNA-seq) of eighty-six formalin-fixed, paraffin embedded (FFPE) samples from primary lung tumors and paired brain metastases of 43 patients was conducted to comprehensively analyze the tumor immune microenvironment. Results: Our data revealed that brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs) (all 28 immune cell subtypes P < 0.05), lower fraction of activated CD8 T cell and effector memory CD8 T cell in total TILs (P = 0.028, P < 0.001, respectively); higher fraction of macrophage and neutrophil in total TILs (P < 0.001, P < 0.01, respectively). Comparing with the primary lung tumors, the scores of some immune related signatures, including MHC non-class signature, IFN gamma signature and T-cell-inflamed gene-expression profile (GEP) signature, were significantly lower in brain metastases (P = 0.004, P = 0.009, P = 0.004, respectively), while the score of MHC class-II signature was higher in brain metastases (P = 0.045). We found the distributions of tumor microenvironment immune types (TMIT) in brain metastases and primary lung tumors were different. Brain metastases contained significantly lower proportion of TMIT I (high PD-L1/ high CD8A) (23%) than primary lung tumors (47%) (P < 0.05). Besides, we found three immune inhibitory checkpoint molecules, namely C10orf54 (VISTA), CTLA4 and CD274 (PD-L1) were downregulated in brain metastases than in primary lung tumors (P < 0.001, P < 0.001, P = 0.034, respectively). Moreover, there was poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors (R = 0.28, P = 0.068). Unsupervised hierarchic cluster analysis revealed the primary lung tumors had two distinct patterns of immune gene signatures, namely Cluster A and Cluster B, and the tumors in Cluster B were immune rich, but associated with poor prognosis (log-rank P = 0.021). Conclusions: Our work illustrates the immune landscape of brain metastases from NSCLC, and suggests that the tumor immune microenvironment in brain metastases compared with primary lung tumors is further immunosuppressed, that may help guide immunotherapeutic strategies for NSCLC brain metastases.
Outcomes of immunotherapy (ICI) alone vs tyrosine kinase inhibitors (TKI) alone versus ICI and TKI combined in renal cell carcinoma brain metastasis.
Authors: O'Shea Patrick Joseph , Tatineni Vineeth , Rauf Yasmeen , Jia Xuefei , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Peereboom David M. , Ahluwalia Manmeet Singh
Published: June 2021

2030

Background: Renal cancer is the fourth most common cause of metastatic tumors to the brain. Tyrosine kinase inhibitors (TKIs) targeting VEGFR and other receptors, such as sunitinib, pazopanib, etc., have been used as first line for renal cell carcinoma brain metastasis (RCCBM). Immune Checkpoint Inhibitors (ICIs) targeting PD-L1 and CTLA-4 interactions, such as nivolumab and ipilimumab respectively, have also been used as first line treatment for RCCBM. However, the efficacy of TKIs alone, ICIs alone, or TKIs and ICIs combined as first line treatment has emerged as a topic of interest. Methods: Patients with RCCBM treated with either TKIs, ICIs, or both at our tertiary care center from 2010-2019 were evaluated. Overall Survival (OS) was measured from initiation of either TKI or ICI therapy to date of death or last follow up. The Cox proportional hazard model was used to determine differences in OS. Results: 218 patients with RCCBM were included. Of these, 32 were treated with ICIs alone, 112 were treated with TKIs alone, and 76 were treated with a combination of ICIs and TKIs. For ICI treatment alone the median age at diagnosis was 61 years (Interquartile range (IQR) 38-82), 72% of the patients were male, and 97% were white. For TKI treatment alone the median age at diagnosis was 58 years (IQR 37-82), 70% of the patients were male, and 92% were white. For the combination cohort the median age at diagnosis was 63 years (IQR 45-79), 69% of the patients were male, and 97% were white. OS for patients receiving ICI, TKI, and combination treatment had a median of 69.1, 42.7, and 126.0 months and a 2-year rate of 77%, 69%, and 93%, respectively. With ICI treatment as a reference, TKI treated patients had an OS hazard ratio of 1.32 (95% CI = 0.78 - 2.21, p = 0.30) and ICI/TKI combination had an OS hazard ratio of 0.52 (95% CI = 0.30 - 0.92, p = 0.024). Conclusions: A combination treatment of ICIs and TKIs was associated with an increase in OS when compared to treatment with either TKIs or ICIs alone in patients with RCCBM. These results should be interpreted cautiously due to treatment selection bias. Further studies need to be done to control for other patient variables such as performance status, number of intracranial lesions, and extra-cranial metastasis.[Table: see text]
Outcomes of first-generation versus third-generation epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer with brain metastases (NSCLCBM).
Authors: Tatineni Vineeth , O'Shea Patrick Joseph , Rauf Yasmeen , Jia Xuefei , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Peereboom David M. , Ahluwalia Manmeet Singh
Published: June 2021

2031

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases, with 10-30% of patients developing brain metastases. EGFR is a transmembrane glycoprotein that is mutated in up to 50% of NSCLCs. First-generation EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, are limited by blood-brain barrier (BBB) penetration and exon 20 (T790M) tumor mutations. Third-generation EGFR TKIs, such as osimertinib, have shown better BBB penetration and efficacy against T790M mutations. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first and third-generation EGFR TKIs. Methods: NSCLCBM patients diagnosed between 2010 and 2019 at our tertiary care center were investigated. Information regarding molecular marker status, systemic therapies, and date of progression were collected. OS was defined as the start date of systemic therapy to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: A total of 193 NSCLCBM patients with an EGFR mutation were identified. 33 EGFR mutant patients received first-generation EGFR TKIs, of which 56.7% were females, 82.1% were white, and had a median age of 63.2 years. 22 patients received third-generation EGFR TKIs, 64.1% being female, 76.9% being white, and with a median age of 71.5 years. The median OS (mOS) in patients who received first and third-generation EGFR TKIs was 59.8 months and 65.9 months respectively (p-value (p) = 0.06). The median PFS (mPFS) between the first and third-generation EGFR TKI cohorts was 44.3 months and 66.9 months respectively (p= 0.048, hazard ratio (HR) = 0.50 (95% confidence interval (CI) = 0.25, 0.99). Conclusions: Newer generation of targeted therapies in NSCLCBM have focused on overcoming previous efficacy hurdles, including BBB penetration and resistant mutations. We determined that there was a significant mPFS benefit in osimertinib compared to erlotinib or gefitinib, and a trend towards significant mOS benefit in osimertinib compared to erlotinib or gefitinib in patients with NSCLCBM. However, these results should be interpreted cautiously due to treatment selection bias, and further studies need to be conducted on brain metastases lesion size and response rates.[Table: see text]
An investigation into the impact of next generation sequencing on the use of targeted treatments in glioblastoma.
Authors: John Jordan , Lukas Rimas Vincas , Kumthekar Priya
Published: June 2021

2035

Background: Next-generation sequencing (NGS) provides clinicians immense amounts of information about a patient’s cancer. NGS allows the detection of a wide range of gene alterations undetectable by older techniques. This has the promise to help guide clinicians in their decision-making as genetic alterations can be both prognostic and predictive. NGS may reveal new treatment options for patients with glioblastoma. The goal of this project was to evaluate how often NGS results influence the use of targeted treatment agents in glioblastoma. This study did not investigate the impact of NGS on reclassification of cancers, prognosis, or treatment decisions outside of the use of targeted therapy. Methods: We conducted a retrospective chart review to see if adult glioblastoma patients received treatments for potentially actionable gene alterations and for fusion variants because of NGS. Here we looked at alterations labeled as actionable from the Tempus company’s NGS results. We collected diagnosis and treatment information from the Electronic Medical Record and from the Electronic Data Warehouse. We examined if patients after receiving NGS would receive targeted treatment, as that likely indicated these treatments were given due to NGS indication. We excluded cytotoxic chemotherapy agents and bevacizumab as these therapies are utilized regardless of a targeted gene indication. This analysis excluded treatments received in clinical trials in which enrollment was independent of NGS. This analysis looked at the proportion of patients with actionable alterations that were treated with targeted agents. Results: 261 glioblastoma patients were found on NGS to have mutations which were potentially actionable. Thirty-three of these patients (12.6%) received a respective targeted therapy, and the other 228 patients (87.4%) did not receive an NGS guided targeted therapy. 97 patients had EGFR copy number gains or EGFR gain of function mutations of which 21 were treated with depatuxizumab mafodotin, and one additional patient who was treated with ABBV 321. Of the NGS treatment guided therapies, depatuxizumab mafodotin was the most used targeted agent in our sample set. Additionally, there were 30 patients with fusion variants and 11 of them were FGFR3-TACC3 fusions. Of these 11, 4 received targeted regimens (36.4%) with either TAS-120, pemigatinib, erdafitinib, or erdafitinib with ponatinib. The other fusion variants were not acted upon. Conclusions: These preliminary results suggest that NGS data currently does not frequently impact treatment decisions for glioblastoma. Although this study is limited by being a single institution study, future efforts include expanding this analysis to multiple institutions. With improvements in therapeutics as well as with wider availability of NGS testing, sequencing data may impact a larger percentage of glioblastoma patients.
Pilot trial treating recurrent GBM patients with precision medicine regimens.
Authors: Clarke Jennifer Leigh , Solomon David , Oberheim Bush Nancy Ann , Grabowsky Jennifer A. , Kline Cassie , Kroetz Deanna L. , Taylor Jennie Webster , Villanueva-Meyer Javier , Molinaro Annette , Gibson David , Tedesco Meghan , Rabbitt Jane E , Rodriguez Almaraz Eduardo , Schulte Jessica , Buerki Robin Arthur , Hervey-Jumper Shawn L. , Aghi Manish K. , Berger Mitchel S. , Chang Edward , Chang Susan Marina
Published: June 2021

2045

Background: Recurrence of GBM after initial treatment with surgery, radiation, and chemotherapy is nearly universal. Salvage therapies have limited efficacy with median overall survival (OS) of approximately 9 months and 6-month-progression-free survival (PFS-6) of 10-25% for both targeted and traditional therapies. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. Methods: The primary objective was to demonstrate the feasibility of implementing a personalized drug regimen for patients (pts) with surgically resectable recurrent GBM within 35 days of surgery. Secondary objectives included safety and efficacy. Eligible pts signed consent before surgery, and tumor tissue was analyzed using the CLIA-approved “UCSF500” next-generation sequencing panel with paired tumor/germline sequencing. A specialized genomic tumor board made individualized treatment recommendations incorporating sequencing results of the recurrent tumor and clinical history for each pt, using up to 4 FDA-approved drugs in combination (all drugs provided by study). Correlative studies will be reported separately. Results: 19 pts signed consent and 16 pts had surgery on trial, 1 with pathology showing treatment effect only. The remaining 15 pts were all genetically profiled and successfully started their individualized treatment within 35 days of surgery, meeting the primary feasibility endpoint. Conclusions: Implementation of an individualized treatment regimen was feasible in a timely fashion in surgically resectable recurrent GBM pts, with encouraging preliminary efficacy results. Further investigation is warranted, both to validate efficacy and to streamline this approach in larger pt populations. Clinical trial information: NCT03681028. [Table: see text]
Health-related quality of life for glioblastoma short and long-term survivors receiving treatment with TTfields.
Authors: Palmer Joshua David , Chuang Po-Ya , Chavez Gordon , Wang Bruce CM , Proescholdt Christina
Published: June 2021

2055

Background: The aim of this study was to administer the first large-scale, international survey eliciting real-world patient-reported quality-of-life (QoL) for patients with newly diagnosed and long-term glioblastoma (GBM) currently receiving treatment with TTFields. Methods: A survey was designed and mailed to 2,815 patients actively using TTFields for treatment of GBM in the United States (US, n = 2,182) and Europe (EU, n = 633). The survey included 1) demographic information, 2) patient-reported clinical information and 3) EuroQol’s EQ-5D-5L and EQ visual analogue scale (EQ-VAS) surveys. Univariate and multivariate analyses were performed on five dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) of the EQ-5D-5L and EQ-VAS to understand the impact of patient demographics and clinical characteristics on QOL. Results: A total of 1,106 patients were included (39.3% response rate) with 782 and 324 responses in the US and EU, respectively. The median time from diagnosis was 14 mos (range, 0-301 mos) and ≥24 mos in 28.4% of patients. Patients were mostly male (62.3%) with a mean age of 58.5 (SD = 12.5) and 69.3% had stable disease. Mean EQ-VAS was 68.2 for all patients and was significantly higher for those with > 15 months since diagnosis compared to < 15 months since diagnosis (p = 0.008). There were significantly fewer problems reported on self-care ( p = 0.04) and usual activity ( p = 0.007) in patients with a longer time since diagnosis in the univariate analysis. In the multivariate analysis, patients with a longer time since diagnosis reported significantly better EQ-VAS ( p = 0.04). The effect size in the multivariate analysis for time since diagnosis on EQ-VAS was higher in the progressed subgroup ( p = 0.17) compared to the broader sample (0.08). The EQ-VAS and all five dimensions including mobility, self-care, usual activity, pain/discomfort, and anxiety/depression were improved for stable patients compared to progressed patients in the univariate and multivariate analyses. However, when stratified by progression status, progressed patients with longer time from diagnosis had significantly fewer reported problems with mobility ( p = 0.04), self-care ( p = 0.004) and usual activity ( p = 0.008), and significantly better self-rated health status ( p = 0.02). Conclusions: GBM survivors receiving TTFields reported significantly improved health status over time since diagnosis. Long-term survival with TTFields does not have a detriment in patient reported quality of life, in fact with longer time from diagnosis QOL significantly improves. This is true for patients with stable and progressed disease. Future prospective clinical trials are needed to further study the impact of our treatment and tumor progression on patient QOL.
Phase I study of ruxolitinib with radiation and temozolomide in patients with newly diagnosed grade III gliomas and glioblastoma.
Authors: Rauf Yasmeen , Hufsey Rachel , Robinson Kathy , Suh John H. , Chao Samuel T. , Murphy Erin Sennett , Yu Jennifer S. , Peereboom David M. , Ahluwalia Manmeet Singh , Wei Wei
Published: June 2021

2060

Background: Ruxolitinib is a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3, respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Methods: Newly diagnosed patients with unmethylated MGMT Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3+3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily and level -1 was 5 mg twice daily. Arm 2 was started once safe dose was established for Arm 1 for each dose level. Patients with methylated MGMT glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimate by Kaplan-Meier method and compared using log rank test. Results: 45 patients had survival data, 25 patients were Arm I and 20 arm II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p = 0.01 and p = 0.002), respectively. Conclusions: Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Clinical trial information: NCT03514069.
Predictive value of lymphocyte immunophenotyping (LIP) in primary central nervous system lymphoma (PCNSL).
Authors: Berthelot Axel , Boucard Celine , Petrirena Gregorio , Campello Chantal , Chinot Olivier L. , Tabouret Emeline
Published: June 2021

2063

Background: Immunity plays an important role in PCNSL development. PCNSL predictive factors need to be improved. Objective: to evaluate the characteristics and predictive value of blood LIP in PCNSL patients. Methods: we prospectively analyzed blood LIP in all newly PCNSL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). All patients presented with cerebral involvement, 13 (25%) with cerebrospinal fluid extension and 8 (15%) with ocular extension. Thirty-four patients (62%) benefited of steroid treatment at the time of LIP. Patients characteristics did not differ depending on steroid intake. Forty-eight patients (95%) benefited of polychemotherapy with high-dose methotrexate as first line treatment. We observed three (6%) lymphoproliferative syndromes on the LIP and 33 patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4/CD8 ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results, including CD4 (p = 0.475) or CD8 (p = 0.726) rates and CD4/CD8 ratio (p = 0.727). Complete or partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4/CD8 ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077). A ROC curve analysis was performed with an AUC of 0.684 allowing the selection of a CD4/CD8 ratio cutoff of 1.97 with a sensibility, specificity, positive predictive value, and negative predictive value to identify refractory patients of 90%, 55%, 35% and 95% respectively. Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI: 6.5-22.9) and 43.2 (95%CI: 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4/CD8 ratio > 1.97 was associated with poor PFS (p = 0.043, HR = 3.32 [1.02-4.88]) and tended to be associated with worse OS (p = 0.064). Conclusions: LIP at baseline may predict refractory disease and exhibits a prognostic value in PCNSL patients.
Pan cancer analysis of the intra-tumoral microbiome’s correlation with racial disparities.
Authors: Li Wei Tse , Uzelac Matthew , Chakladar Jaideep , Wong Lindsay M. , Gnanasekar Aditi , Lee Abby C. , John Daniel , Lopez Jay Patrick , Ongkeko Weg M.
Published: June 2021

2519

Background: Microbiome composition can influence cancer development and is moderated by diet, hygiene, sanitation, and other environmental variables. For example, a Mediterranean diet could increase breast Lactobacillus abundance, while the gut microbiome changes dramatically with fructose intake. Recent studies have revealed correlations between microbial abundance and racial disparities in cancer. Given these reports, it is critical to examine whether environmental influences on the microbiome contribute to racial disparities in cancer incidence and prognosis. Methods: We examined the intra-tumoral microbiome in the lungs, breasts, bladder, colon, rectum, cervix, head and neck, prostate, and pancreas (n = 4,169). Raw tumor RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) and aligned to bacterial genomes. Microbial abundance was correlated to race, ethnicity, and prognostic variables (Kruskal-Wallis test or Cox regression, p< 0.05). Results: We identified several microbes correlated with racial disparities for breast and bladder cancer, two microbes for lung squamous cell carcinoma, and one microbe for colon cancer. For breast cancer, African Americans have the highest mortality rate, followed by white Americans and Asian Americans. We found that four microbes, all under the order Burkholderiales, were positively correlated with poor prognosis and were most abundant in African Americans and least abundant in Asian Americans. Therefore, increased abundance of these microbes may contribute to the observed mortality differences between races. For bladder cancer, Asian Americans have the lowest incidence and mortality rates. Seven microbes, including two Geobacillus, two Pseudomonas, and two Burkholderiales, positively correlate with good prognosis and are upregulated in Asian Americans. High Pseudomonas fluorescens abundance is positively correlated with decreased risk of death (HR: 0.57, 95% CI: 0.38-0.85). High abundance of the Burkholderiales R. pickettii (HR: 0.62, 95% CI: 0.42-0.92) and V. paradoxus (HR: 0.59, 95% CI: 0.36-0.98) also exhibit the same trend. Geobacillus and Pseudomonas are both present in food, while Burkholderiales can cause nosocomial infections and are altered by diet. Conclusions: Our study is the most comprehensive to date investigating racial differences in the intra-tumoral microbiome. Our data serve as a starting point for exploring whether environmental influence of microbial abundance contributes to racial disparities in cancer.