tbuckley/cabot-search huggingface dataset:
Neutrophil to Lymphocyte ratio (NLR): A prognostic marker in melanoma patients receiving immunotherapy.
Authors: Richard Thomas O'Dwyer, Colum Dennehy, Jane Sze Yin Sui, Catherine Margaret Kelly, Paula Calvert, John McCaffrey
Journal: Journal of Clinical Oncology (2019)

9573 Background: Cancer related inflammatory processes have been shown to have an important role in tumourigenesis, disease progression, and patient prognosis. An elevated neutrophil to lymphocyte ratio (NLR) is associated with a worse outcome in several malignancies. The relationship between NLR and immune checkpoint blockade is poorly understood. We sought to investigate the role of NLR in patients receiving immune checkpoint inhibitors for metastatic melanoma (MM). We aimed to do this by comparing outcomes of patients with MM with high ( &gt; 3) and low ( &lt; 3) NLRs receiving immunotherapy, and investigating whether NLR acts as a prognostic biomarker. Methods: We performed a retrospective review of electronic medical records and collected data on 40 patients with MM treated with immunotherapy from 2013 to 2018 in MMUH, Dublin. NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. Continuous variables were expressed as a median. We examined NLR at baseline and at 6 weeks (+-2 weeks). We also examined percentage change in NLR. These parameters were tested for association with PFS and OS using the log rank test. Results: 40 patients received immune checkpoint inhibitors in the form of ipilimumab, nivolumab, and pembrolizumab. The median age was 61.2 ( 29.7 to 77.1). The median baseline NLR was 3.39 ( 1.05 to 26.03). The median NLR at 6 weeks (+-2 weeks) was 2.86 ( 0.83 to 19.9). The median change in NLR was -8.02% (- 80.99% to 409.38%). Median time to progression was 4.7 months (0.4 to 51.4 months). Overall survival was 12.9 months (0.4 to 67.7 months). When baseline NLR &lt; 3 patients had a significantly longer PFS: 11.7 vs 2.8 months (p = 0.02). When NLR at approximately 6 weeks was &lt; 3, patients also had significantly longer PFS: 10.8 vs 2.9 months (p = 0.04). When NLR decreased by &gt; 20% from baseline, there was no significant difference in PFS (p = 0.82). When NLR &lt; 3, patients had significantly longer OS: 18 months vs 8.2 months (p = 0.02). When NLR at approximately 6 weeks was &lt; 3, patients had significantly longer OS: 20.3 months vs 7.4 months (p = 0.003). Conclusions: Baseline NLR &lt; 3 and NLR &lt; 3 approximately 6 weeks after initiation of treatment is associated with improved PFS and OS. Change in NLR after initiation of treatment is not significantly associated with improved outcomes, however our sample size was small. NLR may be used as a readily available and cheap prognostic marker in MM patients receiving immunotherapy.
Real-world immuno-oncology treatment patterns and outcomes in US patients with metastatic non-small-cell lung cancer.
Authors: Amanda Bruno, Kelly Bell, Dana Stafkey-Mailey, Sharanya Murty, Marc S. Ballas
Journal: Journal of Clinical Oncology (2019)

e20537 Background: Three immune-oncology (IO) agents are approved by the FDA to treat metastatic NCSLC (mNSCLC). This retrospective observational study aimed to observe treatment patterns and real-world outcomes of mNSCLC patients treated in the community setting, predominantly in the southern region of the U.S. Methods: Electronic health records and charts were reviewed for patients with a diagnosis of mNSCLC initiating an IO between September 1, 2015 to September 30, 2017. Patient data were examined from the date of IO therapy initiation until death, loss to follow-up, or study end date (December 31, 2017), whichever was earliest. This study was hypothesis generating thus no statistical tests were performed. Results: Of the 2,864 patients who met initial study criteria, 750 were randomly chosen for full chart review and 577 met inclusion/exclusion criteria among whom 571 had metastatic NSCLC prior to initiating IO therapy. 464, 97, and 16 patients were initiated on nivolumab, pembrolizumab, and atezolizumab, respectively. Average age was 69.7 years and 65% of patients initiated treatment in 2015 or 2016. At diagnosis, 36% of patients had an Eastern Cooperative Oncology Group performance status of 0 versus 16% at time of therapy initiation. Duration of IO therapy was 5.15 months among all metastatic patients (5.37 months for 1L only) and 4.13. months among those who completed therapy during the study period. Median real world progression free survival (rwPFS) was 5.53 (4.31. 7.20) months for 1L patients and 3.32(2.76, 4.01) months for 2L+. Real world overall survival (rwOS) was 19.04 (13.03, NR) months for 1L patients and 12.01 (8.82, 15.92) months for 2L+. Conclusions: Median rwPFS and rwOS were slightly higher than published clinical trials, yet patients were older and with poorer performance status compared to clinical trial enrollees. Despite the differences in patient characteristics, results suggest that clinical real world outcomes for this population fall within the range of median OS and PFS values observed in immune checkpoint inhibitor trials. Future research should explore the use of EHR, chart and other data sources to confirm benefit and risk in the real world.
Aspirin for the Prevention of Preeclampsia and Potential Consequences for Fetal Brain Development
Authors: Antonis Voutetakis, Panagiota Pervanidou, Christina Kanaka-Gantenbein
Journal: JAMA Pediatrics (2019)

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Neutrophils lymphocyte ratio role in predicting response to checkpoint inhibitors in metastatic non-small lung cancer.
Authors: Hosam Hakim, Ahmed Abdalla, Tarik H. Hadid
Journal: Journal of Clinical Oncology (2019)

e20646 Background: There have been numerous advances in the management of metastatic lung cancer, including targeted therapy against certain mutations in cancer cells and later developing immune therapy with check point inhibitors.From the pre-immune therapy era, a simple blood test allowing the calculation of the neutrophil-to-lymphocyte ratio (NLR) was established as a strong prognostic marker associated with worse overall survival (OS) in several tumor types including non-small cell lung cancer (NSCLC). Methods: We have retrospectively reviewed electronic medical records for patients with Metastatic NSCLC whom received at least one dose of Checkpoint Inhibitors from January 2014 till January 2019 in Van Eslander Cancer Center.The analysis was done using SPSS v. 25.0 and a p-value of 0.05 or less was considered to indicate statistical significance. A univariant analysis was done using Student’s t-test, the Mann-Whitney U test and the chi-squared test. Survival analysis was conducted using Kaplan Meier methodology as well as Cox proportional hazards models. Results: There were 80 patients with metastatic NSCLC received at least one dose of a checkpoint inhibitor. Median age was 63.9 ± 9.3; Males were 45%; Whites were 62.5%. 67.5% of patient had adenocarcinoma and 24% had squamous cell carcinoma. Twenty patients had brain metastasis (25%) and nineteen patients had liver metastasis (24.6%). Eleven patients (13.8%) had PDL-1 greater than 50% and 11 patients (13.8%) had PDL-1 between 1%-50% and 22 patients (27.5%) had negative PD-L1 status. 18.8% received immunotherapy as a first-line treatment and 65% got immunotherapy on their second line and 16.3% had immunotherapy as the third line of treatment or more. Sixty-one patients (76.2%) received Nivolumab and nineteen patients (23.8%) received pembrolizumab. Mean duration of immunotherapy was 13.7 months ± 20.7. Mean NLR was 6.1 ± 5. Patient with NLR &gt; 5:1 had statistically significant higher progression-free survival (PFS) 27.5 months compared to 12 months P = 0.02. Also, Patients with baseline NLR &gt; 5:1 had a trend toward higher median overall survival (OS) but was not statistically significant 41 months compared to 12 months P = 0.08. Conclusions: Our data showed similar finding to Bagley et al and other retrospective analysis from multiple institutes showing that NLR could be a good predictor of response to checkpoint inhibitors And a cutoff of NLR higher than 5.1 was associated with statistically significant better PFS and a trend towards a better OS.
Characterization of mutational processes in ER+ metastatic breast cancer.
Authors: Jorge Buendia-Buendia, Ofir Cohen, Dewey Kim, Esha Jain, Eric P. Winer, Nancy U. Lin, Nikhil Wagle
Journal: Journal of Clinical Oncology (2019)

1019 Background: Diverse mutational processes are active at different stages of cancer development and cause the mutational burden in cancer cells. These processes leave distinctive signatures, characterized by varying frequencies of nucleotide substitutions and their flanking base-pairs. Mutational signatures found in early stage breast cancer have been described, but less is known about the mutational processes in metastatic breast cancer (MBC). Methods: We performed whole exome sequencing (WES) on 209 metastatic tumor biopsies from patients with ER+ MBC. In a subset of patients, we obtained and performed WES on the matched primary biopsy (n = 62). Decomposition of mutational signatures was done by determining the linear combination of 30 previously reported mutational signatures (Alexandrov et al., 2013) that most accurately reconstructs the mutational profile of each tumor sample. For comparison, signature decomposition was also performed on 695 treatment-naïve primary ER+ breast cancers form The Cancer Genome Atlas (TCGA). Results: Cohort-level comparison of signature activity between our cohort of MBC biopsies versus the primary ER+ breast cancers from TCGA demonstrated enrichment of Signature 13 in MBC samples (q = 0.002), attributed to activity of the APOBEC family of cytidine deaminases and implicated in resistance to endocrine therapies. Activity of Signature 22, associated to activity of the nucleotide-excision repair mechanism, was depleted in MBC tumors relative to TCGA ER+ breast tumors (q = 0.02). Decomposition of mutational signatures at the clone level in the subset of patients with both metastatic and matched primary samples allowed us to infer signatures acquired in the metastatic setting. Among mutations in acquired clones, we found enrichment of APOBEC signatures (Sig. 2, q = 0.018; Sig. 13, q = 0.003). Conversely, activity of Signature 1, attributed to the normal aging process, was enriched in mutations shared between primary and MBC samples (q = 0.004). This suggests that mutations developed early in tumor evolution may be driven primarily by natural processes, while later mutations may reflect selective pressures imposed by therapies and cellular defects acquired during disease progression. Conclusions: The profile of somatic mutations in MBC differs from early stage breast cancer. APOBEC-related mutations arising late during tumor evolution are one possible mechanism for this difference. Further studying the associations between clinical features and therapies to mutational processes could inform design of clinical trials and management of MBC.
Phase 2 trial of tisotumab vedotin in platinum-resistant ovarian cancer (innovaTV 208).
Authors: Haider Mahdi, Steven Robert Schuster, David M. O'Malley, Donna M. McNamara, Reshma A. Rangwala, Shang-Ying Liang, Shweta Jain, Leonardo Nicacio, Hye Sook Chon
Journal: Journal of Clinical Oncology (2019)

TPS5602 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer, accounting for ≈185,000 deaths worldwide in 2018. Most patients (pts) initially respond to platinum-based chemotherapy (chemo), but more than 50% of pts recur. Pts who recur in ≤6 months have platinum-resistant OC (PROC), which is associated with poor prognosis. Standard therapy for PROC includes chemo ± bevacizumab (bev). However, many pts receive single-agent chemo, which demonstrates limited response and survival (≈12% ORR, 3-4 mo PFS, ≈12 mo OS). Therefore, there is an urgent need for novel therapeutic strategies. Tissue factor (TF) is a novel oncogenic target expressed in OC. Tisotumab vedotin (TV) is a first-in-class antibody drug conjugate comprising a TF-targeted fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. TV has shown encouraging antitumor activity and a manageable safety profile in PROC in the multicohort phase 1/2 innovaTV 201 study. innovaTV 208 is a multicenter, open-label, phase 2 trial with a safety run-in phase for a dose-dense regimen (DDR) evaluating the efficacy and safety of TV in pts with PROC. Methods: innovaTV 208 will enroll ≈142 adult pts with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable disease by RECIST v1.1; and ECOG score 0-1. Eligible pts must have received bev-containing treatment for OC. Pts with platinum-refractory disease, increased risk of bleeding, active ocular surface disease, or grade &gt; 1 peripheral neuropathy will be excluded. A safety run-in phase for the DDR will be performed in up to 12 pts who received ≤5 prior treatment regimens for PROC. In the DDR, TV will be given at previously decided lower doses IV 3Q4W for the same dose intensity as the standard 1Q3W dose; the primary endpoint is incidence of DLTs. In phase 2, pts who received ≤1 prior cytotoxic chemo regimen for PROC will be randomized to receive TV administered as IV 1Q3W or as IV 3Q4W, if shown to be tolerable. The primary endpoint for phase 2 is confirmed ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, DCR, CA-125 response rate by GCIG criteria, PFS, OS, pharmacokinetics, and safety. Clinical trial information: NCT03657043.
Application of artificial intelligence to predict a new class of novel synthetic lethal targets.
Authors: Spyro Mousses, David Schneider, Jeff Kiefer, Pieter Derdeyn, Kendyl Douglas, Abhishek Kothari, Daniel D. Von Hoff, Chris Yoo
Journal: Journal of Clinical Oncology (2019)

2598 Background: Synthetic lethal targets are proteins that are contextually vulnerable. Inhibitors of PARP1, for example, selectively produce a lethal phenotype in the context of cancer cells which have lost BRCA1 or BRCA2 function. As a high mutation rate is a hallmark of many cancers, targeting synthetic lethal interactions to selectively inhibit cancer cells with altered genetic backgrounds may increase the specificity and efficacy of therapeutics. Recently, clinical trials have targeted synthetic lethal pairs such as EGFR and BRAF, TP53 and BCL2, and PTEN and CHD1. Previous attempts to identify synthetic lethal targets have relied on empirical results from published studies of biological pathways perturbed in cancer cells. Developing strategies to rapidly identify synthetic lethals by combining multiple experimental and computational approaches would result in a new class of potential cancer drug targets beyond the existing efforts that rely on single experimental or computational methods alone. Methods: Here we present Expansive AI, an artificial intelligence augmented knowledge network that enables rapid hypothesis generation for accelerated discovery research. Using a purpose-built, hypergraph database of massive, integrated genomic and biomedical data, we can query all synthetic lethals and their component genes, as well as a wealth of data related to these genes. The database of biological data includes 11,000+ cancer genomes from TCGA, prior knowledge resources such as gene ontology and pathway resources, and experimental data including chemical and protein interaction and patent data. The hypergraph’s architecture allows for linking and nesting data, enabling efficient extraction of biologically-relevant features. Results: Using these features, a neural network classified 540 new candidate pairs that have previously not been reported. The candidate pairs were filtered to include only known oncogenes and least-studied genes. This produced a list of gene pairs which may represent the most novel class of synthetic lethal target candidates identified to date. Conclusions: We highlight the results of this AI-based approach and discuss validation efforts of the predicted interactions in specific cancer contexts.
Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.
Authors: Michael Gregory Cushion, Bhavani Krishnan, Jeff Paul Hodge, Jaya Chandra Balusu, Joseph Wagner, Cristina Oliva, Dana Edwards
Journal: Journal of Clinical Oncology (2019)

e20568 Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]
Abstract 12714: Symptom-Based Screening of Rheumatic Heart Disease in School-Aged Children and Development of an Effective Tool for Self-Screening in Rural India
Authors: Madhab Ray, Santanu Guha, Meghna Ray, Avik Karak, Basabendra Choudhury, Bipasha Ray, Haroon Zubair, Prakash C Hazra, Santanu Goswami, Jill Brierley, Philippe Vuylsteke, Victoria Zappi, Harry P Selker, Robert Goldberg, Deepak L Bhatt
Journal: Circulation (2018)

Background: Rheumatic heart disease (RHD), if detected early, can benefit from secondary prevention to reduce long term complications, morbidity, and mortality. However, there are no national scree...
Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening
Authors: David J. Marcus, Gaurav Bedse, Andrew D. Gaulden, James D. Ryan, Veronika Kondev, Nathan D. Winters, Luis E. Rosas-Vidal, Megan Altemus, Ken Mackie, Francis S. Lee, Eric Delpire, Sachin Patel
Journal: Neuron (2020)
A retrospective analysis of elderly population with metastatic colorectal cancer treated with raltitrexed in the target therapy era.
Authors: Lisardo Ugidos, Jesus Rodriguez-Pascual, Rafael Alvarez-Gallego, Cesar Munoz, Enrique Sanz, Lucia Ceniceros, Antonio Cubillo
Journal: Journal of Clinical Oncology (2019)

e23022 Background: Raltitrexed is a antifolate chemotherapy agent with activity against metastatic colorectal cancer (mCRC). Most clinical trials with raltitrexed were performed before approval of anti-EGFR and anti-VEGF therapies. Its toxity profile suggests that might be a useful drug to treat elder patients, but there are no specific data in this population group. Methods: A retrospective review of elderly patients (70 years or older) with mCRC treated with raltitrexed monotherapy in our hospital between 2008 and 2017 was conducted. All of them had received previously oxaliplatin, irinotecan, fluoropyrimidines, and bevacizumab as standard therapy. All RAS native patients had received also anti-EGFR drugs. Results: Eighteen elder patients were reviewed, 11 (61%) male. Age ranged 70-85 years (median 78). All patients had ECOG PS 0 or 1. Locations were rectum (4), right colon (8), and left colon (6). Number of treatment lines ranged 2-5 (median 3). Three pts (16%) had received regorafenib previously. KRAS and BRAF were mutated in 61% and 5% respectively. Median number of cycles was 3 (1-13). Response rate was 11% (2 partial responses). Stable disease was achieved in 33%. Median progression-free and global survival were 2.8 (95% CI 1.2-10) and 5.9 (95% CI 1.6-18) months respectively. Grade 3-4 hematologic and non-hematologic toxicities were present in 22% and 5.5% respectively. Dose reduction was needed only in 11%. Sex, location, RAS status were not related to response or survival. Conclusions: Raltitrexed is a well tolerated option por elderly patients after standard treatment of mCRC.
The role of postradiation temozolomide in patients with newly diagnosed MGMT methylated glioblastoma.
Authors: Yuqing Sun, Carlos G Romo, Pavan Shah, Stuart A. Grossman
Journal: Journal of Clinical Oncology (2019)

e13530 Background: Standard therapy for patients with newly diagnosed glioblastoma (GBM) includes concurrent temozolomide (TMZ) and radiation (RT) followed by six monthly cycles of adjuvant TMZ. Although TMZ improves survival for MGMT methylated patients, it is unclear if this benefit is from the TMZ given with the radiation, the adjuvant TMZ, or if both are required. This retrospective study was designed to identify MGMT methylated patients who started treatment with near-normal functional status, completed concurrent RT+TMZ, but did not receive adjuvant TMZ to estimate if their survival was significantly less than expected. Methods: We reviewed charts from 190 adults diagnosed with GBM at Johns Hopkins Hospital from 2013 to 2015 recording their Karnofsky Performance Score (KPS), extent of resection, MGMT-methylation and IDH1 mutation status, and treatment records. We selected patients with MGMT-methylated GBM who received concurrent RT+TMZ without adjuvant TMZ for this study. Patients with a KPS &lt; 70 or severe post-radiation complications were excluded. Results: Six patients met the selection criteria. They had a median age of 65 years, average KPS of 80, 2/6 had a gross total resection, and all were IDH1 wildtype. Their overall survival ranged from 17 to &gt; 46 months. Conclusions: The overall survival of these patients who received no adjuvant TMZ is very similar to the median of 23 months reported in the literature for MGMT methylated patients who received adjuvant TMZ. This preliminary data suggests that a prospective study in MGMT methylated patients comparing concurrent RT+TMZ followed by either standard adjuvant TMZ or observation could be considered without placing patients in the experimental arm at excessive risk.[Table: see text]