bluuebunny/crossref_metadata_2025_split huggingface dataset:
A network meta-analysis of immunotherapy-based regimens for first-line treatment of advanced non-squamous non-small cell lung cancer.
Authors: Agg Himani , Ndirangu Kerigo , Muehlenbein Catherine , Winfree Katherine B. , Zhu Yajun Emily , Thom Howard , Tongbram Vanita 
Published: February 2020

52 Background: Immunotherapy (IO) for initial treatment of patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC) has led to improved progression free survival (PFS) and overall survival (OS) vs chemotherapy. The objective of this network meta-analysis (NMA) was to compare the efficacy of IO-based therapies to chemotherapy in the first-line treatment until progression for advanced nsqNSCLC. Methods: A systematic literature review was conducted to identify randomized controlled trials reporting PFS and/or OS data in adult patients who received first-line treatment for stage IIIB or IV nsqNSCLC until progression. MEDLINE, EMBASE and Cochrane Central Register were searched from the start of databases to June 2018. The NMA used fixed-effects models to estimate hazard ratios (HRs) and credible intervals (Crl) for PFS and OS of IO therapies vs pemetrexed + platinum. A subgroup of patients with PD-L1 tumor proportion score (TPS) ≥50% was also analysed. Results: Evidence networks comprised of 18 studies for the overall population and 3 studies for the PD-L1 TPS ≥50% subgroup. In PFS analysis for the overall population, HRs were lower for atezolizumab + bevacizumab + paclitaxel + platinum (HR 0.62; 95% CrI 0.48, 0.8), ipilimumab + nivolumab (HR 0.55; 95% CrI 0.38, 0.8) and pemetrexed + pembrolizumab + platinum regimens (HR 0.52; 95% CrI 0.43, 0.63) vs pemetrexed + platinum. In the PD-L1 TPS ≥50% subgroup, PFS HRs were lower for pembrolizumab (HR 0.81; 95% CrI 0.67, 0.98) and pemetrexed + pembrolizumab + platinum (HR 0.36; 95% CrI 0.25, 0.52) vs pemetrexed + platinum. In the OS analysis for the overall population, pemetrexed + pembrolizumab + platinum had a lower HR (HR 0.5; 95% CrI 0.4, 0.64) vs pemetrexed + platinum. This difference in OS was magnified in the PD-L1 TPS ≥50% subgroup (HR 0.42; 95% CrI 0.26, 0.68). Conclusions: Among all IO-based therapies in this analysis, pemetrexed + pembrolizumab + platinum had the highest PFS and OS benefit vs pemetrexed + platinum in the first-line treatment until progression for advanced nsqNSCLC for both the overall population and high PD-L1 subgroup. These comparative efficacy data may inform clinicians in treatment selection.
Real-world outcomes for metastatic non-small cell lung cancer patients treated with checkpoint inhibitor immunotherapy in Canada.
Authors: Yusuf Dimas , Ko Jenny J. , Cho Hyokeun , Sheremeto Corey , Wang Ying , Juergens Rosalyn A. , Ellis Peter Michael , Billawala Alkarim , Kay Amin , Kulkarni Swati , Elfiki Tarek A. , Gupta Rasna , Naccarato Krista , Pennetti Alex , Patel Devalben , Smith Elliot Charles , Walton Ryan , Hurry Manjusha , Liu Geoffrey , Cheung Winson Y. 
Published: February 2020

54 Background: The majority of patients with non-small cell lung cancer (NSCLC) are diagnosed with incurable, metastatic disease. Immunotherapy (IO) agents have improved overall, long term survival. There is a need to better understand how these drugs are utilized and perform in the real world to further inform physicians and policymakers. Methods: In this retrospective study, we analyzed characteristics, treatment patterns, and outcomes of patients with metastatic NSCLC treated with checkpoint inhibitors nivolumab or pembrolizumab at five Canadian cancer centres, with a focus on patients who received these treatments in the 2nd (2L) or 3rd line (3L) setting. We excluded patients who were in blinded clinical trials, exposed to multiple IO drugs, or who had tumors with EGFR or ALK mutations. Primary endpoints were overall survival (OS) and progression free survival (PFS) from start of IO. Secondary endpoints included immune-related toxicities. Results: Across all sites, we screened 322 patients and included 230 who met criteria: 49 (21%) from Alberta; 60 (26%) from British Columbia; and 121 (53%) from Ontario. Patients were diagnosed with metastatic NSCLC from 2009 to 2018, but the majority were diagnosed after 2015. Median age at diagnosis was 66.6 years, 54% were female, and 86% were either current or former smokers and 67% had stage IV disease. About 88% received nivolumab; 87% (n=200) received IO in 2L (n=111) or 3L (n=89). The median OS from start of IO was 10.9 (8.7–15.6) months, and were similar for 2L vs 3L (9.3 vs 12.0 months, p = 0.2). Median PFS was 5.7 (4.4–8.1) months. Pneumonitis was the most frequently reported toxicity affecting 7% of patients. Thyroiditis was reported in 4%; colitis, while dermatitis and hepatitis were each reported in 3%, and nephritis in 1%. Conclusions: In the real world, IO for advanced NSCLC was well-tolerated and had outcomes that were comparable to landmark clinical trials.
DPX-Survivac, a novel T-cell immunotherapy, to induce robust T-cell responses in advanced ovarian cancer.
Authors: Dorigo Oliver , Fiset Stephan , MacDonald Lisa Diana , Bramhecha Yogesh , Hrytsenko Olga , Dirk Brennan , Rosu Gabriela Nicola , Stanford Marianne 
Published: February 2020

6 Background: Survivin has emerged as an attractive target for T cell-based immunotherapy because of its essential role in tumor biology and its tumor-specific expression in multiple tumor types. DPX-Survivac is a novel T cell immunotherapy that uses the DPX platform to elicit strong and sustained survivin-specific T cell responses against tumor cells. DPX is designed to extend the duration and robustness of targeted immune responses by requiring active uptake of antigens by antigen presenting cells at the injection site. DPX-Survivac incorporating survivin targets within the DPX platform is therefore a relevant approach for treatment of survivin-expressing cancers to generate strong T cell responses that infiltrate tumors and result in measurable anti-tumor responses. Methods: 121 patients with platinum sensitive or resistant, advanced ovarian, fallopian tube or peritoneal cancer were treated with DPX-Survivac with or without drug combinations. Data from 3 different clinical trials were analyzed for systemic immune responses, tumor immune infiltrates and clinical tumor responses. Patients were enrolled in both the maintenance (N = 56) and recurrent (N = 65) disease settings. Results: DPX-Survivac generated survivin-specific T cells in 80% of patients as demonstrated by IFN-γ ELISPOT of PBMCs. Paired pre- and post-treatment tumor samples were collected from 37 patients. Survivin-specific T cells were found in the tumor microenvironment post-treatment using TCR-β sequencing. Clinical anti-tumor responses were correlated with increased infiltration of T cells into tumors following treatment with DPX-Survivac. An increase in T cell signaling in post-treatment tumor tissue was shown by RNAseq along with upregulation of cytotoxic markers, NK and B cell markers. Importantly, the antigen-specific T cells retain their functionality throughout the duration of treatment. Conclusions: DPX-Survivac stimulates significant clinical anti-tumor responses by inducing strong and sustained survivin-specific T cell responses and increasing infiltration of target-specific T cells into tumors. Clinical trial information: NCT01416038; NCT03332576; NCT02785250.
Causal modeling of TCGA, NSCLC, and HNSCC data to identify network drivers of tumor immune subtypes.
Authors: Das Rahul K , Yan Raymond T. , Davis Craig B. , Maciejewski Mateusz , Mu Xinmeng Jasmine , Krishnakumar Aishwarya , Church Bruce W. , Khalil Iya 
Published: February 2020

68 Background: Immune checkpoint inhibitors have achieved unprecedented success in several cancer types, yet only a subset of patients derives clinical benefit. Better understanding of tumor-immune interactions is imperative to improve clinical outcomes. Bayesian causal machine learning was applied on real world data to elucidate the molecular drivers of immune subtypes of tumors. Methods: Using a Reverse Engineering Forward Simulation (REFS) platform, ensembles of causal models were built on genomics, transcriptomics, and clinical data from 681 non-small cell lung carcinoma (NSCLC), 328 lung adeno (LUAD) and 353 lung squamous cell (LUSC), and 413 head and neck squamous cell carcinoma (HNSCC) patients from TCGA. The outcomes modeled were six tumor immune subtypes (Thorsson et al., 2018): wound-healing, IFNγ dominant, inflammatory, lymphocyte-depleted, immunologically quiet, and TGFβ dominant. Causal drivers of immune subtypes were identified from average causal effect (ACE) of the variables, as computed from the counterfactual simulations. ACE was defined as median of posterior distribution of odds ratio (1 vs 0 for discrete; 95th vs. 5th %ile for continuous variables). Results: The models showed impressive k-fold cross validation predictive performance (AUC ~ 0.8-0.9) for the most prevalent immune subtypes in TCGA: wound-healing and IFNg dominant in both LUAD and HNSCC, as well as inflammatory in LUAD. The potential causal drivers of the tumor immune subtypes and their ACE are listed in Table. The findings suggest that macrophage activation and polarization, which is driven in part by metabolic reprogramming, is a primary driver of tumor immune subtypes. Conclusions: Bayesian causal modeling revealed literature-supported hypotheses regarding predictors of response (CXCL13) and resistance (STK11 mutation, mTOR pathway) to PD-(L)1 blockade therapy. The additional target pathways such as AKT1/mTOR may be actionable for altering immunogenicity of tumors. [Table: see text]
Tumor mutational burden (TMB) as a predictive biomarker of immune checkpoint blockade (ICB) in metastatic solid tumors.
Authors: Kao Chester , Powers Eric , Datto Michael B. , Green Michelle , Harrison Michael Roger , Armstrong Andrew J. , George Daniel J. , Clarke Jeffrey Melson , Strickler John H. , Zhang Tian 
Published: February 2020

80 Background: TMB is a promising predictive biomarker for ICB, but recent studies have shown that TMB varies substantially between tumor types. We examined the association between TMB and clinical response to ICB in metastatic urothelial carcinoma (mUC), renal cell carcinoma (mRCC), and non-small cell lung cancer (mNSCLC). Methods: We conducted a single center retrospective study inclusive of 1444 consecutive patients (pts) initiating ICB prior to 1/2019, cross-referenced with pts with Foundation One testing with TMB (mut/Mb), resulting in 17 mUC, 10 mRCC, and 60 mNSCLC. PD-L1 status was determined by the Dako 22C3 antibody. Pts were divided into clinical responders (R) and non-responders (NR) based on clinical assessment per their oncologist. The primary outcome of the study was to describe the relationship between TMB and clinical benefit, including duration of clinical response and overall survival (OS). A t-test was performed between R groups. Kaplan Meier (KM) curves and Cox-Mantel log rank tests were performed for PFS/OS comparing high TMB (≥ median) to low TMB pts. Results: For mUC, 8/17 (47%) were R with median TMB 7.74 (Interquartile range or IQR 6.04-9.78) compared to 9 NR, median TMB 7.57 (IQR 3.78-11.41) [p = 0.36]. For mRCC, 4/10 (40%) were R with median TMB 1.75 (IQR 1.75-1.97), versus 6 NR with median TMB 5.79 (IQR 3.07-7.48) [p = 0.02]. For mNSCLC, 30/60 (50%) were R with median TMB 11.38 (IQR 9.65-16.24), significantly higher than 30 NR with median TMB 9.46 (IQR 7.65-13.87) [p = 0.05]. For mNSCLC, no difference in PD-L1 positivity was found between R (17/30, 56%) and NR (16/30, 53%), and concurrent chemotherapy with ICB was the same in both R (10/30 (33%)) and NR (10/30 (33%)). KM analysis showed equivocal results for duration of clinical response and OS between high TMB vs low TMB in the three solid tumors, except OS in mUC which favored high TMB (p = 0.03) [cutoff TMB: mUC 7.57, mRCC 2.63, mNSCLC 11.35]. Conclusions: Higher TMB was associated with a greater likelihood of clinical benefit to ICB in our cohort of NSCLC patients and mUC. This correlation was not detected among mRCC patients, although these data are limited by relatively small number of cases.
Real-world evidence data (RWED) of financial toxicity (FT) in patients (pts) receiving cancer immunotherapy treatments.
Authors: Vorobiof Daniel A. , Hasid Lior , Litvin Alon , Deutsch Irad , Malki Eliran 
Published: February 2020

90 Background: RWED denotes data accumulated via EHR as well as cutting edge technology paired with consumer mobile devices. We are reporting data on 105 pts, users of Belong.life, a worldwide mobile application, who received immunotherapy for their various cancers and were asked to reply to a short, targeted survey on their FT while on treatment. Methods: 105 pts anonymously and voluntarily replied to a survey which included 14 general information questions and those describing FT, its most common encountered causes and their personal financial coping strategies. Results: 79% of the pts were USA based. 21% of the pts were < 50 years of age (yoa), 32% were 51-60 yoa and 47% were > 61 yoa. Pts’s stages were Stage 3 in 23% and 4 in 62% with unknown in 15%. There were 36% males and 64% females. The most common cancer diagnosis was lung in 46% followed by kidney in 17%, malignant melanoma in 14% and colorectal in 10%. The prevalent immunotherapy drugs were nivolumab and pembrolizumab in 36% respectively, and ipilimumab in 14% and durvalumab in 10%. Frequently reported FTs were high medical copayments in 35% of the pts, loss of income in 33% and high drugs and treatments copayments in 21%. 41% of the pts were insured by Medicare and 25% by Medicaid and other HMOs. Only 48% of the pts were aware of possible financial difficulties as a result of their diagnosis and treatment, and 34% received pre-treatment financial advice from their doctors which reduced the reported FT from 48% to 30%. When asked about coping strategies, 39% used personal savings, 28% trimmed their private expenses, and 24% received financial support from their families and friends. Conclusions: 105 users of the Belong.life application reported on their FTs experienced while receiving cancer immunotherapy. FT was most prevalent in the older group ( > 61 yoa) due to high medical and treatment copayments. Nearly half of the pts was not aware of the possible FT and only 38% received advisory information from their doctors. Reduced FT prevalence (from 48% to 30%) was reported by those informed pts. Physicians should become aware of their pts’s possible risks for FTs, therefore appropriate advice should be given prior to immunotherapy initiation.
Venous thromboembolism (VTE) in melanoma patients (pts) on immunotherapy (IO).
Authors: Sussman Tamara A. , Roopkumar Joanna , Li Hong , Hobbs Brian , Khorana Alok A. , Funchain Pauline 
Published: February 2020

94 Background: VTE in cancer significantly contributes to morbidity and a worse overall prognosis. Little is known about the incidence of VTE in melanoma pts receiving IO. This study aims to assess the incidence of VTE in melanoma pts on IO, interrogate potential association with specific therapies, and ascertain its prognostic utility. Methods: We conducted a retrospective cohort study of melanoma pts who received any IO including ipilimumab (ipi), nivolumab (nivo) or pembrolizumab (pembro) from July 2015 to December 2017 at the Cleveland Clinic. VTE including deep venous thrombosis and pulmonary embolism were identified by chart review. VTE-free survival and overall survival (OS) were estimated by Kaplan-Meier and Cox proportional hazard models; association between VTE and IO was examined using the Pearson’s chi-squared test. Results: This cohort comprised 219 pts with median age of 65 years (range 24-92) and 66.7% male. Pembro was most common (36.5%), followed by ipi/nivo (26.9%), ipi (21.9%), and nivo (14.6%). Most had distant metastatic disease (79.9%), and 16.4% had brain metastases. VTE occurred in 14.2% (n = 31) of pts on therapy. Of those with VTE, 12 (38.7%) were receiving ipi/nivo and 19 (61.3%) single agent IO. Median VTE-free time was 4.9 months on ipi/nivo compared to 9.2 months on single agent IO (p = 0.05). The 6-month VTE-free survival was 18.5% for ipi/nivo and 71.8% for single agent IO. Among pts with distant metastatic disease, ipi/nivo was significantly associated with earlier time to VTE when adjusted for age, gender, and presence of brain metastases, (median VTE-free time 4.9 months vs. 9.3; p = 0.024; HR 2.96 [95% CI, 1.15-7.59]). Among pts without brain metastases, VTE was associated with worse OS (median OS 1.3 years vs. NR; p<0.001; HR 3.47 [95% CI, 1.66-7.24]). Conclusions: VTE risk may be elevated for melanoma pts on IO, specifically those receiving ipi/nivo. Further studies are needed to identify pathophysiology, risk factors, and benefit of thromboprophylaxis in this setting. [Table: see text]
The real-world incidence of immunotherapy-related thyroid dysfunction: A retrospective analysis of a single center's experience over five years.
Authors: Brody Heather Mae , Macherla Shravanti , Bulumulle Anushi , Namireddy Praveen , Cherry Cynthia R. 
Published: February 2020

98 Background: Immunotherapy related thyroid abnormalities are well described. Any grade abnormality has been reported in 6-18% of patients. The clinical relevance of thyroid abnormalities in a real-world setting is still unclear. In this retrospective study, we analyzed immunotherapy type with time to thyroid dysfunction, grade of thyroid dysfunction, and number that ultimately required treatment. Methods: We retrospectively collected data for patients who received immunotherapy from April 2015 to August 2019. We recorded the type of immunotherapy, any abnormal TSH and grade of abnormality using the immune checkpoint inhibitor related adverse events Common Terminology Criteria for Adverse Events (IRAE-CTCAE), number of days from start of treatment to first noted abnormal TSH, and number requiring treatment with levothyroxine. At our large academic center, we analyze thyroid function prior to starting immunotherapy and at every treatment. Results: Of our 374 patients, 159 had some grade of thyroid dysfunction after receiving immunotherapy. Of the 159 patients with thyroid dysfunction, 23 had atezolizumab, (A), 81 had nivolumab (N), and 55 had pembrolizumab (P). Within these sub-groups, the majority of the adverse events were grade one, 74% in the A group, 57% in the N group, and 76% in the P group. Of these, zero were treated with levothyroxine. Grade two toxicities were seen in 22% in the A group, 31% in the N group, and 22% in the P group. Of these, a total of eight patient required treatment with levothyroxine. Average days to abnormal TSH was 97 in the A group, 94 in the N group, and 130 in the P group. Conclusions: In our population, 42.5% of patients had some grade of thyroid dysfunction which is higher than the previously reported values, however, the majority of abnormalities were grade one and self-resolved. This may indicate that transient changes in TSH are much more common than previously noted but not necessarily clinically relevant.
Mapping the Associations of the Plasma Lipidome With Insulin Resistance and Response to an Oral Glucose Tolerance Test
Authors: Beyene Habtamu B , Hamley Steven , Giles Corey , Huynh Kevin , Smith Alexander , Cinel Michelle , Mellet Natalie A , Morales-Scholz Maria G , Kloosterman Danielle , Howlett Kirsten F , Kowalski Greg M , Shaw Christopher S , Magliano Dianna J , Bruce Clinton R , Meikle Peter J 
Published: February 2020

Abstract

Context
Insulin resistance (IR) remains a global health challenge. Lipidomics offers an opportunity to identify biomarkers and better understand mechanisms of IR associated with abnormal lipid metabolism.

Objective
The objective of this article is to determine plasma lipid species associated with indices of IR and evaluate the lipidome response to an oral glucose tolerance test (OGTT).

Design and setting
This study was community based and cross-sectional.

Participants and sample
Plasma samples (collected at 0 and 120 min during an OGTT) from nonobese, young adults age 18 to 34 years (n = 246) were analyzed using liquid chromatography–tandem mass spectrometry.

Main outcome measures
The associations between indices of IR and lipid classes and species (with a sex interaction term), or changes in lipid levels during an OGTT, were tested using linear models (adjusted for age, sex, body mass index, total cholesterol, high-density lipoprotein cholesterol, and triglycerides).

Results
Some (213) and (199) lipid species were associated with the homeostatic model assessment of insulin resistance and insulin area under curve (AUC), respectively. Alkylphosphatidylcholine (10), alkenylphosphatidylcholine (23), and alkylphosphatidylethanolamine (6) species were associated with insulin AUC in men only. Species of phosphatidylcholine (7) and sphingomyelin (5) were associated in women only. In response to an OGTT, a perturbation in the plasma lipidome, particularly in acylcarnitine species, was observed; and the changes in many lipid species were associated with insulin AUC.

Conclusions
The plasma lipidome and changes in lipid levels during an OGTT were associated with indices of IR. These findings underlie the involvement of molecular lipid species in the pathogenesis of IR and possibly crosstalk between IR and sex-specific regulation of lipid metabolism.
AMH is Higher Across the Menstrual Cycle in Early Postmenarchal Girls than in Ovulatory Women
Authors: Ortega Madison T , Carlson Lauren , McGrath John A , Kangarloo Tairmae , Adams Judith Mary , Sluss Patrick M , Lambert-Messerlian Geralyn , Shaw Natalie D 
Published: February 2020

Abstract

Context
Adolescents have more small, growing follicles and larger ovaries than normal women and are prone to anovulatory cycles (ANOV). It is unknown if a higher antral follicle count (AFC) per se contributes to ANOV in early postmenarchal girls.

Objective
To determine the relationship between AMH (an AFC biomarker), other reproductive hormones, and ANOV in postmenarchal girls and to compare AMH in girls and regularly cycling adults.

Methods
A total of 23 girls (1.7 ± 0.2 years postmenarche) and 32 historic adult controls (≤34 years) underwent serial hormone measurements during 1 to 2 menstrual cycles. Girls also had pelvic ultrasounds. AMH was measured 5 times/subject using the Ansh ultrasensitive ELISA.

Results
Girls had higher AMH than women (5.2 ± 0.3 vs. 3.3 ± 0.4 ng/mL; P &lt; 0.01) and girls with more ovulatory (OV) cycles tended to have lower AMH than those with ANOV (2 OV 4.5 ± 0.2, 1 OV 5.7 ± 1.1, 0 OV 6.8 ± 1.1 ng/mL; P = 0.1). In girls, AMH correlated with natural-log (ln) transformed LH (r = 0.5, P = 0.01), ln_androstenedione (r = 0.6, P = 0.003), ln_testosterone (r = 0.5, P = 0.02), and ovarian volume (r = 0.7, P &lt; 0.01) but not with FSH, estradiol, P4, or body mass index. In women, AMH correlated with estradiol and P4 (both r = -0.4, P ≤ 0.03) but not with ln_LH or body mass index.

Conclusions
In postmenarchal girls, AMH is higher than in ovulatory women and is associated with LH, androgens, and a propensity for anovulatory cycles. The cause of the transient increase in AMH and AFC during late puberty and the steps underlying the transition to a mature ovary deserve further study.