bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative molecular analysis of metastatic Merkel cell carcinoma to identify predictive biomarkers of response to avelumab.
Authors: Georges Sara , Shah Parantu K. , Shapiro Irina , Hicking Christine , Lu Lei , Hennessy Meliessa , D'Angelo Sandra P. , Cai Ti 
Published: May 2019

9569 Background: Avelumab, an FDA-approved human anti–PD-L1 IgG1 monoclonal antibody for patients (pts) with metastatic Merkel cell carcinoma, showed an objective response rate (ORR; by RECIST v1.1) of 31.8% in a second-line phase 2 trial (NCT02155647). We assessed the association of tumor mutational burden (TMB; nonsynonymous somatic variants/megabase), PD-L1 expression, Merkel cell polyomavirus (MCPyV) status, and CD8+ tumor-infiltrating T-cell density with ORR and survival. Molecular profiles (RNAseq and WEX) also were analyzed. Methods: Baseline tumors (n = 36) were profiled using RNAseq and WEX sequencing. PD-L1 expression (≥1% cutoff), MCPyV status, and CD8+ T-cell density at the tumor invasive margin were evaluated by IHC. MHC locus expression was measured with OptiType and loss of heterozygosity (LOH) with LOHHLA. Results: Of 36 pts profiled, 12 had a response, 27 were PD-L1+, and 23 were MCPyV+. The TMB upper tertile and quartile values were 1.34 and 3.16, respectively. Consistent with literature, MCPyV− pts had a higher median TMB (2.72) than MCPyV+ pts (0.49). PD-L1+ tumors trended toward a higher TMB. An empirical cohort-specific TMB cutoff of ≥2 was chosen to include sufficient pts per subgroup. Pts with TMB ≥2 vs TMB < 2 had higher ORR (5 of 11 [45.5%] vs 7 of 25 [28.0%]) and 6-mo PFS rates (60% vs 38%). Among pts with TMB ≥2, the highest ORRs were reported in MCPyV− (4 of 7 pts), PD-L1+ (5 of 9 pts), and CD8+ T-cell density higher than median (5 of 6 pts) subgroups. MHC expression trended with ORR and survival. Higher mean MHC expression was found in pts with CD8+ T-cell density higher than median (p < 0.05). Mutations in antigen presentation genes were detected: LOH at the HLA locus in 9 of 30 pts (28%), including 4 with a response; an NK cell activation signature was also associated with response. These data may suggest that ADCC contributes to response. Factorial analysis of gene signature scores identified signatures (eg, IFNγ, TP53 pathway) associated with MCPyV status and response. Conclusions: Responses in this data set were not attributed to any specific biomarker alone. Future analysis is focused on validating these results and identifying rational drug combinations with avelumab. Clinical trial information: NCT02155647.
Neutrophil to Lymphocyte ratio (NLR): A prognostic marker in melanoma patients receiving immunotherapy.
Authors: O'Dwyer Richard Thomas , Dennehy Colum , Sui Jane Sze Yin , Kelly Catherine Margaret , Calvert Paula , McCaffrey John 
Published: May 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 ( > 3) and low ( < 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 < 3 patients had a significantly longer PFS: 11.7 vs 2.8 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients also had significantly longer PFS: 10.8 vs 2.9 months (p = 0.04). When NLR decreased by > 20% from baseline, there was no significant difference in PFS (p = 0.82). When NLR < 3, patients had significantly longer OS: 18 months vs 8.2 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients had significantly longer OS: 20.3 months vs 7.4 months (p = 0.003). Conclusions: Baseline NLR < 3 and NLR < 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.
Plasma proteomic analyses and treatment predictive biomarker candidates in melanoma patients receiving immune checkpoint blockade or targeted therapy.
Authors: Eriksson Hanna , Babacic Haris , Lehtio Janne , Pernemalm Maria 
Published: May 2019

9574 Background: The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Still, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs or MAPKis. Methods: We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis, respcetively. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used.We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models. Results: HiRIEFLC-MS/MS detected 1,835 proteins.We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p= 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient <0.05, pLRT<0.05, qLRT<0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient< 0.05, pLRT< 0.05, qLRT < 0.05). Conclusions: By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs or MAPKis. Our findings require further validation.
Prediction of distant melanoma recurrence from primary tumor digital H&E images using deep learning.
Authors: Robinson Eric , Kulkarni Prathamesh M. , Pradhan Jaya Sarin , Gartrell Robyn Denise , Yang Chen , Rizk Emanuelle M. , Acs Balazs , Rohr Bethany , Phelps Robert , Ferringer Tammie , Horst Basil , Rimm David L. , Wang Jing , Saenger Yvonne M. 
Published: May 2019

9577 Background: Patients with resected melanoma are at high risk for systemic recurrence. Quantifying the risk of recurrence can help identify the need for adjuvant immunotherapies, and accelerate the acquisition of survival statistics in clinical trials. Methods: 75 patients with stages I, II, and III melanoma seen at Columbia University Medical Center between 2001 and 2014 and The Icahn School of Medicine at Mount Sinai between 2000 and 2010 were included based on availability of tissue and 24 months of clinical follow-up. Images were scanned into tiff files (Aperio Biosystems). Deep neural net (DNN) architecture was designed consisting of convolutional and recurrent neural networks (CNN, RNN). Using QuPath open source software for nuclear segmentation and cell classification, we generated cell location, density, and clustering features to identify tissue areas for training of network parameters. DNN analyzes image and feature information locally within an H&E image, generating a prediction vote per region, and votes are averaged. Results: The model was validated on two independent external sets of stage I-III primary melanomas. Cohort 1 (Yale Medical Center), had n = 86 patients, of whom 49 were alive or had no evidence of disease at death (no DMR) and 37 died from melanoma. The second set, Cohort 2 (Geisnger Health Systems), had n = 29 patients, 15 without DMR and 14 with DMR. Prediction scores correlated with DMR status in both sets (AUC = 0.94 and 0.77 for Cohorts 1 and 2, respectively). A multivariable Cox proportional hazard model showed DNN recurrence prediction to be an independent prognostic factor for both Cohort 1 (HR = 2.54, 95% CI: 1.54-4.19, p = .0004***) and Cohort 2 (HR = 8.43, 95% CI: 2.58-27.51, p = .001**). Conclusions: We designed a DNN for quantitative prediction of melanoma recurrence from a H&E stained tissue. The prediction score warrants further study in larger patient cohorts and may constitute a novel digital pathology tool for the selection of melanoma patients for adjuvant immunotherapy. [Table: see text]
Association of baseline body mass index (BMI) with response and survival in patients (Pts) with advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar 
Published: May 2019

9579 Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. < 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI < 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI < 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI < 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer.
Patient-reported outcomes of patients treated with (neo)adjuvant immune checkpoint combination therapy in high-risk stage III macroscopic melanoma: A matched cohort study.
Authors: Boekhout Annelies H. , Józwiak Katarzyna , Rozeman Elisa A. , Janssen Silvie HM , van de Poll-Franse Lonneke V , Blank Christian U. 
Published: May 2019

9588 Background: Results from the phase 1b (OpACIN) study comparing neoadjuvant to adjuvant ipilimumab (3mg/kg) plus nivolumab (1mg/kg) demonstrated a high clinical activity of neoadjuvant treatment in high-risk melanoma. However, the toxicity was high, with 90% grade 3 to 4 toxicity. These findings raise questions about long-term quality of life (QoL) in these patients (pts) who were treated with curative intent. Here we present the first analysis of patient-reported outcomes of patients treated with (neo)adjuvant immune checkpoint combination therapy. Methods: Sixteen of 20 pts had completed study treatment and were currently in follow-up (FU). Pts were asked to fill in The European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). The QLQ-C30 was used to assess health-related QoL and is composed of functional, symptomatic dimensions and a dimension of global health/QoL. A reference population (controls without a diagnosis of cancer) was obtained from the ‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship’ registry. Pts were individually matched on age, gender, education and marital status with up to 9 controls. Pts and controls were compared on QLQ-30 scores using univariable linear regression analyses. Results: Thirteen out of 16 invited pts (81% response) returned a completed questionnaire. Median FU was 30 months after randomization. Pts scored significantly lower in emotional (std coeff. = -1.0, p = .007), role (std coeff. = -0.7, p = .08), cognitive (std coeff. = -0.8, p = .018) and social (std coeff. = -1.0, p = .014) functioning and higher in symptom burden of fatigue (std coeff. = .9, p = .024) compared to controls, which were all clinically relevant. The physical functioning and global QoL score did not differ between pts and controls. Conclusions: High risk stage III melanoma pts treated with (neo)adjuvant immune checkpoint combination therapy showed significantly lower emotional, role, cognitive and social functioning scores than controls. Pts reported higher levels of fatigue, however, there was no difference on physical functioning and global QoL between pts and controls.
A population-based model for predicting sentinel lymph node (SLN) status for cutaneous melanoma patients and a clinical decision rule (CDR) for sparing a SLN biopsy (SLNB).
Authors: Gimotty Phyllis A. , Karakousis Giorgos , Buckley Meghan A. , Guerry DuPont 
Published: May 2019

9589 Background: Generally, a SLNB is offered to the patient whose likelihood of positivity is ≥ 5%. Using population-based cohorts, we sought to [1] develop and validate a predictive model to estimate the individualized risk (IR) of SLNB positivity (SLNBp) and its confidence interval (CI), [2] evaluate an IR-based CDR to identify patients with sufficiently low IRs to avoid SLNB, and [3] compare the performance of the CDR with that of the 2019 NCCN guideline. Methods: The learning cohort (n = 18,214; SLNBp rate = 10.7%; 2010-2014) and validation cohort (n = 3,924; SLNBp rate = 11%; 2015) included SEER patients 18-99 years old who had a SLNB as part of definitive surgery. A multivariable logistic regression model for SLNBp, including 4 AJCC related-factors (thickness, ulceration, level and mitotic rate) and age, was used to estimate the IR of SLNBp and its one-sided 95% CI. The CDR was defined using the IR and CI and then used to classify patients into 3 categories: SLNB not indicated (IR and upper limit of the one-sided CI < 5%), SLNB indicated (IR and lower limit of the one-sided CI ≥ 5%), and borderline. Results: In the learning cohort all 5 factors were significant in the multivariate model, which had a c-statistic of 0.742 (95%CI, 0.731-0.753). In the validation cohort the model c-statistic was 0.728. Based on the CDR, 21.6%, 56.9%, and 21.5% of patients would not be offered SLNB, would be offered SLNB, or would need further shared decision making. Compared to the guideline, the CDR classified more patients as “SLNB not indicated” (21.6% vs. 7.1%) and fewer as “SLNB indicated” (56.9% vs. 68.5%). Of the 16,137 SLNB negative patients, 3815 (23.6%) would not be offered SLNB based on the CDR compared to 1258 (7.8%) who would not be offered SLNB based on the guideline. The false negative rates associated with “not indicated” by the CDR and guideline were 4.6% and 1.2%, respectively. Conclusions: Use of this CDR rather than the NCCN guideline will spare more low-risk patients the expense and harms of SLNB and increase only marginally their likelihood of a false negative test (still < 5%).
Effect of cyclin E overexpression on resistance to trastuzumab and phosphorylation of SMAD3 in HER2+ breast cancer.
Authors: Kandagatla Pridvi , Decker Joseph , Wan Lei , Bernstein Regan , Shea Lonnie , Jeruss Jacqueline Sara 
Published: May 2019

e12006 Background: Trastuzumab, an effective treatment for HER2+ breast cancer, can be limited by development of resistance. Cyclin E (CCNE) overexpression was implicated in trastuzumab resistance, though the association is not well understood. We sought to explore a potential mechanism focusing on altered phosphorylation of the TGFβ signaling protein, SMAD3, in CCNE overexpressing HER2+ breast cancer cells, leading to trastuzumab resistance. Methods: A transcriptional activity cell array (TRACER) was used to examine the relationship between specific transcription factors and trastuzumab resistance in BT474 HER2+ human breast cancer cells. Immunoblotting examined phosphorylation patterns of SMAD3 in trastuzumab sensitive and resistant conditions. Effects of blocking CCNE overexpression with a CDK2 inhibitor were measured. To test the relative influence of SMAD3 and SMAD3 linker region phosphorylation on cell proliferation, BT474R2 cell lines were created overexpressing SMAD3 (BT474R2-SMAD3), a mutant construct blocking CCNE-mediated SMAD3 linker region phosphorylation (BT474R2-5M), and a control (BT474R2-Blank). In vitro and in vivo studies measured response to trastuzumab. Results: Resistance to trastuzumab was confirmed for BT474R2 cells, showing a markedly increased resistance to treatment when compared to the parental line. Network analysis of TRACER data identified decreased SMAD3 activity was central to resistance. Immunoblotting showed SMAD3 expression was significantly downregulated in BT474R2 cells (p < 0.01). Noncanonical phosphorylation of SMAD3 was increased in CCNE-overexpressing cells. Blocking CCNE mediated noncanonical phosphorylation of SMAD3 with CDK2 inhibition resulted in decreased proliferation of BT474R2 cells. In vitro studies examining response to trastuzumab showed an increased sensitivity for BT474R2-5M cells. Findings were validated in NSG mice inoculated with BT474R2-5M cells that developed significantly lower tumor volumes (p < 0.001) when treated with trastuzumab. Conclusions: These results identified a mechanism of CCNE-mediated trastuzumab resistance, regulated through noncanonical SMAD3 phosphorylation, which may be effectively treated with CDK2 inhibition to help enhance the efficacy of trastuzumab for patients with HER2+ breast cancer.
Cardioprotection in patients with cancer undergoing chemotherapy: A network meta-analysis.
Authors: Kancharla Pragnan , Ivanov Alexander 
Published: May 2019

e12008 Background: Introduction of anthracycline or trastuzumab based regimen for various types of cancer during the past two decades led to substantial improvement in life expectancy, yet resulting in increased prevalence of unintended side effects. Left ventricular systolic dysfunction is a known complication of the currently employed chemotherapy regimens with anthracycline or trastuzumab which not only affects patient’s cardiac outcome but also limits their therapeutic opportunities, especially continuation or reintroduction of chemotherapy treatment. We aimed to perform comprehensive network meta analysis to synthesize data from randomized clinical trials (RCT) comparing all modern regimens to prevent cardiotoxicity in such patients. Methods: We performed a comprehensive search of pubmed, embase, google scholar and TRIP database for all RCT comparing cardioprotective effects of medication in patients with various types of cancer on chemotherapy with either an anthracycline or trastuzumab based regimen from 1997 to 2019. Left ventricular ejection fraction (LVEF) was measured by transthoracic echocardiogram or cardiac magnetic resonance imaging. Patients treated with either Angiotensin Converting Enzyme-Inhibitor(ACE) or Angiotensin receptor blocker(ARB) were combined into one group. Primary outcome was change in LVEF between start and end of the chemotherapy. Network meta-analyses were conducted using consistency and inconsistency models. Results: A total of 16 studies with 1459 patients were included in the analysis where either an Anthracycline or Trastuzumab based chemotherapy regimen was administered. 369 patients received beta blockers(BB), 351 received either an ACE or ARB, 61 received a combination of BB and either an ACE or ARB, 20 received a statin and 657 were given a placebo. The primary cancer was breast cancer in 8 studies, one each of lymphoma, blood cancers and remaining 6 being mixed. Mean age was 48.81 years. Compared to patients on placebo there was a significant cardioprotective effect (smaller reduction in LVEF) noted with ACE/ARB (beta coef 5.2 (1.5-8.9), p<0.01), BB(beta coef 4.62 (0.8-7.8), p<0.02), and spironolactone beta coef 12.9 (1.9-23.4), p<0.03) There was an evidence of inconsistency with all p>0.3, other than in spironolactone arm as there were suggestion of inconsistency with p<0.01 likely due to the presence of single study. Conclusions: BB and ACE/ARB are associated with reduction in cardiotoxicity in patients with cancer undergoing cancer chemotherapy with an anthracycline or trastuzumab based regimen.