bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paradoxical effect of regulatory T-cell density in the invasive margin on colon cancer disease-free survival.
Authors: Lombardo Jamie , Messersmith Lynn , Williams Grant , Hickerson Annelies , Campf Jessica , Collins Ryan , Brady Robert , Peoples George Earl , Clifton Guy T. 
Published: July 2019

47 Background: Increased numbers of FoxP3+ regulatory T cells (Treg), an immunosuppressive T cell subpopulation, in the tumor microenvironment (TME) has been associated with decreased recurrence risk in colon cancer. We assessed the association of Treg levels and disease-free survival (DFS) to confirm correlation with recurrence risk and to evaluate the impact on DFS in patients with colon cancer. Methods: Cases of colonic adenocarcinoma with endoscopic biopsies who had curative resection were collected from 2006-2016. The tissue sections were stained with FoxP3 immunohistochemical stain. FoxP3+ cells (Tregs) were counted with a digital imager software program and reported as cells per square mm. DFS from time of surgery was determined with a retrospective chart review. FoxP3 levels were compared with a Man-Whitney U test and DFS was compared with a Spearman’s test and regression. Results: 109 matched endoscopic biopsy colonic adenocarcinoma specimens were gathered. 94 cases had at least 4 months of follow up and were analyzed. The recurrence rate was 21.3% (20/94) with a median recurrence time of 13.5 months. The median time to follow up in patients with no recurrence was 39 (range 4-116) months. Tregs in those that recurred had a mean density of 152 (range 9-1267) at the invasive margin compared to 251 (range 15-485) in the cases that did not yet recur (p = 0.005). The same association was observed with Treg density in the center of the tumor (p = 0.03). In the cases that had a recurrence, there was a moderate, inverse correlation between Tregs at the invasive margin and time to recurrence (Spearman’s correlation coefficient = -0.46, p = 0.04.) A logarithmic inverse relationship between Tregs at the invasive margin and time to recurrence was observed (Correlation coefficient -0.63, p = 0.003). Conclusions: Treg density in endoscopic biopsies in colon adenocarcinoma is associated with recurrence risk, consistent with previously reported observations. Paradoxically, in patients who did recur, higher Treg density was associated with shorter time to recurrence. This discordant relationship of Treg density and colon cancer prognosis warrants further investigation.
Modeling of prognostication based on genomic expression in the tumor microenvironment of muscle invasive urothelial carcinoma via machine learning.
Authors: Lee Sunyoung S. , Lee Dong Eun , Baird Andrew , Lee Seongwon , Park Shinyoung , Dolan Jillian , George Saby 
Published: July 2019

64 Background: Stroma in the tumor microenvironment (TME) influences prognosis and response to therapy. Few mathematical models exist to prognosticate patients (pts), based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 401 pts with muscle invasive urothelial carcinoma were obtained from TCGA. Expressivity of 191 genes enriched in cellular and structural elements of TME and clinical data were analyzed by Kaplan-Meier (KM) analysis, correlation analysis, and multivariate nonlinear regression assisted by machine learning to achieve confined optimization with model-data minimization among multiple distribution functions. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in stage 2-4 (Table, stage 1 data not available from TCGA). P/G is the ratio of genes associated with poor (19 genes) to good (11) prognosis (refer to presentation). Based on RS, pts in each stage were clustered into 2 groups (high and low RS), showing 2 KM curves with p < 0.01 in each stage, confirming the validity of RS modeling. Analysis of immune profiles in these 2 groups shows that regardless of stage, expression of genes associated with Desmoplasia, Angiogenesis, and Epithelial-mesenchymal transition (DAE) is higher in high RS groups. Furthermore, expression of DEA genes in stage 4 correlated more strongly with poor prognosis than observed in stage 2-3 as evidenced by smaller p-value. Among stage 4 tumors, expression of genes related to IFN response, NK cells, and T1 helper cells is higher in low RS groups. In stage 2 and 3, genes related to immune activation and inhibition have no association with prognosis (p > 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis show that genes related to immune activation are associated with better prognosis, while DAE genes correlate with poorer prognosis among advanced stages. RS enables prognostication of pts encountered in the clinic, given genomic profiles. [Table: see text]
Relationship between tumor burden to growth rate and treatment outcomes of nivolumab for patients with head and neck squamous carcinoma.
Authors: Suzuki Chiaki , Kiyota Naomi , Imamura Yoshinori , Rikitake Junpei , Sai Satoshi , Koyama Taiji , Hyogo Yasuko , Nagatani Yoshiaki , Funakoshi Yohei , Toyoda Masanori , Otsuki Naoki , Nibu Ken-ichi , Minami Hironobu 
Published: July 2019

68 Background: Nivolumab improved overall survival (OS) in the treatment of platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) in a phase III clinical trial. However, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy may have better outcomes with cytotoxic treatment. Here, we explored suitable conditions and candidates of predictive factors for nivolumab for R/M HNSCC. Methods: We retrospectively reviewed the clinical records of 28 consecutive patients with HNSCC from 2014-2018. Tumor size was evaluated by computed tomography according to RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3Log (Dt/D0)/t, where D0 and Dt are the sum of the longest diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1 t defined as the 4-week interval between tumor evaluations. Results: After exclusion of 2 patients with unevaluable responses, 26 patients were included in the study. Median follow-up time for survivors was 9.5 months. Median SumTLs at baseline was 43.2 mm (range, 10.1-135.3). Median Gr was 0.22 (range, 0.05-0.76). Median OS and PFS was 7.9 months (95% CI, 5.8 to 34.5) and 3.7 months (95% CI, 2.1 to 12.9), respectively. Patients with progression within 3 months showed significantly worse survival (HR 6.33, 95% CI 2.08-21.67, p=0.001). Moreover, higher Gr and bigger SumTLs appeared to be associated with poorer outcomes. We therefore explored the association between prognosis and the ratio of SumTLs to Gr (SumTLs/Gr). The cut off value of SumTLs/Gr was calculated by ROC analysis. Pre-treatment SumTLs/Gr > 212 was associated with significantly worse OS (HR 8.87, 95% CI 2.33-58.29, p<0.001) and PFS (HR 2.86, 95% CI 1.10-8.33, p=0.03). Conclusions: Although retrospective with a small sample size, these results suggest that pre-treatment SumTLs/Gr > 212 was significantly associated with inferior OS and PFS in R/M HNSCC patients treated with nivolumab. R/M HNSCC patients with pre-treatment SumTLs/Gr > 212 might be unsuitable for treatment with nivolumab.
Expression of T-cell populations and molecular markers of human myocardium with checkpoint-induced myocarditis.
Authors: Zarifa Abdulrazzak , Kim Peter Y. , Gilchrist Susan , Iliescu Cezar , Suarez-Almazor Maria E. , Lopez-Mattei Juan , Balanescu Dinu Valentin , Donisan Teodora , Palaskas Nick , Upadhyay Ankit , Moudgil Rohit , Zhao Bihong , Buja Maximillian , Durand Jean-Bernard 
Published: July 2019

79 Background: Checkpoint Inhibitors have become first line therapy for a variety of solid and liquid malignancy. Immunotherapeutic agents predominantly target CTLA-4 and PD-L1. Efficacy has been demonstrated, and toxicities, especially cardiac manifested as myocarditis. The incidence of myocarditis is relatively low, fatality with monotherapy approaches 50% and with dual Immunotherapy is over 75%. No screening biomarkers or cardiac imaging predict a priori whom will develop myocarditis, nor which patients will be at risk. The frequency of these targets are unknown in the human heart. Methods: We present a case study of a patient with a diagnosis of urothelial carcinoma to lung and lymph nodes treated with systemic nivolumab plus NKTR after cycle 2 he presented with one week history of shortness of breath and hemodynamically unstable complete heart block requiring temporary transvenous pacemaker. Initial Troponin = 356, BNP = 2106. Given high suspicion for cardiovascular disease and or myocarditis, a left heart angiogram, right heart catheterization and endomyocardial biopsy of right ventricle were performed. RV biopsies were obtained percutaneously from right internal jugular approach with fluoroscopic guidance. Pulmonary capillary wedge pressure was 23mmHg. Persistent complete heart block was present during weaning attempts from temporary pacemaker and a percutaneous dual chamber pacemaker was implanted. Results: Coronary angiogram showed non obstructive disease, endomyocardial biopsy revealed lymphocytic infiltrate with necrosis based on Dallas Criteria. Immunohistochemistry showed, predominance of CD3,CD4,CD8,CD20,CD68 and PD-L1 staining was grossly positive compared to control samples. The patient was treated with methylprednisone 1mg/kg IV BID, plasmapheresis times 5 cycles, mycophenolate mofetil 500mg IV BID with resolution of symptoms and discharged to home. Conclusions: We present a patient with nivolumab induced myocarditis complicated with myocarditis and complete heart block. The pathological approach of T-Cell phenotyping is unique and identifies a novel approach to precision driven diagnosis, the incidence of PD-L1 expression in the human heart is unknown.
Patient (pt) experiences with avelumab in treatment-naive metastatic Merkel cell carcinoma (mMCC): Qualitative interview findings from a registrational clinical trial.
Authors: Bharmal Murtuza , Lambert Jeremy , Russell Jeffery Scott , Lebbé Celeste , Chmielowski Bartosz , Hennessy Meliessa , Marrel Alexia , D'Angelo Sandra P. 
Published: July 2019

90 Background: MCC is a rare, aggressive skin cancer with a poor prognosis. Avelumab is the only anti–PD-L1 monoclonal antibody approved for treatment of mMCC. This qualitative research embedded in a clinical trial aimed to explore pt experiences on treatment with avelumab. Methods: All treatment-naive pts with mMCC entering the registrational, open-label, multicenter trial to investigate the clinical activity and safety of avelumab were invited to participate in optional, semistructured, 30-min phone interviews at baseline (prior to study drug administration) and at weeks 13 and 25. Interviews were conducted by trained professionals, audio-recorded, transcribed, and analyzed using a qualitative software package, ATLAS.ti V7. Key concepts identified from the baseline interview for each pt were assessed during follow-up interviews. Results: A total of 29 pts (mean age, 71 y; 76% male) completed the baseline interview; 19 pts (6 in USA, 4 in France, 5 in Italy, 3 in Germany, 1 in Australia) had ≥1 follow-up interview. The baseline interviews revealed the negative psychological burden on pts living with a symptomless disease and the hope for avelumab to be a successful therapy. Over the course of the trial, most pts reported an increased or continued sense of hope and willingness to fight MCC. Pts who self-reported their disease to be improved (n=12) also reported being stable or experiencing improvements in their ability to do their daily activities and in their physical well-being and having more energy than before starting avelumab. They also reported worrying less and being optimistic. Six pts among the 7 who reported their condition as stable (n=4) or worsened (n=3) reported a worsening of their physical well-being. Nine pts reported fatigue/tiredness on the day of and the day after receiving the avelumab infusion. The reported baseline and longitudinal experiences were similar across pts from all countries. Conclusions: This qualitative study alongside a registrational trial showed that pts experienced perceptible benefits in their physical and psychological well-being following treatment success with avelumab in mMCC. Clinical trial information: NCT02155647 part B.
Smoking history and PD-1/PDL-1 pathway blockade: Predicting response to treatment in metastatic cancer.
Authors: Sullivan Caitlin Marie , Lu Jonathan , Kucharczyk John Ross , Vesselinovitch Diana , Khurana Neharika , KC Madhav , Matrana Marc Ryan 
Published: July 2019

95 Background: Identifying patients who will benefit from immune-checkpoint inhibitor therapy is a challenge as proven predicative indicators remain to be elucidated. High tumor mutational burden (TMB) represents a possible biomarker for response to PD1 blockade such as in nivolumab or pembrolizumab. Genomic analyses have shown that patients with heavy smoking history are more likely to have high TMB. However smoking status alone has not been examined independently in relation to treatment response. We sought to determine whether a relationship existed between smoking history and response to treatment in metastatic non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mMelanoma). Methods: A retrospective analysis was conducted of Ochsner Health System patients with mRCC, mMelanoma, and NSCLC receiving a minimum of two cycles of nivolumab or pembrolizumab between 12/2014 and 01/2018. Pre- and post-treatment target lesions were analyzed using RECIST criteria to calculate best response to treatment. Patient demographic information was gathered including age, sex, smoking history, and performance status pre and post treatment. Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) outcomes. Results: Heavy smokers (>10 pack-years) had a higher response to immunotherapy than light (< 10 years) and never smokers (p = 0.0500). Heavy smokers with NSCLC treated with immuno-therapy also had significantly improved OS compared to light smokers with NSCLC (p=0.003). mRCC immuno-therapy patients with heavy smoking history showed increased PFS compared to light/never smokers (p=0.026). Conclusions: In summary, in response to PD-1 blockade heavy smokers showed improved survival compared to light and never smokers suggesting smoking history may represent a potential predictor of treatment response to PD-1 inhibitor therapy.[Table: see text]
A phase I trial combining plinabulin and nivolumab for metastatic NSCLC: Trial in progress.
Authors: Villanueva Nicolas , Son Klarissa , Yeh Shihfan , Jain Sonia , Eng Elaine , Lloyd Ken , Huang Lan , Mohanlal Ramon W. , Bazhenova Lyudmila 
Published: July 2019

TPS128 Background: Plinabulin (Plin) is a microtubule-destabilizing agent (MDA) that inhibits the polymerization of tubulin monomers and leads to disruption of the tumor vasculature. It has been shown in clinical studies of advanced NSCLC to produce a significantly longer duration of response when combined with docetaxel versus docetaxel alone (NCT00630110). MDAs were also shown to trigger the maturation of dendritic cells and the production of pro-inflammatory cytokines, thereby enhancing T-cell proliferation. Pre-clinical studies have shown that MDAs in combination with immune checkpoint inhibitors (ICI) demonstrated a superior response rate and survival when compared to ICI alone. Nivolumab is an anti-PD-1 antibody that is FDA approved for previously treated metastatic NSCLC regardless of PD-L1 expression. We hypothesized that the combination of Plin and Nivolumab will enhance the immune response, resulting in a higher response rate and longer overall survival. Methods: This is an open label single center phase I trial. The Dose Escalation Portion (Part 1) employs a 3+3 design with dose escalation of Plin starting at 13.5mg/m2 (biologically effective dose as single agent), combined with the FDA approved dose of Nivolumab 240mg. Plin is given on days 1,8, and 15 of 28- day cycles and Nivolumab is given on days 1 and 15. The dose of Plin will be escalated to 20mg/m2, 30 mg/m2, and 40mg/m2 until the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) is determined. The Expansion Cohort (Part 2) will enroll 20 patients with NSCLC to be treated at the RP2D, including the patients who will have received this dose in Part 1. Treatment will continue until disease progression, development of unacceptable toxicity, or a protocol-defined reason for discontinuation. Eligible patients include metastatic NSCLC who have failed platinum-based doublet and regardless of prior anti-PD-1/PD-L1 antibody treatment. Part 1 is enrolling in an expanded cohort 2 due to one dose-limiting toxicity (DLT) in this group. Clinical trial information: NCT02812667.
Phase III KEYNOTE-716 study: Adjuvant therapy with pembrolizumab versus placebo in resected high-risk stage II melanoma.
Authors: Luke Jason J. , Ascierto Paolo Antonio , Carlino Matteo S. , Eggermont Alexander M. M. , Grob Jean-Jacques , Hauschild Axel , Kirkwood John M. , Long Georgina V. , Mohr Peter , Robert Caroline , Gershenwald Jeffrey E. , Poklepovic Andrew Stewart , Ross Merrick I. , Scolyer Richard A. , Yoon Charles , Anderson James R. , Ahsan Sama , Ibrahim Nageatte , Sondak Vernon K. 
Published: July 2019

TPS145 Background: Adjuvant pembrolizumab showed significantly longer recurrence-free survival compared with placebo in resected stage III melanoma in the KEYNOTE-054 study [1]. KEYNOTE-716 is a randomized, placebo-controlled, multicenter phase 3 study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Methods: Patients must be ≥12 years of age and have newly diagnosed, completely resected stage IIB/IIC cutaneous melanoma, defined by the AJCC Cancer Staging Manual, 8th edition [2] (wide excision and negative sentinel lymph node biopsy, with no evidence of distant metastasis). Patients cannot have mucosal or uveal melanoma or have received prior treatment for melanoma, including radiation, beyond resection of primary disease within 12 weeks of the start of study therapy. The study has a 2-part design. In the double-blind phase (part 1), patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg for patients ≥18 years or 2 mg/kg for patients 12-17 years (maximum dose, 200 mg) or placebo every 3 weeks for 17 cycles. Stratification: 1 stratum for pediatric patients (12-17 years); 3 strata for adult patients per T stage (T3b/T4a/T4b). Study treatment will begin within 12 weeks of complete resection. Tumor imaging will be performed every 24 weeks while treatment is ongoing, at the end of treatment, every 6 months for the first 3 years off treatment, and then yearly for up to 2 years or until recurrence (up to 5 years of total imaging). Adverse events will be graded per NCI Common Terminology Criteria for Adverse Events, version 4.0. In the unblinded phase (part 2), patients with confirmed recurrence may be rechallenged (patients received pembrolizumab in part 1) or crossed over to pembrolizumab (patients received placebo in part 1). Resected local or distant recurrence or unresectable disease will be treated for an additional 17 or 35 cycles, respectively. Tumor imaging in part 2 will occur every 12 weeks while treatment is ongoing. The primary end point is recurrence-free survival; secondary end points are distant metastasis-free survival, overall survival, and safety. Approximately 954 patients will be enrolled. Clinical trial information: NCT03553836.
A phase I study evaluating COM701 in patients with advanced solid tumors.
Authors: Rasco Drew W. , Papadopoulos Kyriakos P. , Adewoye Adeboye H. , Hunter John , Ramsey Denise , ElNaggar Adam , Patnaik Amita , Vaena Daniel A. 
Published: July 2019

TPS40 Background: Novel checkpoint therapies are needed for the treatment of patients who relapse/refractory to treatment with checkpoint inhibitors. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with it's ligand, PVRL2. We have demonstrated in preclinical experiments that inhibition of PVRIG leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with R/R solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with R/R solid tumors. The initial part of this study will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Accelerated titration design consisting of single subject cohorts has been implemented for the initial cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission a third single subject dose cohort has been filled.