tbuckley/cabot-search huggingface dataset:
Can biomarkers differentiate psoriatic arthritis from osteoarthritis?
Authors: Jian Tian, Chao Cheng, Fangjie Zhang
Journal: Annals of the Rheumatic Diseases (2019)

We read with deep interest the article by Chandran V et al ,1 which was aimed at identifying soluble biomarkers that differentiate psoriatic arthritis (PsA) from osteoarthritis (OA). Their results showed that cartilage oligomeric matrix protein,monocyte chemoattractant protein-1 and nerve growth factor were found to be independently associated with PsA versus OA in a multivariate analysis, and they obtained the conclusion that a panel of four biomarkers may distinguish PsA from OA. We really appreciate the work that has been done by the authors. However, there are some worthwhile issues that need to be explored.

First, the conclusion ‘A panel of four biomarkers may distinguish PsA from OA’ might be not appropriate. The potential meaning of ‘differentiate PsA from OA’ is that detection of these biomarkers helps to diagnose and distinguish PsA from OA when the clinical manifestations of the two diseases are …
CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids
Authors: Reyes Gonzalez-Exposito, Maria Semiannikova, Beatrice Griffiths, Khurum Khan, Louise J. Barber, Andrew Woolston, Georgia Spain, Katharina von Loga, Ben Challoner, Radhika Patel, Michael Ranes, Amanda Swain, Janet Thomas, Annette Bryant, Claire Saffery, Nicos Fotiadis, Sebastian Guettler, David Mansfield, Alan Melcher, Thomas Powles, Sheela Rao, David Watkins, Ian Chau, Nik Matthews, Fredrik Wallberg, Naureen Starling, David Cunningham, Marco Gerlinger
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity. <h3>Methods</h3> We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells. <h3>Results</h3> PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA<sub>hi</sub> (<i>n</i>&nbsp;= 3), CEA<sub>lo</sub> (<i>n</i>&nbsp;= 1) and CEA<sub>mixed</sub> PDOs (<i>n</i>&nbsp;= 4), that stably maintained populations of CEA<sub>hi</sub> and CEA<sub>lo</sub> cells, which has not previously been described in CRC cell lines. CEA<sub>hi</sub> PDOs were sensitive whereas CEA<sub>lo</sub> PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA<sub>lo</sub> cells maintain cancer cell growth. Culture of FACS-sorted CEA<sub>hi</sub> and CEA<sub>lo</sub> cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA<sub>lo</sub> cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway. <h3>Conclusions</h3> Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
Clinical outcomes and cost-effectiveness of breast cancer screening for childhood cancer survivors treated with chest radiation: A comparative modeling study.
Authors: Jennifer Yeh, Kathryn P. Lowry, Clyde B. Schechter, Lisa Diller, Oguzhan Alagoz, Gregory T. Armstrong, John M. Hampton, Wendy Leisenring, Qi Liu, Jeanne S. Mandelblatt, Diana L Miglioretti, Chaya S. Moskowitz, Kevin C. Oeffinger, Amy Trentham-Dietz, Natasha K. Stout
Journal: Journal of Clinical Oncology (2019)

6525 Background: Survivors of childhood cancer previously treated with chest radiation face elevated breast cancer risk similar to BRCA1 carriers. Children’s Oncology Group (COG) guidelines recommend annual mammography with breast MRI, yet the benefits and costs of various screening strategies are uncertain. Methods: We used two breast cancer simulation models (Model 1 and 2) from the Cancer Intervention and Surveillance Modeling Network (CISNET) and data from the Childhood Cancer Survivor Study to reflect high breast cancer and competing mortality risks among survivors. We simulated 3 screening strategies: annual mammography with MRI starting at age 25 (COG25), annual MRI starting at 25 (MRI25), and biennial mammography starting at 50 (Mammo50). Performance of mammography+/-MRI was based on published studies in BRCA1/2 carriers who have similar cancer risk. Costs and quality of life weights were based on US averages and published studies. Results: Among a simulated cohort of 25-year-old survivors treated with chest radiation, the lifetime breast cancer mortality risk in the absence of screening was 10-11% across models. Compared to no screening, Mammo50, MRI25, and COG25 screening avert approximately 23-25%, 56-62% and 56-71% of deaths, respectively; averted deaths for COG25 compared to MRI25 were higher in Model 1 than Model 2 (9% vs. &lt;1%). In Model 1, both MRI25 and COG25 were cost-effective; in Model 2, MRI25 was preferable (more effective, less costly than COG25). Conclusions: Compared to no screening, initiating annual screening at younger ages for at-risk survivors averts &gt;50% of breast cancer deaths and is cost-effective. Additional data on test performance are needed to inform recommendations on screening modality. [Table: see text]
It needs more than just eosinophils to cause emphysema in COPD
Authors: Florence Schleich, Renaud Louis
Journal: European Respiratory Journal (2019)

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airways. It is of utmost importance to obtain smoking cessation in COPD patients exhibiting eosinophilic inflammation <http://bit.ly/2VkkxQv>
Patient reported outcomes and predictors of distress.
Authors: Patrick Leland Meadors, Sally J Trufan, Kendall Walsh, Declan Walsh
Journal: Journal of Clinical Oncology (2019)

6559 Background: ASCO/NCCN guidelines recommend screening for multifactorial distress in cancer patients. Understanding predictors of cancer related distress can lead to early intervention and improve clinical outcomes, symptom management, and operational efficiency. Through electronic distress screening (EDS), patient reported outcomes (PRO) were collected across 42 practice locations. Methods: EDS has 39 questions related to cancer related distress including: distress, cancer symptoms/side effects, malnutrition, depression, anxiety, social/family support, financial, and spiritual concerns. 27,106 patients completed screens between 2017-2018. Multivariate analysis and logistic regressions determined predictors of distress for completed screens overall, registry matched, and within 60 days of diagnosis. Results: Median age was 59 (IQR 18-101) and 65% were female. Five symptoms consistently predicted clinically significant distress ≥ 4: anxiety, fatigue, pain, poor emotional coping, and sleep. Diagnosis (dx), staging at time of dx, and timing of screen did not independently predict distress. Factors predicting clinically significant distress varied across geographic regions. Conclusions: In large patient population, five key PROs are predictive of clinically significant distress and could potentially impact clinical outcomes. Early PROs predictive of distress were consistent along the continuum, thus the importance of early symptom identification. EDS can help custom tailor supportive oncology programs to mitigate symptoms related to cancer distress. [Table: see text]
Efficacy and safety of PD-1 inhibitors in combination with chemotherapy versus chemotherapy as first and second line treatment in advanced gastric and gastroesophageal junction cancer: Preliminary data from a real-world setting.
Authors: Yi Hu, Tao Li, Fan Zhang, Lei Zhao, Xiaochen Zhao, Shangli Cai, Jing Zhao, Shun Chang Jiao
Journal: Journal of Clinical Oncology (2019)

e14079 Background: Unresectable locally advanced or metastatic gastric and gastroesophageal junction (G/GEJ) cancer is an aggressive disease with poor outcomes. Although pembrolizumab monotherapy has been approved as third-line therapy for selected G/GEJ tumors expressing programmed death ligand 1 (PD-L1), the combination regimens of PD-1 inhibitor with chemotherapy are rarely studied. Our study explored the efficacy and safety of PD-1 inhibitors combined with conventional therapy as first and second line treatment in advanced G/GEJ cancer. Methods: Patients with stage IV G/GEJ cancer treated with PD-1 combination therapy or chemotherapy alone in the Cancer Center of the Chinese People’s Liberation Army from January 2016 to January 2019 were screened for eligibility. Patients with third-line treatment and beyond were excluded. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety profile. Kaplan-Meier estimates and Cox regression were performed in the analysis of PFS and OS. Results: 60 patients were included in our analysis, including 20 patients with PD-1 inhibitors plus chemotherapy and 40 patients with chemotherapy alone. ORR was achieved in 7 of 20 (35%) patients in combination group versus 7 of 40 (17.5%) in chemotherapy group. In the first-line setting, ORR was 70% in combination group versus 16.1% in the chemotherapy group. Combination group showed significant favorable PFS compared with chemotherapy alone (median PFS, not reached versus 4.95 months; HR, 0.41; 95% CI, 0.48 to 0.93; P = 0.03). Preliminary data of OS showed a trend of superiority of combination group but did not present statistically significance (HR 0.33, 95% CI 0.08-1.33, P = 0.10). Incidence of grade 3 or worse treatment-related adverse event was similar between groups (3 of 20 [15%] in combination group, 7 of 40 [17.5%] in chemotherapy group). Conclusions: Addition of PD-1 inhibitor into chemotherapy could be effective and tolerable as first and second line treatment in advanced G/GEJ cancer. These findings need further evaluation by randomized controlled studies. Survival follow-up of present cohort is ongoing.
Prediction the clinical outcomes of cancer patients after peptide vaccination.
Authors: Eniko Rita Toke, Mónika Megyesi, Levente Molnar, József Tóth, Orsolya Lőrincz, Sjoerd H. van der Burg, Marij Welters, Cornelis Joseph Melief, Wolfgang Schönharting, Sybille Urban, Tim Roehnisch, Uwe Heine, Eszter Somogyi, Zsolt Csiszovszki, Katalin Pántya, Péter Páles, István Miklós, Franco Lori, Julianna Lisziewicz
Journal: Journal of Clinical Oncology (2019)

e14295 Background: Neoantigen vaccines can activate T-cells that specifically kill tumor cells. However, most vaccine peptides, selected either as HLA-binders or as HLA-presented epitopes, do not induce T-cell responses in HLA allele-matched individuals. We hypothesized that personal-epitopes (PEPIs) binding to multiple autologous HLA-alleles induce potent T-cell responses. Methods: Epitopes binding to single HLA and PEPIs binding to 3 autologous HLA-alleles were identified with our novel and validated PEPI Test (CE Marked) and correlated with CD8+ and CD4+ T-cell responses of (pre)malignant patients vaccinated with Synthetic Long Peptides (SLPs) in 2 clinical trials. A Model Population of 433 HLA-genotyped individuals was used to determine the percentage of subjects with PEPIs from SLPs (PEPI-Score). As a proof of principle, a personal vaccine was developed matching with 14 HLA-alleles of a cancer patient with PEPIs from 12 tumor-antigens. T-cell reactivities were tested by interferon-γ ELISPOT. Results: There was no correlation between single HLA-binding epitopes and HPV-specific T-cell responses of patients. In contrast, there was 90% and 69% agreement between HLA-class-I PEPIs and CD8+ T-cell responses (p &lt; 0.001) and HLA-class-II PEPIs and CD4+ T-cell responses (p = 0.005), respectively. PEPI-Score predicted the T-cell response rate of SLP vaccine clinical trials. As predicted by the PEPI Test, personal vaccine treatment activated tumor-specific T-cells: 91% and 100% of the vaccine peptides elicited CD8+ and CD4+ T-cell responses, respectively. Conclusions: A patient’s HLA genotype is a major determinant of vaccine responses and PEPIs are genetic biomarkers of T-cell responses. PEPI Test prediction of vaccine responses can be utilized by clinicians for selecting the vaccine treatment and for the development of highly immunogenic personal vaccines matched to a patient’s complete HLA genotype (NCT03391232).
Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation
Authors: Sara Martire, Aishwarya A. Gogate, Amanda Whitmill, Amanuel Tafessu, Jennifer Nguyen, Yu-Ching Teng, Melodi Tastemel, Laura A. Banaszynski
Journal: Nature Genetics (2019)
Clinical and prognostic significance of serum levels of fatty acid binding proteins in hepatocellular carcinoma (HCC).
Authors: Yehia I. Abugabal, Ahmed Omar Kaseb, Asif Rashid, Roberto Pestana, Reham Abdel-Wahab, Lianchun Xiao, Aliya Qayyum, Lauren Girard, Kanwal Pratap Singh Raghav, Jeffrey Morris, Robert A. Wolff, James C. Yao, Hesham M. Amin, Manal Hassan
Journal: Journal of Clinical Oncology (2019)

4099 Background: Limited data are available about the prognostic effect of fatty acid binding proteins (FABP) in viral and non-viral-related hepatocellular carcinoma (HCC). Previous studies suggested that selected FABP could be a potential target markers for HCC chemotherapy response and may correlated with presence of cirrhosis and poor outcome. We aimed to test the association between plasma levels of Liver (L)-FABP, Heart (H)-FABP, and Adipose (A) FABP and HCC. Methods: we enrolled 767 HCC patients from MD Anderson Cancer Center. Under IRB approval, baseline patients’ characteristics were retrieved from medical records and blood samples were collected and tested form plasma levels of L-, A-, H-, FABPs. Descriptive statistics were performed and the median values of FABPs among 200 normal controls (NC) were used as cutoff values of FABPs. Overall survival (OS) was estimated by Kaplan Meier curve and log rank test. Results: FABPs were highly expressed in HCC cases than controls. Mean values (±SE) of AFABP, HFABP, and LFABP were significantly higher in cases [25.6 (.7), 10.8 (.5), and 47.8 (1.9)] than controls [19.1 (.8), 7.7 (2), 22. 9 (.5)], P &lt; .001. All FABPs were significantly associated with cirrhosis, higher Child Pugh Score (CTP), advanced stage in Barcelona clinic liver cancer stage (BCLC), higher AFP levels, vascular invasion and thrombosis, and tumor nodularity. Median OS (months) (95%CI) were significantly short in patients with higher level of AFABP, HFABP, and LFABP [9.3 (6.8-11.9), 9.4 (6.8-11.9), and 11.1 (8.8-13.3)] as compared to patients with low levels [16.4 (13.8-18.9), 16.4 (14.2-18.6), and 17.9 (14.9-20.9) respectively (P &lt; .01). The significance was observed in non-viral related HCC for LFABP and HFABP, but not AFBABP. Conclusions: To the best of our knowledge, we describe the largest study correlating FABPs levels with clinical and prognostic characteristics of HCC. Higher levels were associated with poor survival. These findings suggest that LFABP and HFABP may be used as potential prognostic biomarkers for non-viral-related HCC.
Prognostic value of circulating cytokines in breast cancer: A prospective study in sixty breast cancer patients in Tunisia.
Authors: Jihene Braham Ayari, Shourouk Haj Ammar, Mehdi Balti, Mouna Ben Azaiz, Aref Zribi, Sana Fendri, Sonia Ben Nasr, Ezzedine Ghazouani, Faida Agili, Sharif Ahmed Kullab, Abderrazek Haddaoui
Journal: Journal of Clinical Oncology (2019)

e12592 Background: Breast cancer is the second most common cancer and the fifth most common cause of cancer mortality worldwide. The functional relationship between inflammation and cancer is an old concept of cancero- genesis, and it is now clear that inflammatory process certainly potentiates and/or promotes neoplastic risk. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. The aim of this study is to measure the level of circulating cytokines (IL17, IL6, IL22, IL23 and TNFα) in breast cancer patients in Tunisia, and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from sixty breast cancer patients in Tunisia. TNF-α and IL6 levels were determined using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, USA). Serum levels of IL17, IL22 and IL23 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 48 years, and fourth of them were metastatic. The mean level of cytokines IL6, IL17, TNFα, IL22 and IL23 were respectively 4.80 ± 7.26 pg/ ml (min 2, max 36.80 pg/ ml), 0.27 ± 0.69 pg/ ml (min 0, max 3.62 pg/ ml), 5.93 ± 2.27 pg/ ml (min 4, max 15.30 pg/ml), 50.82 ± 34.78 p/ml (min 26.48, max 199.48 pg/ ml) and 18.05 ± 30.91 pg/ ml (min 0, max 200.21 pg/ml). Serum IL6 level was significantly higher in advanced stages (p = 0.013), especially in metastatic cases (p = 0.001) and in patients who had recurrent disease (p = 0.010). High level of TNFα was also significantly associated with advanced stage (stage III and IV) (p = 0.019), and high level of IL22 was significantly associated with a high histopathological grade (Grade III of Bloom-Richardson grade (SBR)) (p = 0.028). IL23 was found to be significantly increased in lymph node metastatic cases (p = 0.042) and in young patients &lt; 35 years (p = 0.034). Finally, the level of IL17 was significantly higher in patients who had recurrent disease (p = 0.018). Conclusions: Our results highlight the role of certain circulating cytokines as potential prognostic biomarkers in breast cancer patients. The serum analysis of these cytokines, which could contribute to tumor growth and progression, may help to identify groups of patients with poor prognosis and who may need more aggressive treatment. This correlation needs to be evaluated in large prospective validating trials and suggests a rational for the development and use of cytokine blockade in treatment of some groups of breast cancer patients.
Phase II trial combining atezolizumab concurrently with chemoradiation therapy in locally advanced non-small cell lung cancer.
Authors: Steven H. Lin, Yan Lin, Isabel Mok, Jenean A. Young, See Phan, Alan Sandler, Vassiliki Papadimitrakopoulou, John Heymach, Anne S. Tsao
Journal: Journal of Clinical Oncology (2019)

8512 Background: Consolidation durvalumab after chemoradiation (CRT) is the new standard of care in locally advanced NSCLC (LA-NSCLC). We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without significant additive toxicity. To test this concept, we conducted a phase II trial called DETERRED combining atezolizumab (atezo) with cCRT followed by consolidation full dose carboplatin/paclitaxel (CP) with atezo (CP-atezo) for 2 cycles and then maintenance atezo for 1 year. The primary endpoint was safety/toxicity and feasibility. Methods: This study enrolled patients (pts) between February 2016 - April 2018 and was done in two parts: In part 1 (N=10), conventionally fractionated CRT (60-66 Gy in 30-33 fractions combined with weekly low dose CP) was followed by CP-atezo then maintenance atezo. Part 2 was cCRT (N=30) with atezo followed by CP-atezo then maintenance atezo. Atezo was given at 1200 mg IV Q3 weeks. Severe adverse events (SAEs) ≥ grade 3 were defined by CTCAE v5.0. Evaluable pts received at least one dose of atezo. PD-L1 staining utilizes the DAKO 22C3 platform. Kaplan Meier were analyzed for progression free survival (PFS) and overall survival (OS), and chi-square test for PD-L1 levels on any recurrence, with significance set at &lt;0.05. Results: In Part 1, atezo related SAEs were seen in 4 pts (40%) (2 grade 3 arthralgia, 1 grade 3 dyspnea and 1 grade 5 TE fistula). Grade 2 radiation pneumonitis (RP) was seen in 1 pt. In Part 2, seven (23%) pts had atezo related SAEs (diarrhea, nephritis, dyspnea, fatigue and heart failure). RP was seen in 3 pts, 2 grade 2 and 1 grade 3, which led to atezo discontinuation. In Part 1, with an overall median follow up (f/u) time of 22.5 months and 27.4 months for survivors, the 1-year PFS is 50%, and OS is 79%. In part 2, with a median f/u time of 11.8 months and 13.7 months for survivors, the 1-year PFS was 57%, and OS is 79%. Baseline tumor biopsy PD-L1 status was evaluable for 34 pts. There were no significant differences in cancer recurrence for PD-L1 &lt;1% (7/16=44%) vs ≥1% (6/18=33%), or for the PD-L1 cutoff of &lt;50% (11/26=42%) vs ≥50% (2/8=25%). Conclusions: Concurrent atezo with CRT followed by CP-atezo and maintenance atezo is safe without increased toxicities compared to CRT alone followed by CP-atezo and maintenance atezo. Updated efficacy results from DETERRED will be presented. Ultimately, the clinical benefit of immunotherapy with cCRT followed by consolidation chemo-immunotherapy will need to be compared to the PACIFIC regimen in a larger randomized trial. Clinical trial information: NCT02525757.