tbuckley/cabot-search huggingface dataset:
Comparison of efficacy and safety of checkpoint inhibitors in patients with genitourinary cancers aged below and above 75 years.
Authors: Gerald Bastian Schulz, Bernadett Szabados, Annabel Spek, Michael D. Staehler, Christian Stief, Jozefina Casuscelli
Journal: Journal of Clinical Oncology (2019)

e16101 Background: Checkpoint-inhibitors have recently been introduced in the treatment of patients with genitourinary cancers. However, the use in elderly patients is controversial due to putative age-associated changes including the dysregulation of the immune system. We sought to investigate the safety and efficacy of immunotherapy in patients younger and older than 75 years of age. Methods: We conducted a retrospective review of patients with renal cell carcinoma and urothelial cancer treated with different immunotherapeutic agents between August 2015 and September 2018 at a high-volume single institution. Eligible patients received at least one cycle of single agent or a combination of checkpoint inhibitors as first or following treatment line. Immune-related adverse events (irAE) were graded using the NCI CTCAE v 4.0. Clinicopathological parameters including gender, cancer entity, ECOG, adverse events, comorbidities and response to treatment were stratified by age ≥ 75 vs. &lt; 75 years and tested with a Pearson's chi-squared test. Additionally, we evaluated the impact of irAE on oncological outcome using the log-rank test. Results: 79 patients were identified, of those 27 (34.2%) were 75 years and older (15 renal cell carcinoma and 12 urothelial cancer patients) and 52 (65.8%) were younger than 75 years (39 renal cell carcinoma and 13 urothelial cancer patients). 2 complete responses were achieved in the elderly group and 6 in the younger group (p = 0.56). Disease control rate (stable disease, partial and complete response) was 48,1% in the elderly group and 53.8% in the younger group (p = 0.631). We observed a total of 30 irAEs (18 grade 1-2 and 12 grade 3-4), with an even distribution among the groups (≥75 years: 1 grade 4 AE; &lt; 75 years: 12 grade 3-4 AEs). Except for ECOG ≥2 (p = 0.009) and ≥2 comorbidities (p &lt; 0.001), there was no difference when groups were stratified by age. Both disease control rate and irAE did not differ between age subgroups. Occurrence of irAE showed no impact on oncological survival. Conclusions: The study demonstrates that patients over 75 years of age with renal cell and urothelial cancer treated with checkpoint-inhibitors respond with a good toxicity profile and an efficacy comparable with the younger population. irAE seem to have no impact on prognosis.
Demoralization and associated features in an Italian sample of end-of-life cancer patients.
Authors: Mario Airoldi, Andrea Bovero, Rossana Botto, Beatrice Adriano, Marta Opezzo, Valentina Tesio, Riccardo Torta
Journal: Journal of Clinical Oncology (2019)

e23004 Background: Demoralization is an expression of cancer-related existential distress that emerges from feelings of loss and changes linked to a life-threatening clinical condition. It is characterized by subjective incompetence, sense of failure, hopelessness, loss of purpose/meaning and low self-esteem. The study aimed to explore prevalence, latent dimensions and associated features of demoralization in a sample of end-of-life cancer patients. Methods: Participants were recruited for a cross-sectional assessment. For each patient, demoralization, anxiety, depression, physical symptoms, pain, spiritual well-being, and dignity were evaluated through validated rating scales and personal and medical data were gathered by a clinician. Final sample consisted of 235 end-of-life cancer patients with a Karnofsky Performance Status (KPS) lower than 50 and a life expectancy of few weeks. Results: High levels of demoralization occurred in 22.6% (n = 53) of patients. Sixty-four participants (27.2%) had low demoralization and 50.2% (n = 118) had moderate demoralization. Emotional Distress and Inability to Cope, Loss of Purpose and Meaning, Worthlessness, Sense of Failure and Dysphoria were the five latent dimensions of demoralization emerged from the factor analysis. Demoralization was significantly associated with depression, anxiety, dignity, spiritual well-being and the physical symptoms except for nausea and breathing problems. Conclusions: Demoralization levels seem to be higher in this distinctive population than in advanced cancer patients. This could be due to the fact that end-of-life cancer patients are in a severe clinical condition and nearing death. The emerged demoralization dimensions could be five forms of expression of the existential distress typical of this illness phase. The considerable number of patients suffering from demoralization strengthen the need for psychological interventions in order to reduce the existential distress at the end of life, focusing on finding meaning and detecting spiritual concerns.
The use of metformin to enhance radiation effects on M1 macrophage subtype polarization in bone marrow-derived macrophage in glioblastoma tumor environment.
Authors: Fei Wang, Nan Zhao, Chi Lin, Chi Zhang
Journal: Journal of Clinical Oncology (2019)

e13513 Background: Given the clinical relevance of tumor-associated macrophage (TAM) with its pro-tumor role and as a cell type compromising a large portion in glioblastoma (GBM), reversing the imbalance of TAM polarization in the tumor environment has emerged as a promising novel field for GBM treatment. Radiation therapy (RT) is the standard treatment for GBM patients after surgery, which has been shown to transiently induce M1 polarization of macrophage (M1Ø). Recent studies suggested that metformin could also promote M1Ø in tumor microenvironment. We thus postulate that metformin may enhance and sustain the M1-inducing effect of radiation in GBM. Methods: We first examined the polarization effect of metformin (0.1mM, 1mM and 2mM) on mouse bone marrow-derived macrophage (BMDM) cultured in GBM tumor environment, including media conditioned by GBM cells in monolayer culture or tumor spheres as well as in trans-well co-culturing system. We irradiated GBM cells with different doses (2 Gy, 8 Gy, and 20 Gy) after the treatment of Metformin at various time points; then we used conditioned media to treat BMDM either cultured alone or co-cultured with GBM cells in trans-well system for 24 or 48 hours. A separate set of experiment was conducted by first irradiating GBM cells and then co-culturing them with BMDM at 24 or 48 hours after radiation with metformin added at the start of co-culture. Percentage of various subtypes of BMDM was calculated after flow cytometry. Results: High concentrations of metformin (1mM and 2mM) significantly increased M1Ø and inhibited M2Ø in all culture conditions. Co-culture with irradiated GBM cells or treatment with medium conditioned by irradiated GBM cells could temporally induce M1Ø polarization in BMDM, with the effects being RT dose-dependent. Metformin at high concentrations further promoted M1Ø and suppressed M2Ø polarization in those conditions mimicking tumor microenvironment. This enhancing effect was sustained for at least 48 hours. Conclusions: Metformin at mili-molar concentrations significantly enhances the effects of radiation on M1Ø polarization in BMDM in vitro.
Comparative analysis of profiles of second-line stage IV renal cell carcinoma patients by first-line to second-line treatment sequencing in the United States.
Authors: Corrina DaSilva, Julie Spindel, Alessandra Franceschetti
Journal: Journal of Clinical Oncology (2019)

e16110 Background: Treatment of metastatic renal cell carcinoma (RCC) is evolving. With new agents, 2 nd line (2L) therapies becoming frontline (1L) options, and growing research on outcomes, optimal treatment sequencing is increasingly complex. Methods: Real world data from Ipsos Global Oncology Monitor © : geographically representative physicians in US reported on 1,120 stage IV RCC anti-cancer drug-treated patients seen in consultation from 10/2017–9/2018, providing patient demographics, current and historic treatment data. Analysis of 1L to 2L treatment algorithm was conducted for current 2L patients. Patient profiles of 2 most frequent algorithms [TKI-TKI (n = 298) and TKI-CKI (n = 443)] were compared using inferential statistics. Results: Patients treated with 1L TKI and 2L CKI (TKI-CKI) vs. those treated with 1L TKI and 2L TKI (TKI-TKI) are older (mean: 65.8 vs 62.7; p &lt; 0.05), have metastases in ≥ 2 sites (52% vs 36%; p &lt; 0.01) and maintained 1L treatment for longer (mean: 10.0 vs 8.8 months; p &lt; 0.05). 2L CKI patients were more likely to have achieved CR, VGPR or PR from 1L TKI (60% vs. 50%; p &lt; 0.05) and less likely to have distant progression (19% vs. 26%; p &lt; 0.05) or discontinued 1L TKI due to toxicities (9% vs. 16%; p &lt; 0.01). 2L CKIs are more likely prescribed due to new clinical data (20% vs 12%; p &lt; 0.05) and biomarker results (7% vs 2%; p &lt; 0.05); 2L TKIs are prescribed more for convenience (10% vs 4%; p &lt; 0.01). Physicians prescribed 2L CKIs more frequently with intent to extend life (53% vs 40%; p &lt; 0.01) than palliative intent (47% vs 60%; p &lt; 0.05). TKI-CKI patients were more involved in 2L treatment choice (17% vs 8%; p &lt; 0.01) and physicians stated higher satisfaction with their current CKI (36% vs 26%; p &lt; 0.01) relative to TKI-TKI patients.Conclusions: TKI-CKI patients are likely to have a more progressed disease, but also to have had a more positive outcome from 1L TKI, suggesting a therapeutic strategy driven by clinical attributes. New clinical data reinforce prescribing CKIs to extend life rather than for palliative purposes. When prescribing CKIs, patient involvement is higher (possibly due to mode of administration requiring more commitment) and physicians are more satisfied with results (despite these patients being older and with more metastases).
Whole exome sequencing of germline DNA of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung adenocarcinoma (LUAD) according to KRAS status.
Authors: Jose Luis Perez-Gracia, Guillermo Pita, Victor Segura, Maria Jose Pajares, Juan Pablo Fusco, Maria Pilar Andueza, Rodrigo Sanchez-Bayona, Elisabet Guruceaga, Maria Isabel Mora, Alfonso Gurpide, Juan Pablo de Torres Tajes, Javier Zulueta, Ruben Pio Oses, Ignacio Melero Bermejo, Miguel F. Sanmamed, Maria E. Rodriguez-Ruiz, Carlos E De Andrea, Luis M. Montuenga, Anna Gonzalez-Neira, Ana Patiño-García
Journal: Journal of Clinical Oncology (2019)

1540 Background: Individual susceptibility to carcinogens may depend on the genetic background. We characterized the constitutional exome of individuals presenting extreme phenotypes of high sensitivity and resistance to develop tobacco induced LUAD, correlating the results to KRAS status. Methods: From an identification cohort (n=3,631) we selected 100 caucasian heavy smokers that either developed LUAD at early age (cancer cohort, n=50) or did not develop LUAD or other tumors at advanced age (cancer free cohort, n=50). We sequenced their germline DNA with the Agilent Human Exome Capture v5 (21,522 genes, 357,999 exons). Using logistic regression we selected the most significant variants between both cohorts and correlated them with KRAS mutation status of LUAD patients. Results: mean ages for the cancer and cancer free cohorts were 50 (range 34-55) and 78 years (72-90). Mean tobacco consumptions were 44 (range 6-72) and 55 pack-years (20-124). Median coverage was 96% at &gt;10X; median depth was 97X. Table shows the most significant variants. rs7240666 ( ALPK2) achieved top significance (p=8.14x10-5, OR 0.18). rs78898229 ( ANKRD36C) and rs74866537 ( PTPN4) were predominantly represented in patients with KRAS+ tumors, OR: 16 (3.3-78) and 11.9 (3.3-43); and rs12426243 (CCDC41) in KRAS- tumors (OR: 13 (3-53). Conclusions: Our study characterizes for the first time the genotype of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced LUAD according to KRAS status. Our results warrants further study to assess their value to screen these clinically relevant phenotypes; and to identify mechanisms of high susceptibility and resistance to carcinogens. [Table: see text]
Can texture analysis of pre-immunotherapy CT imaging predict clinical outcomes for patients with advanced NSCLC treated with Nivolumab?
Authors: Benjamin Oren Spieler, Diana Saravia, Gilberto Lopes, Gregory Azzam, Deukwoo Kwon, Alan Dal Pra, Raphael Yechieli, Tejan Diwanji, Ivaylo Mihaylov
Journal: Journal of Clinical Oncology (2019)

e20720 Background: Targeted therapies are ineffective in most NSCLC patients and response rates remain &lt; 20% for patients with advanced NSCLC on immuno-monotherapy. Predictive models that distinguish responders from non-responders to immunotherapy could help guide clinical practice. Texture analysis is a data-mining tool used to identify intensity patterns in diagnostic imaging. We hypothesized that texture features on pre-immunotherapy CT imaging can be associated with clinical outcomes for patients with advanced NSCLC treated with Nivolumab. Methods: In an IRB-approved database containing 159 patients with advanced NSCLC treated with Nivolumab monotherapy, 20 patients with the longest overall survival (OS) and 20 with the shortest were selected for retrospective analysis. Patient characteristics were compared using paired t-tests. The last pre-immunotherapy PET CT for each patient was transferred to MIM software for segmentation. All FDG-avid intrathoracic tumors were delineated on the CT scan per RTOG contouring guidelines. Ninety-two texture features within each tumor were analyzed for association with the primary endpoint, OS. OS time was dichotomized to less than 1 year vs. more than 1 year. A univariate logistic regression model was used to estimate odds ratio (OR), 95% confidence interval and p-value for each feature. Multiple testing adjustments were performed using false discovery rate. Results: Eleven out of 92 texture features showed significant association with OS time (p-values from 0.009 to 0.044), of which 7 exhibited large effect (OR &lt; 0.5 or &gt; 1.5). Fifteen additional texture features trended toward statistical significance with p-values from .05 to .10. In all, 26 out of the 92 texture features showed significant association or trended toward significance with duration of OS. Conclusions: This preliminary study suggests that texture features on pre-immunotherapy CT imaging may help in predicting OS duration for patients with advanced NSCLC treated with Nivolumab monotherapy. We are in the process of validating a multivariate predictive model. Future directions include expansion of this study across the full database, survival analyses and correlation of texture features with tissue biology.
Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer
Authors: Kim N. Chi, Neeraj Agarwal, Anders Bjartell, Byung Ha Chung, Andrea J. Pereira de Santana Gomes, Robert Given, Álvaro Juárez Soto, Axel S. Merseburger, Mustafa Özgüroğlu, Hirotsugu Uemura, Dingwei Ye, Kris Deprince, Vahid Naini, Jinhui Li, Shinta Cheng, Margaret K. Yu, Ke Zhang, Julie S. Larsen, Sharon McCarthy, Simon Chowdhury
Journal: New England Journal of Medicine (2019)

Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression–free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined.
Predictors of peritoneal metastasis in gastric cancer.
Authors: Irina V. Kaplieva, Oleg I. Kit, Elena M. Frantsiyants, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Nikolay S. Samoylenko, Dmitry A. Kharagezov
Journal: Journal of Clinical Oncology (2019)

e15528 Background: Carcinogenesis is a complex process with still poorly understood mechanisms allowing cancer cells to disseminate from the primary tumor, spread in the body and colonize other organs forming secondary tumors – metastases. The ability of some distant organs to attract malignant cells may be caused by factors released by primary tumors. The purpose of the study was to determine levels of oncofetal proteins CA-19.9, CA-125, CA-72.4 and He-4 in tissues of gastric cancer (GC) and its metastatic niches, the peritoneum and omentum. Methods: The study included 62 patients: 21 (10 men, 11 women) – gastric cancer with peritoneal and omental metastases T 3-4 а N 0-3 M 1 ; 24 (15 men, 9 women) – gastric cancer without metastases T 3-4 а N 0-3 M 0 ; 17 (6 men, 11 women) – non-cancer patients (controls). Levels of oncofetal proteins were measured by ELISA in tissues of the peritoneum, greater omentum, and gastric tumors. Results: Levels of practically all studied factors were elevated in tissues of GC, omentum and peritoneum. Levels of He-4 and CA-19.9 in all tissues of patients with T 3-4 а N 0-3 M 1 increased higher than in the majority of patients with T 3-4 а N 0-3 M 0 : in GC – respectively by 2.6 and 1.8 times (p &lt; 0.05), in the omentum – respectively by 24.4 and 4.8 times, in the peritoneum – respectively by 2.1 and 8.5 times. Omental tissues of patients with advanced cancer showed a higher increase in levels of CA-72.4 and CA-125 as well – by 6.1 and 2.1 times, respectively. A small number of patients with T 3-4 а N 0-3 M 0 gastric cancer, who had CA-19.9 in the omentum and peritoneum as high as in patients with T 3-4 а N 0-3 M 1 , developed metastases in the corresponding tissues 4-6 months after the study. Conclusions: The content of oncoprotein markers in tissues of the peritoneum and omentum is one of the factors associated with metastatic characteristics of GC, and CA-19.9 level can serve as an informative laboratory test for the predictive assessment of the further disease development.
Comparison of the effects of tocilizumab monotherapy and adalimumab in combination with methotrexate on bone erosion repair in rheumatoid arthritis
Authors: Stephanie Finzel, Sebastian Kraus, Camille Pinto Figueiredo, Adrian Regensburger, Roland Kocijan, Juergen Rech, Georg Schett
Journal: Annals of the Rheumatic Diseases (2019)

Objective To compare the effects of interleukin-6 (IL-6) receptor and tumour necrosis factor inhibition on inducing repair of existing bone erosions in patients with very early rheumatoid arthritis (RA). Methods Prospective non-randomised observational study in patients with active erosive RA with inadequate response to methotrexate (MTX) receiving either tocilizumab (TOC) monotherapy or adalimumab (ADA) with MTX for 52 weeks. Erosion volumes were assessed in metacarpal heads (MCH) and the radius by high-resolution peripheral quantitative CT at baseline and after 52 weeks. Clinical response was monitored using Clinical Disease Activity Index, Simple Disease Activity Index and Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) scores every 12 weeks. Results TOC (N=33) and ADA/MTX (N=33) treatment groups were balanced for age, sex, body mass index, comorbidities, disease and activity, functional state, autoantibody status, baseline bone damage and baseline bone biomarkers. Both TOC (DAS28-ESR: baseline: 6.2±0.5; 52 weeks: 2.3±1.0) and ADA/MTX (6.3±0.6; 2.8±1.2) significantly reduced disease activity. Erosion volumes significantly decreased in the MCH and radius of patients with RA treated with TOC (p&lt;0.001) but not in patients treated with ADA/MTX (p=0.77), where they remained stable in size. Mean decrease in erosion volume in TOC-treated patients was −1.0±1.1 mm 3 and −3.3±5.9 mm 3 in the MCH and radius of TOC-treated patients, respectively, and −0.05±0.9 mm 3 and −0.08±4.1 mm 3 in patients treated with ADA/MTX. Conclusions The REBONE study shows that TOC monotherapy achieves more pronounced repair of existing bone erosions than ADA/MTX. Hence, IL-6 is a central factor for the disturbed bone homeostasis in the joints of patients with RA.
Theranostic Nanomedicine Carrying L‐Menthol and Near‐Infrared Dye for Multimodal Imaging‐Guided Photothermal Therapy of Cancer
Authors: Chunyang Zhang, Jie Liu, Huanling Guo, Wei Wang, Ming Xu, Yang Tan, Tongyi Huang, Zhong Cao, Xintao Shuai, Xiaoyan Xie
Journal: Advanced Healthcare Materials (2019)

Abstract Photothermal therapy (PTT) as an emerging technique for cancer treatment has drawn great attention owing to its minimally invasive nature. However, it is difficult to achieve a complete tumor regression due to the heterogeneous heat distribution over the tumor. Application of photothermal conversion agents may enhance PTT efficiency, and a multifunctional imaging may provide guidance for the implementation of PTT. Herein, an L‐menthol/IR‐780 loaded liposome (MIL) is prepared to achieve NIR‐triggered cavitation for enhancing photothermal ablation. The synthesized MIL possesses outstanding colloidal stability and photoacoustic/near infrared fluorescence/ultrasound (PA/NIRF/US) imaging contrast to offer multimodal imaging‐guided photothermal therapy of cancer. Upon irradiation, the IR‐780 acts as the photoabsorber to convert NIR light into heat energy. More importantly, the produced hyperthermia can not only induce ablation of tumor cells but also trigger vaporization and bubbling of encapsulated L‐menthol (menthol). Consequently, the generated menthol bubbles obviously enhance the US imaging signal and promote photothermal ablation of the tumor.
Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression
Authors: Qin Wu, Lingyun Zhou, Duoduo Lv, Xia Zhu, Hong Tang
Journal: Journal of Hematology & Oncology (2019)

The tumor microenvironment (TME) is an essential intrinsic portion of hepatocellular carcinoma (HCC) for the regulation of its origination, development, invasion, and metastasis. As emerging components of the tumor-host interaction, exosomes are increasingly recognized as professional carriers of information in TME and as pivotal molecular entities involved in tumorigenic microenvironment setup. However, much remains unknown about the role of the exosome communication system within TME in the development and progression of HCC. In this review, we focus on the roles and probable mechanisms of TME in HCC and show the exosome-based immune regulation in TME to promote HCC. Multiple processes are involved in HCC, including tumor survival, growth, angiogenesis, invasion, and metastasis. We also discuss the specific roles of exosomes in HCC processes by molding hospitable TME for HCC, such as providing energy, transmitting protumor signals, and evading inhibitory signals. In addition, exosomes induce angiogenesis by changing the biological characteristics of endothelial cells and directly regulating proangiogenic and propermeability factors. Furthermore, exosomes may lead to HCC metastatic invasion by epithelial-mesenchymal transformation, extracellular matrix degradation, and vascular leakage. Finally, we summarize the therapeutic usage of exosomes in the HCC microenvironment and attempt to provide a theoretical reference for modern antitumor agents designed to target these mechanisms.