tbuckley/cabot-search huggingface dataset:
Correlation between immune-related adverse events and outcomes in nivolumab/ipilimumab combination therapy for metastatic melanoma.
Authors: Daan Rauwerdink, Dennie T. Frederick, Tatyana Sharova, Genevieve Marie Boland
Journal: Journal of Clinical Oncology (2020)

58 Background: Systemic immune checkpoint blockade therapy anti-PD1 nivolumab combined with anti-CTLA-4 ipilimumab is an effective therapy for metastatic melanoma. The treatment, however, has a high frequency of immune related adverse events. Interestingly, immune-related adverse events in anti-PD1 and anti-CTLA4 monotherapy have been associated with an improved overall survival in melanoma. Whether immune-related events correlate with enhanced outcomes in ipilimumab/nivolumab combination therapy is unknown. Methods: Clinical data from patients diagnosed with untreated cutaneous stage IV melanoma receiving ipilimumab/nivolumab combination therapy between 2015-2018 at the Massachusetts General Hospital (MGH) and have been analyzed retrospectively. Tumor response was measured using RECIST criteria. Primary endpoints were frequencies and characteristics of immune-related adverse events, overall survival, and response to therapy. Results: A total of 57 patients received ipilimumab/nivolumab combination therapy. During a mean follow-up period of 26 months, 28 (49%) patients completed the therapy. Immune-related adverse events were observed in 45 (79%) patients, with rash (28%), colitis (23), hepatitis (21%) and fever (21%) being the most frequent. Overall survival was 29 months in patients with immune-adverse related events and 14 months in the group without any adverse events (p-value &lt; 0.01). The onset of hypophysitis correlated with tumor response (p = 0.02) and hepatitis showed a trend in a correlation to response of therapy (p = 0.06). Conclusions: Our study demonstrates the association between improved overall survival and the onset of immune-related adverse events in ipilimumab/nivolumab combination therapy. A trend correlated with improved outcomes and onset of immune-related adverse events was seen in hepatitis and was significantly associated with hypophysitis, however these results must be interpretated carefully as larger studies must confirm our findings. Despite small study size, we are the first to describe an association between immune-related adverse events in ipilimumab/nivolumab combination therapy.
Post hoc safety and effectiveness analysis of aflibercept + FOLFIRI for patients with metastatic colorectal cancer (mCRC) previously treated with antiepidermal growth factor receptor (EGFR) therapy in OZONE.
Authors: Thomas H. Cartwright, Marwan Fakih, Pilar Garcia-Alfonso, Zdenĕk Linke, Ana Ruíz Casado, Eduardo Polo Marques, Pascaline Picard, Marina Celanovic, Arvind Rup Singh, Taylor Salinardi, Ian Chau
Journal: Journal of Clinical Oncology (2020)

212 Background: Anti-EGFR therapies are frequently given as first-line therapy for patients with mCRC, while anti-angiogenic therapies may be suitable at any line. Despite improving outcomes for patients with mCRC, there is still an unmet need regarding the optimal treatment sequence. In this post hoc analysis, the safety and effectiveness of aflibercept + FOLFIRI was evaluated for patients with mCRC based on their prior anti-EGFR therapy use. Methods: OZONE is a prospective, multicenter, observational, non-comparative study evaluating patients receiving aflibercept + FOLFIRI in the clinical setting, for 24 months from aflibercept initiation or until death. Patients were retrospectively assessed according to prior use of anti-EGFR therapy (defined as patients who received cetuximab and/or panitumumab as previous anti-cancer therapy). Overall survival (OS) and progression-free survival (PFS) were analyzed by hazard ratios (HR) and 95% confidence intervals (CI); overall response rate (ORR) was analyzed by odds ratios (OR) and 95% CI. Results: Among the overall treated population (N = 766), 19.2% (n = 147) received prior anti-EGFR therapy. Prior anti-EGFR therapy had no significant impact on the median OS (11.47 vs 12.58 months; HR [95% CI] 1.112 [0.889–1.390]), median PFS (5.29 vs 6.24 months; HR [95% CI] 1.022 [0.830–1.260]), or ORR (14.96% vs 18.75%; OR [95% CI] 0.597 [0.332–1.071]) of patients vs those who did not receive prior anti-EGFR therapy. Rates of grade ≥ 3 treatment-emergent adverse events (TEAEs) were similar between patients who did vs did not receive prior anti-EGFR therapy (70.7% vs 67.7%). The most frequently reported grade ≥ 3 TEAEs for patients who did vs did not receive prior anti-EGFR therapy were neutropenia (12.2% vs 15.0%), hypertension (8.8% vs 10.3%), and diarrhea (10.2% vs 9.4%). Conclusions: This post hoc analysis of the OZONE study did not reveal major differences in safety and effectiveness according to prior anti-EGFR therapy. Clinical trial information: ENCEPP/SDPP/4836.
The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling
Authors: Samuel A. Stoner, Katherine Tin Heng Liu, Elizabeth T. Andrews, Mengdan Liu, Kei-Ichiro Arimoto, Ming Yan, Amanda G. Davis, Stephanie Weng, Michelle Dow, Su Xian, Russell C. DeKelver, Hannah Carter, Dong-Er Zhang
Journal: Blood Cancer Journal (2020)

Abstract Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 ( RASSF2 ) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.
A phase II study evaluating safety and efficacy of niraparib in patients with previously treated homologous recombination (HR) defective or loss of heterozygosity (LOH) high-metastatic esophageal/GEJ/proximal gastric adenocarcinoma: A Big Ten Cancer Research Consortium study.
Authors: Hirva Mamdani, Rutika Mehta, Christos Fountzilas, Milan Radovich, Susan Perkins, Shadia Ibrahim Jalal
Journal: Journal of Clinical Oncology (2020)

TPS472 Background: Adenocarcinoma of esophagus (EAC) and GEJ is the fastest rising cancer in the US. The outcomes are extremely poor with median overall survival (OS) being 12 mo in patients (pts) with metastatic disease. The standard first line treatment for metastatic EAC is platinum-based regimen with median progression free survival (PFS) of 6 mo. Second line options are associated with limited efficacy. An analysis of TCGA has shown 40% of EAC harboring abnormalities in HR genes, most likely resulting from chronic acid reflux induced DNA damage. HR dysregulation is commonly associated with high LOH. Sensitivity to PARP inhibition has been shown to be a surrogate for HR defects or BRCAness phenotype. Clinically PARP inhibitors have shown activity in HR defective prostate and ovarian cancers. These findings provide the basis for this study. Methods: Pts with metastatic esophageal/GEJ/proximal gastric adenocarcinoma, previously treated with 1 line of platinum containing chemotherapy, and harboring high LOH and/or deleterious alteration(s) in HR genes ( BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A, GEN1) are eligible for this study. Pts can be prescreened at the time of diagnosis of locally advanced or metastatic disease by genomic analysis of the most recent available tumor tissue. Pts will receive oral niraparib until disease progression or unacceptable toxicity. Primary objective is response rate (RR). Secondary objectives are safety and tolerability, progression free survival (PFS), and disease control rate (DCR). Exploratory objectives include correlation between high LOH and response to niraparib, mechanisms of resistance to PARP inhibition, EZH2 expression and its correlation with response and resistance to PARP inhibition, and analysis of germline HR gene mutations and correlation with response to niraparib. Estimated sample size is 43. The study has recently opened to accrual at Indiana University with intended collaboration with 2 additional sites. Clinical trial information: NCT03840967.
Thermoresponsive Inverted Colloidal Crystal Hydrogel Scaffolds for Lymphoid Tissue Engineering
Authors: Jun‐Goo Kwak, Jungwoo Lee
Journal: Advanced Healthcare Materials (2020)

Inverted colloidal crystal (ICC) hydrogel scaffolds represent unique opportunities in modeling lymphoid tissues and expanding hematopoietic-lymphoid cells. Fully interconnected spherical pore arrays direct the formation of stromal networks and facilitate interactions between stroma and hematopoietic-lymphoid cells. However, due to the intricate architecture of these materials, release of expanded cells is restricted and requires mechanical disruption or chemical dissolution of the hydrogel scaffold. One potent biomaterials strategy to release pore-entrapped hematopoietic-lymphoid cells without breaking the scaffolds apart is to transiently increase the dimensions of these materials using stimuli-responsive polymers. Having this mindset, thermoresponsive ICC scaffolds that undergo rapid (<1 min) and substantial (>300%) diameter change over a physiological temperature range (4-37 °C) by using poly(N-isopropylacrylamide) (PNIPAM) with nanogel crosslinkers is developed. For a proof-of-concept study, the stromal niche by creating osteospheroids, aggregates of osteoblasts, and bone chips is first replicated, and subsequently Nalm-6 model hematopoietic-lymphoid cells are introduced. A sixfold increase in cell count is harvested when ICC hydrogel scaffolds are expanded without termination of the established 3D stromal cell culture. It is envisioned that thermoresponsive ICC hydrogel scaffolds will enable for scalable and sustainable ex vivo expansion of hematopoietic-lymphoid cells.
Effectiveness of airport screening at detecting travellers infected with novel coronavirus (2019-nCoV)
Authors: Billy J Quilty, Sam Clifford, Stefan Flasche, Rosalind M Eggo
Journal: Eurosurveillance (2020)

We evaluated effectiveness of thermal passenger screening for 2019-nCoV infection at airport exit and entry to inform public health decision-making. In our baseline scenario, we estimated that 46% (95% confidence interval: 36 to 58) of infected travellers would not be detected, depending on incubation period, sensitivity of exit and entry screening, and proportion of asymptomatic cases. Airport screening is unlikely to detect a sufficient proportion of 2019-nCoV infected travellers to avoid entry of infected travellers.
Capecitabine and cisplatin as a second-line chemotherapy for patients with advanced biliary tract cancer.
Authors: Kabsoo Shin, In Seok Lee, Tae Ho Hong, Joori Kim, Myung Ah Lee
Journal: Journal of Clinical Oncology (2020)

543 Background: Few data are available on second-line chemotherapy for patients with advanced biliary tract cancer. We retrospectively analyzed the efficacy and safety of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer. Methods: Between Mar, 2014 and Dec, 2018, advanced BTC patients who received second-line capecitabine and cisplatin after the failure of the gemcitabine-platinum combination were analyzed. Progression‐free survival (PFS) and overall survival (OS) were estimated with the Kaplan‐Meier method. Cox models were used for multivariate analyses. Results: Of total 40 patients, male: female was 24(60%) to 16(40%), and the median age was 68 years old (range: 45-77) . As primary tumor site, 8(20%) was intrahepatic, 16(40%) was extrahepatic and 16(40%) was gallbladder. Initially metastatic disease was 22(55%), and recurrent disease after curative surgery was 17(42.5%) and locally advanced unresectable disease was 1(2.5%). 30(75%) patients had ECOG performance status of 0-1. The mean number of the chemotherapy cycles was 3.3 ± 2.0. Objective response rates and stable disease were 12.5% and 25%, respectively. Median PFS and median OS from the beginning of the capcitabine and cisplatin combination were 2.8 and 7.0 months, respectively. Grade 3-4 adverse event were neutropenia (n = 7, 17.5%), anemia(n = 3, 7.5%), hand-foot syndrome (n = 3, 7.5%), nausea and vomiting(n = 2, 5%), peripheral neuropathy (n = 2, 5%) and mucositis(n = 1, 2.5%). And there was no treatment related death. Conclusions: This study showed the possible survival benefit of capecitabine and cisplatin combination as second-line chemotherapy for advanced biliary tract cancer.
Abstract 11020: Legacy Effects of Baseline Blood Pressure ‘Treatment Naivety’ on All-cause and Cardiovascular Mortality in the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Authors: Chau Ho, Monique Bresliln, Enayet Chowdhury, Jenny Doust, Christopher M Reid, Barry R Davis, Lara M Simpson, Mark R Nelson
Journal: Circulation (2019)

Introduction: Contemporary guidelines for the primary prevention of cardiovascular disease (CVD) are predominantly based on absolute CVD risk stratification for drug treatment decision making. Indi...
Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion<i>BRCA</i>Mutations among Patients with Advanced Solid Tumors
Authors: Neelima Vidula, Thereasa A. Rich, Oliver Sartor, Jennifer Yen, Aaron Hardin, Tracy Nance, Michael B. Lilly, Mohammad Amin Nezami, Sandip P. Patel, Benedito A. Carneiro, Alice C. Fan, Adam M. Brufsky, Barbara A. Parker, Benjamin B. Bridges, Neeraj Agarwal, Benjamin L. Maughan, Victoria M. Raymond, Stephen R. Fairclough, Richard B. Lanman, Aditya Bardia, Massimo Cristofanilli
Journal: Clinical Cancer Research (2020)

Abstract Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations. Experimental Design: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion–deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy. Results: Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy. Conclusions: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.
Authors: Ganapathy Sriram, Lauren Milling, Jung-Kuei Chen, Wuhbet Abraham, Darrell J. Irvine, Michael B. Yaffe
Journal: Journal of Clinical Oncology (2020)

77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-K b /SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-K b /SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.
左右冠動脈左室ろうの一例 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: 別府徹也, 土肥薫, 倉地英志, 仲田智之, 石倉健, 玉田浩也, 北村哲也, 沖中務, 中野たけし
Journal: Circulation (2002)
Cruel to Be Kind: Epithelial, Microbial, and Immune Cell Interactions in Gastrointestinal Cancers
Authors: Shabnam Shalapour, Michael Karin
Journal: Annual Review of Immunology (2020)

A plethora of experimental and epidemiological evidence supports a critical role for inflammation and adaptive immunity in the onset of cancer and in shaping its response to therapy. These data are particularly robust for gastrointestinal (GI) cancers, such as those affecting the GI tract, liver, and pancreas, on which this review is focused. We propose a unifying hypothesis according to which intestinal barrier disruption is the origin of tumor-promoting inflammation that acts in conjunction with tissue-specific cancer-initiating mutations. The gut microbiota and its products impact tissue-resident and recruited myeloid cells that promote tumorigenesis through secretion of growth- and survival-promoting cytokines that act on epithelial cells, as well as fibrogenic and immunosuppressive cytokines that interfere with the proper function of adaptive antitumor immunity. Understanding these relationships should improve our ability to prevent cancer development and stimulate the immune system to eliminate existing malignancies.
Risk factors for cancer-associated thrombosis in advanced cancer patients with chemotherapy or palliative treatment (retrospective study).
Authors: Koki Uehara, Kenta Nio, Haruo Iguchi
Journal: Journal of Clinical Oncology (2020)

819 Background:Cancer-associated thrombosis (CAT) represents the second-leading cause of death in cancer patients and venous thromboembolism (VTE) occurs in about 20% of hospitalized cancer patients. CAT is important for safety cancer treatment.However, the risk factors for CAT in Japanese cancer patients have not been well studied. Methods: We retrospectively examined cases that had received chemotherapy or palliative treatment from April 2017 to February 2018 in our hospital using medical records. Results: Fifty-five cases with 37-94 years (23 males and 32 females) were examined. Primary sites of cancers were as below; pancreatic: n = 14 (25%), colorectal: n = 12 (22%), gastric: n = 7 (13%), breast: n = 4 (7%), lung: n = 3 (5%), esophageal: n = 3 (5%), head and neck: n = 3 (5%), and others: n = 9 (16%).Forty-two patients (76%) were received chemotherapy, and 12 (22%) of them were diagnosed with CAT at the beginning or during the course of chemotherapy (CAT group). The sites of CAT were as follows; lower extremity type venous thrombosis: n = 10, cerebral infarction: n = 3, pulmonary artery thromboembolism: n = 1, portal vein thrombosis: n = 1, subclavian vein thrombosis: n = 1, and others: n = 2. In 12 patients with CAT, primary sites of cancers were as below; pancreatic: n = 6 (45%), gastric cancer: n = 3 (27%), colorectal, esophageal and ovarian cancer: n = 1 (9%), and 8 patients (67%) received anticoagulant therapy, including 7 patients treated with DOACs. 3 patients (38%) discontinued anticoagulant therapy because of gastrointestinal bleeding and 2 patients (25%) had recurrence of VTE during anticoagulant therapy. Overall survival (OS) tended to be shorter in CAT groups than non-CAT group (median OS: 118 days vs 190 days; p = 0.158). Conclusions: As reported in Western countries, the incidence of CAT was about 20%, and higher in Japanese pancreatic and gastric cancer patients. As shorter overall survival in CAT group might be responsible for development of thromboembolism, thromboembolism prophylaxis for high-risk Japanese patients may be recommended. Additionally, the present study showed that recurrence rate of CAT was higher than that of previous clinical trials.