tbuckley/cabot-search huggingface dataset:
Circulating calprotectin, innate inflammatory protein, was decreased under disease control during first-line chemotherapy for advanced pancreatic cancer.
Authors: Taro Shibuki, Shuichi Mitsunaga, Motoyasu Kan, Gen Kimura, Kumiko Umemoto, Kazuo Watanabe, Mitsuhito Sasaki, Hideaki Takahashi, Yusuke Hashimoto, Hiroshi Imaoka, Izumi Ohno, Masafumi Ikeda
Journal: Journal of Clinical Oncology (2019)

218 Background: There is increasing evidence of a close link between inflammation and disease control in pancreatic ductal adenocarcinoma (PDAC). Damaged-associated molecular patterns (DAMPs) were inducers of inflammation in the innate immune system and were detected in PDAC tissue in recent reports. Calprotectin, one of DAMPs, is recognized as a potential mediator of the process of disease control in various tumors. In this study, circulating calprotectin is characterized on disease control in patients with 1 st line chemotherapy for advanced PDAC. Methods: Patients with treatment-naïve advanced PDAC were enrolled in this study. Patients with obvious infectious conditions were excluded. Serum levels of calprotectin and pro-inflammatory cytokines including interleukin-6 (IL-6) were measured at baseline and at one or two months later after the start of 1 st line chemotherapy. Disease control rate (DCR) was evaluated on the Response Evaluation Criteria in Solid Tumors ver. 1.1. Results: A total of 73 patients were evaluated. DCRs of gemcitabine group (GEM) (n = 57) and the patients with modified FOLFIRINOX or GEM + nab-paclitaxel (mFFX/GN) (n = 16) were 52.6% and 75.0%,respectively. In comparison of baseline-and-after data, circulating calprotectin levels were significantly decreased under disease control in GEM (baseline vs. after: 2.9 vs. 2.3 ng/ml in median, p = 0.084) and GN/mFFX (2.7 vs. 0.5 ng/ml, p = 0.024. IL-6 was decreased in GN/mFFX (9.1 vs. 5.9 pg/ml; p= 0.095) but not in GEM (4.3 vs. 3.1 pg/ml; p = 0.303). There were no obvious changes under non-disease control in calprotectin (baseline vs. after: 6.2 vs. 5.9 ng/ml in GEM, 5.1 vs. 4.5 ng/ml in mFFX/GN) and IL-6 (16.5 vs. 25.6 pg/ml in GEM, 3.1 vs. 4.7 pg/ml in mFFX/GN). Conclusions: DCR relateda decrease of circulating calprotectin levelduring 1 st line chemotherapy for advanced PDAC. Innate immune system plays a role in the chemotherapeutic efficacy in advanced PDAC.
Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy
Authors: Julia A. Brown, Gursewak Singh, Joshua A. Acklin, Silviana Lee, James E. Duehr, Anupa N. Chokola, Justin J. Frere, Kevin W. Hoffman, Gregory A. Foster, David Krysztof, Richard Cadagan, Adam R. Jacobs, Susan L. Stramer, Florian Krammer, Adolfo García-Sastre, Jean K. Lim
Journal: Immunity (2019)
In Newly Diagnosed Multiple Myeloma Patients, Longer Procoagulant Phospholipid-Dependent Clotting Time, Higher Levels of P-Selectin, D-Dimers and Thrombin Generation Peak Are Associated with Increased Risk of Resistance to Treatment: Results of the Prospective Roadmap-MM Study
Authors: Grigorios T. Gerotziafas, Despina Fotiou, Patrick Van Dreden, Theodoros N Sergentanis, Ismail Elalamy, Loula Papageorgiou, Matthieu Grusse, Stella Salta, Theodora Psaltopoulou, Annette Larsen, Evangelos Terpos, Meletios A Dimopoulos
Journal: Blood (2018)
Alpha fetoprotein (AFP) response and efficacy outcomes in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC).
Authors: Robin Kate Kelley, Lorenza Rimassa, Baek-Yeol Ryoo, Joong-Won Park, Jean-Frédéric Blanc, Stephen Lam Chan, Vincenzo Dadduzio, Thomas Cheung Yau, Suvajit Sen, David W. Markby, Rajesh Kaldate, Anthony B. El-Khoueiry, Ann-Lii Cheng, Tim Meyer, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2019)

423 Background: AFP response, defined as a decrease in serum levels of the tumor marker AFP after therapy, may be associated with improved survival of patients (pts) with HCC treated with locoregional or systemic therapy, and high baseline AFP levels may be associated with poor prognosis. In the phase III CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus P in pts with previously treated advanced HCC. Here we evaluate clinical outcomes with C in CELESTIAL based on AFP response or progression on treatment. Methods: 707 pts were randomized 2:1 to receive C (60 mg daily) or P. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤ 1. Pts received prior sorafenib and ≤ 2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for pts with baseline AFP ≥ 20 ng/mL based on AFP response ( ≥ 20% decrease from baseline) or progression ( ≥ 20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies. Results: Overall, 331 pts (70%) in the C arm and 160 (68%) in the P arm had baseline AFP ≥ 20 ng/mL; among these pts, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at week 8. Among evaluable pts, 117 pts (50%) in the C arm vs 14 (13%) in the P arm had an AFP response, and 72 (31%) vs 75 (68%) had AFP progression. Median OS with C was 16.1 mo for pts with an AFP response versus 9.1 mo for pts without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with C was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For pts with AFP progression, median OS with C was 8.1 mo, and median PFS with C was 3.6 mo. Hazard ratios for OS and PFS with C also favored AFP responders over non-responders when analyzed using best response through week 24. Conclusions: The AFP response rate was higher with C versus P, and AFP response was associated with longer OS and PFS with C for pts with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response. Clinical trial information: NCT01908426.
A Randomized Controlled Trial on the Safety and Efficacy of Exenatide Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes
Authors: Maya Fayfman, Rodolfo J. Galindo, Daniel J. Rubin, Dara L. Mize, Isabel Anzola, Maria A. Urrutia, Clementina Ramos, Francisco J. Pasquel, J. Sonya Haw, Priyathama Vellanki, Heqiong Wang, Bonnie S. Albury, Rita Weaver, Saumeth Cardona, Guillermo E. Umpierrez
Journal: Diabetes Care (2019)

This multicenter, open-label, randomized trial examined the safety and efficacy of exenatide alone or in combination with basal insulin in non-critically ill patients with type 2 diabetes (T2D).
Validation of cost-effectiveness of trifluridine/tipiracil versus best supportive care and regorafenib for previously treated metastatic colorectal cancer in the UK using phase IIIb PRECONNECT early access clinical trial data in the real world setting.
Authors: Javier Sabater, Lewis Ralph, Rachael Batteson, Grant McCarthy, Jaro Wex, Shanti Ricardo Moreno Vera, Martin Becquart, Nadjat Mounedji, Julien Taieb, Marc Peeters, Alfredo Falcone
Journal: Journal of Clinical Oncology (2019)

639 Background: Trifluridine/tipiracil (FTD/TPI) is indicated and recommended for the treatment of previously treated metastatic colorectal cancer (mCRC). Previous evaluations used pooled clinical evidence from the Phase III (RECOURSE) and Phase II trials to model cost-effectiveness, but FTD/TPI specific utilities were not available and alternative data sources were used. The aim of this study was to utilize EQ-5D data from an ongoing Phase IIIb trial (PRECONNECT) within an updated cost-effectiveness model to validate health-related quality of life (HRQoL) outcomes for mCRC patients receiving FTD/TPI. Methods: EQ-5D-3L data from PRECONNECT trial were analyzed with UK utility tariff applied. Pre- and post-progression health state utilities were estimated using a linear mixed effects regression model. Indirect comparison versus regorafenib was based on evidence from the CORRECT trial. Utilities and UK costs (GBP, 2018) were then implemented into the existing economic model. Results: Mean pre-progression and post-progression utilities were 0.72 and 0.59, respectively, with discounted incremental quality adjusted life years gain of 2.1 months versus best supportive care (BSC) and 0.8 versus regorafenib. Use of FTD/TPI based on PRECONNECT data, as in the previous analysis, was associated with improved mean survival pre-progression (by 1.8 months) and post-progression (by 1.4 months) for the total OS gain of 3.2 months versus BSC. The mean OS gain versus regorafenib was 1.4 months. Updated cost-effectiveness analysis using PRECONNECT derived inputs showed that results remained broadly unchanged with a negligible increase in ICER from £51,589 to £51,792 (£51,101 in the probabilistic sensitivity analysis) when compared to BSC, while FTD/TPI remained dominant (more effective and less costly) versus regorafenib. Conclusions: New HRQoL data from the PRECONNECT study collected in a real-world setting validated previous HRQoL inputs used to model cost-effectiveness of FTD/TPI in previously treated metastatic colorectal cancer. Clinical trial information: NCT03306394.
An updated retrospective review of the safety and efficacy of sorafenib for recurrent hepatocellular carcinoma post-liver transplantation.
Authors: Sophie Feng, Nazanin Fallah-Rad, Yanshuo Cao, Jennifer J. Knox, Raymond Woo-Jun Jang, Neesha C. Dhani, Gonzalo Sapisochin, David Grant, Paul D Greig, Leslie Lilly, Andre Gorgen, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2019)

313 Background: Orthotopic liver transplantation (OLT) is a potentially curative treatment for hepatocellular carcinoma (HCC). Despite an estimated recurrence rate between 15%-20%, there is currently no proven systemic therapy for the treatment of HCC relapse post OLT. Sorafenib has been a standard therapy for advanced HCC however data is lacking for the safety and efficacy of sorafenib in the setting of concurrent immunosuppressive agents. Methods: A retrospective review was performed of patients who received sorafenib for HCC relapse after OLT. Data on patient characteristics, treatment toxicity and efficacy was collected. The primary objectives were to evaluate toxicity and safety of sorafenib when used in combination with immunosuppressive therapies such as calcineurin and mTOR inhibitors. Secondary objectives were objective response rate, progression free survival (PFS), and time on therapy. Results: 35 patients over the last 11 years received sorafenib for HCC recurrence following OLT. 54.3% of patients received concurrent immunosuppression with tacrolimus. Toxicity from sorafenib was as expected, with no cases of acute or chronic organ rejection whilst on treatment. The median maximum tolerated dose was 400 mg a day with 40% of patients requiring dose reductions. The incidence of any adverse events (AEs) was 88.6%, with 17.1% having Grade 3-4 toxicity. Incidence of Grade 3-4 liver dysfunction was higher than historical studies at 6%. The overall response rate was 2.8% with a median PFS of 2.8 months. Median time on sorafenib was 3.1 months. Conclusions: There is a paucity of evidence guiding treatment of HCC recurrence following OLT. This retrospective review is one of the largest in the literature and shows that sorafenib used concurrently with immunosuppressive therapy for organ transplant is safe, with no precipitation of acute or chronic rejection, although liver function should be monitored closely. The median PFS in our cohort was shorter than expected. The efficacy of other agents should be explored in this population.[Table: see text]
Help, hinder, hide and harm: what can we learn from the interactions between <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> during respiratory infections?
Authors: Dominique Hope Limoli, Lucas R Hoffman
Journal: Thorax (2019)

Recent studies of human respiratory secretions using culture-independent techniques have found a surprisingly diverse array of microbes. Interactions among these community members can profoundly impact microbial survival, persistence and antibiotic susceptibility and, consequently, disease progression. Studies of polymicrobial interactions in the human microbiota have shown that the taxonomic and structural compositions, and resulting behaviours, of microbial communities differ substantially from those of the individual constituent species and in ways of clinical importance. These studies primarily involved oral and gastrointestinal microbiomes. While the field of polymicrobial respiratory disease is relatively young, early findings suggest that respiratory tract microbiota members also compete and cooperate in ways that may influence disease outcomes. Ongoing efforts therefore focus on how these findings can inform more ‘enlightened’, rational approaches to combat respiratory infections. Among the most common respiratory diseases involving polymicrobial infections are cystic fibrosis (CF), non-CF bronchiectasis, COPD and ventilator-associated pneumonia. While respiratory microbiota can be diverse, two of the most common and best-studied members are Staphylococcus aureus and Pseudomonas aeruginosa , which exhibit a range of competitive and cooperative interactions. Here, we review the state of research on pulmonary coinfection with these pathogens, including their prevalence, combined and independent associations with patient outcomes, and mechanisms of those interactions that could influence lung health. Because P. aeruginosa–S. aureus coinfection is common and well studied in CF, this disease serves as the paradigm for our discussions on these two organisms and inform our recommendations for future studies of polymicrobial interactions in pulmonary disease.
Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone Vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Ivan Spicka, Enrique M. Ocio, Heather E. Oakervee, Richard Greil, Raymond H. Banh, Laurence Catley, Shang-Yi Huang, James M. D'Rozario, Meletios A. Dimopoulos, José Rodríguez, Sara Martinez, Sonia Extremera, Vicente Alfaro, Angelo Michele Carella, Nathalie Meuleman, Roman Hájek, Argiris Symeonidis, Chang-Ki Min, Paul Cannell, Heinz Ludwig, Pieter Sonneveld, Maria V. Mateos
Journal: Blood (2017)
Regulation of pyruvate dehydrogenase kinase 4 (PDK4) and its role in apoptosis
Authors: Patricia Ntlabati, Zodwa Dlamini, Lungile Shoba-Zikhali
Journal: Cancer Research (2008)

LB-40  Pyruvate dehydrogenase kinase 4 (PDK4), a mammalian mitochondrial serine kinase has emerged as an interesting candidate cancer therapy. The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activity of dedicated PDK isoenzyme or isoform such as PDK4. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate. Understanding the regulation of PDK4 would therefore contribute significantly to the development of therapeutic agents related to cancer. This research outlines the bioinformatics analysis of PDK4, using tools such as Interweaver, ClustalW and Protein Structure Visualiser. These programs were used to determine potentially interacting partners for PDK4. Interweaver database identified 96 proteins which have possible interaction sites for PDK4. Protein p100/p49, containing a death domain that is known to have a role in suppressing apoptosis, was identified as a potential partner for PDK4. The alignment between p100/p49 primary sequence and that of PDK4 using Gene explorer/CalstalW demonstrated sequence similarity between the two proteins. Swiss PDB Viewer then located the positions of the amino acids that are in the hypothetical protein binding motif of p100/p49 within the 3D structure of hPDK4. These amino acids were found to be located in the region of PDK4 which is known to bind protein substrates of PDK4 and may be accessible to other proteins as well. These findings were very interesting as PDK4 have not previously been associated with apoptosis and this could be the link between apoptosis and cancer  Cell biology studies were then performed to verify the relationship between PDK4 and apoptosis. In this regard, HeLa and HepG2 cells were treated with apoptosis inducing agents such as TNFα, C2-Ceramide, and Linoleic acid. These cells were then monitored for apoptosis and PDK4 mRNA expression using a DNA laddering assay as well as Real Time PCR. The results showed that these factors induce apoptosis in a concentration dependent manner. This induction of apoptosis by these three factors indicated to suppress PDK4 mRNA levels. These findings suggested a regulatory role for PDK4 in apoptosis.
Synchronous brain metastasis and impact of primary tumor side in colorectal cancers.
Authors: Mahvish Muzaffar, Abdul Rafeh Naqash
Journal: Journal of Clinical Oncology (2019)

712 Background: 25% of patients with colorectal cancer(CRC) present with synchronous metastatic disease. The incidence of brain metastasis (BM) in CRC is very low (1.2–3.2%) and tend to occur later in the disease course. Synchronous BM(SBM) in CRC is very rare. We sought to explore the impact of primary tumor characteristics on SBM. Methods: Surveillance Epidemiology End Results Program (SEER) 18 registries research data on primary colorectal cancer cases diagnosed during 2010-2015 with brain metastasis at diagnosis were identified. Patients with unlabeled primary site and autopsy alone cases were excluded. Demographic and colorectal cancer characteristics including age, gender, race, tumor grade and primary tumor side were analyzed. Logistic regression model was used to test the association between survival and side of cancer. Results: A total of 475 cases met the inclusion criteria. The mean age was 64.04 yrs. (range 28-95). Majority of the patients (80%) were white, 12% black and others (8%), Male: Female ratio was 1:1.58% patients had primary tumor on left side (splenic flexure, sigmoid, rectosigmoid and rectal) and 42% had right sided (ascending colon, hepatic flexure, cecum, transverse colon) primary tumor. The median overall survival was 5 months with 1-year survival of 26% in the whole cohort. The 1-year overall survival was 21% for patients with right sided primary tumor versus 30% for patients with SBM and left sided primary tumor(p = 0.03). The median disease specific survival was 5 months for right side and 7 months for Left sided tumor with SBM. The regression model showed that higher grade (RR 14, p = 0.003)) and right sided primary tumor (RR 4.2, p = 0.04) were associated with worse outcome among patients with SBM in colorectal cancer. Conclusions: Synchronous brain metastasis is very rare in colorectal cancer. Tumor side seems to be prognostic even in this aggressive disease subset. This differential outcome further indicates that sidedness should be considered in goals of care and treatment discussion.
C3-01: Phase I Trial of Erlotinib-based Multimodality Therapy for Inoperable Stage III Non-small Cell Lung Cancer
Authors: Nicholas W. Choong, Ann M. Mauer, Eric Lester, Philip C. Hoffman, Daniel Haraf, Mark Kozloff, Livia Szeto, Everett E. Vokes
Journal: Journal of Thoracic Oncology (2007)
DNA damage response pathway mutations contribute to a high proportion of hereditary colorectal cancer in patients from the Republic of Macedonia.
Authors: Marija Staninova, Nadica Matevska Geshkovska, Biljana Angelovska, Mitrevski Nenad, Milco Panovski, Aleksandar J Dimovski
Journal: Journal of Clinical Oncology (2019)

512 Background: Hereditary factors are assumed to play а role in 35-45% of all colorectal cancers with 5%-10% associated with high penetrant disease-causing mutations in genes correlating to hereditary polyposis (HP) or hereditary nonpolyposis syndromes (HNPCC). Although inherited germline mismatch repair and APC gene mutations contribute significantly to CRC, still a genetic diagnosis cannot be obtained in &gt; 50% of familial cases. Methods: We performed a targeted NGS sequencing of 103 probands with clinically diagnosed HP (39) or HNPCC (64) using a multigene panel on two different platforms (Illumina Cancer Panel and Ion Torrent custom panel) covering coding and exon/intron sequences of 100 genes implicated in hereditary cancers. Results: Overall, the molecular defect was identified in 60 (58%) index patients. As expected, a large percentage (82%) of these patients exhibited the presence of clearly pathogenic mutations in well-known genes associated with hCRC (APC, MUTYH, BMPR1A, NTHL1 in HP, MLH1, MSH2, PMS6, MSH6 in HNPCC). Surprisingly, all except one (FLCN c.1285dupC, detected in a family with classical FAP), of the remaining mutations were located in genes involved in the DNA damage response pathway, of which 3 in CHEK2 (c.1031delT; c.1229delC; c.599T&gt;G), 2 in BRIP1 (c.2392C&gt;T) and 1 in each of BLM (c.1642C&gt;T), BRCA2 (c.4446_4451dupAACAGA), FANCM (c.2953delG), FH (c.1431_1433dupAAA) and ERCC2 (c.1403C&gt;T). Clinically, six of these cases exhibited the HNPCC type X phenotype (mutations in BRCA2, BRIP1, FANCM and CHEK2) while the other four were classified as oligopolyposis (mutations in BLM, FH and CHEK2). Conclusions: Our data indicate a significant association of DNA damage response pathway deficiencies and carcinogenesis in patients with hCRC syndromes exhibiting either the HNPCC type X or oligopolyposis phenotype. No genetic defect was detected within the analyzed gene panel in 44 (42%) families, indicating the need of extended exome/whole genome analyses in a substantial portion of patients with this disease.
The role of <i>Parvimonas micra</i> in intestinal tumorigenesis in germ-free and conventional APC<sup>min/+</sup> mice.
Authors: Jun Yu, Liuyang Zhao, Risheng Zhao, Xiaohang Long, Olabisi Oluwabukola Coker, Joseph J.Y. Sung
Journal: Journal of Clinical Oncology (2019)

531 Background: Our in-house meta-analysis of fecal shotgun metagenomic sequences from colorectal cancer (CRC) and control subjects from four cohorts of various ethnicities identified a higher abundance of Parvimonas micra in CRC. We aimed to investigate the effect of P. micra in colon tumor formation and development. Methods: We collected 309 fecal samples and 259 colon biopsies from patients with CRC, advanced adenoma and healthy subjects. P. micra strain was isolated from the feces of a CRC patient. APC min/+ mice and germ-free (GF) mice were orally gavaged with P. micra, or Esherichia coli. Colon epithelial cell line NCM460 and cancer cell lines HT-29 and Caco-2 were exposed to P. micra or E. coli conditional medium. Results: P. micra was significantly enriched both in the feces (n = 207, p &lt; 0.01) and tissue biopsies (n = 99, p &lt; 0.01) of CRC patients compared with controls (n = 102 for fecal samples, n = 160 for tissues biopsies). APC min/+ mice gavaged with P. micra exibited significantly higher tumor burden ( p &lt; 0.01) and tumor load ( p &lt; 0.01), compared to mice gavaged with either E. coli or non-bacterial control. Consistently, cell proliferation was significantly higher in the colon tissues of P. micra gavaged GF mice relative to control mice evidenced by increased Ki-67 positive cells ( p &lt; 0.05) and PCNA protein expression ( p &lt; 0.01) at weeks 20 and 32. In line with this, colon cell lines NCM460, HT-29 and Caco-2 exposed to P. micra conditional medium significantly increased proliferation than control group (all p &lt; 0.05). Flow cytometry analyses showed that Th2 and Th17 cells were markedly increased, while Th1 were reduced in the lamina propria of the colon tissues of P. micra gavaged mice compared to control mice (all p &lt; 0.01) . Consistently, P. micra colonization in GF mice was associated with increased expression of pro-inflammatory cytokines, including TNF-α, IL-6 and IL-12 (all p &lt; 0.01). Conclusions: The abundance of P. micra was significantly increased in the feces and tissue biopsies of CRC patients. P. micra promotes intestinal carcinogenesis in APC min/+ mice and increase cell proliferation in GF mice. The tumor promoting effect of P. micra is associated with altered immune responses and enhanced inflammation in the gut.