tbuckley/cabot-search huggingface dataset:
Update result of HGCSG 1403: Phase I trial of oxaliplatin/irinotecan/S-1 (OX-IRIS) as first-line chemotherapy for unresectable pancreatic cancer.
Authors: Shintaro Nakano, Yasuyuki Kawamoto, Satoshi Yuki, Masataka Yagisawa, Kentaro Sawada, Tetsuhito Muranaka, Hiroshi Nakatsumi, Takuro Saiki, Atsushi Ishiguro, Kazuaki Harada, Yoshimitsu Kobayashi, Ichiro Iwanaga, Kazuteru Hatanaka, Yuh Sakata, Yoshito Komatsu
Journal: Journal of Clinical Oncology (2019)

359 Background: FOLFIRINOX has become one of the standard treatment for unresectable pancreatic cancer with distant metastasis. OX-IRIS is the combination therapy of oxaliplatin (L-OHP), irinotecan (IRI) and S-1. It is the useful treatment to dispense with a continuous infusion of 5FU by administering S-1 orally. For establishing OX-IRIS therapy as a new standard treatment, we planned this study for evaluating dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: This study was carried out as a multicenter phase I study. Chemotherapy-naïve patients with unresectable pancreatic cancer were included. L-OHP and IRI were administered on day 1 and 15, and S-1 was taken twice a day in day 1-14, and then 14 days were rest for 1 cycle. The primary endpoints were the frequency of DLT and estimating of MTD. Secondary endpoints were safety, response rate, progression-free survival (PFS) and overall survival (OS). Results: Between January 2016 and August 2017, 13 cases were enrolled. The patients’ backgrounds were median age 62; male /female, 9/4; the primary tumor sites head /body and tail, 8/5; ECOG PS 0/1, 7/6; UR-LA /UR-M, 4/9. Two of five enrolled in level 0 (L-OHP: 85 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. One of six in level -1 (L-OHP: 65 mg/m2, IRI: 100 mg/m2, S-1: 80 mg/m2) had DLT. At level 0, 100% of cases had anemia and fatigue, 80% anorexia, diarrhea, peripheral sensory neuropathy, 60% platelet count decrease. At level -1, 100% had anemia, 75% nausea and fatigue, 63% anorexia. Response rate was 10% and disease control rate was 70% in ten cases with evaluable lesion. Median PFS was 4.1 months (95%C.I.; 0.0-8.6 months). Median OS was 13.7 months (95%C.I.; 5.9-21.5 months). Conclusions: In this study, MTD was estimated to be level 0, and determined recommended dose is level -1 for the planned future study. We are going to evaluate efficacy and safety in a phase II study. (UMIN ID: 000017002) Clinical trial information: 000017002.
Setting targets for HIV/AIDS—What lessons can be learned from other disease control programmes?
Authors: Tazeem Bhatia, Jamie Enoch, Mishal Khan, Sophie Mathewson, David Heymann, Richard Hayes, Osman Dar
Journal: PLoS Medicine (2019)

In a Collection Review, Richard Hayes and colleagues discuss metrics for assessing progress in control of the HIV/AIDS epidemic in the context of prior disease control programmes.
The impact of primary tumor site on outcomes of treatment with etoposide and cisplatin in grade 3 gastroenteropancreatic neuroendocrine carcinoma.
Authors: Sang Eun Yoon, Jung Hoon Kim, Joon Young Hur, Su Jin Lee, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim, Won Ki Kang, Seung Tae Kim
Journal: Journal of Clinical Oncology (2019)

213 Background: Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a heterogeneous disease in terms of embryonic origin, aggressiveness, prognosis, and genomic profiling. Data regarding the efficacy of etoposide and cisplatin (EP) as a standard treatment of the primary tumor site in GEP-NEC are limited. Methods: We analyzed 64 patients with histopathologically confirmed metastatic GEP-NEC who received EP at Samsung Medical Center, Seoul, Korea, between January 2010 and January 2018. Based on primary tumor site, outcome of treatment with EP was evaluated. Results: Primary sites included 22 foregut-derived GEP-NECs (stomach, n = 6; duodenum, n = 4; pancreas, n = 12), 4 midgut-derived GEP-NECs, 5 hindgut-derived GEP-NECs of the rectum, 25 GEP-NECs originating from the hepatobiliary (HB) tract, and 12 GEP-NECs involving only intra-abdominal lymph nodes. No patient had a complete response (CR) and 17 had a partial response (PR), resulting in a 27.9% response rate (RR). When evaluating the efficacy of EP based on primary tumor site, the RR was most favorable in GEP-NECs involving only intra-abdominal lymph nodes, followed by GEP-NECs originating from foregut, midgut, HB, and hindgut. However, no statistically significant difference was observed for RR based on primary tumor site (p = 0.821). Similarly, no significant differences were found for progression-free survival (PFS) among patients with GEP-NECs arising from various primary tumor sites. Conclusions: Results from this study showed thatRR and PFS associated with EP treatment were not different based on the primary tumor site in patients with advanced or metastatic GEP-NEC.
GENETIC POLIMORPHISMS ASSOCIATED WITH A RISK TO SUFFER ASTHMA IN CHILDRENS OF CÓRDOBA – ARGENTINA
Authors: Marcela Rodriguez M, Maria Pereira, María J. Lauria, Ramón E. Pogonza, Marcela O. Miño, Telma E. Varela, Julio C. Orellana, Juan C. Muiño
Journal: Journal of Allergy and Clinical Immunology (2019)
The effect of hepatic stellate cells on hepatocellular carcinoma progression.
Authors: Shuichi Iwahashi, Mitsuo Shimada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yu Saito, Shinichiro Yamada, Feng Rui
Journal: Journal of Clinical Oncology (2019)

265 Background: The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Some manuscripts mentioned that activated HSCs predicted prognoses of hepatocellular carcinoma. The aim of this study is to investigate the effect of HSCs and the role of IL-6 / Stat3 pathway on HCC progression. Methods: HCC cells (Hep G2 and Huh 7) were co-cultured with HSC (LX2 and Li90). The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44), TGF-b and p-STAT3 of cancer cells were evaluated. Then the IL-6 neutralization was performed during HCC cells and HSCs co-culture. The viability and migration ability of cancer cells were detected. Also, the expression of epithelial–mesenchymal transition marker (E-cadherin), stem cell marker (EpCAM and CD44) and p-STAT3 of cancer cells were evaluated. Results: Co-culture with hepatic stellate cell increased cancer cell viability and migration ability. The expression of E-cadherin, EpCAM and CD44 of cancer cells also increased after co-culture with HSCs. The IL-6 expression and secretion of HSCs were elevated by cancer cell stimulation. The over-expressed IL-6 activated STAT3 of cancer cell showed as the level of phosphorylated STAT3 increased. Neutralized IL-6 during co-culture significantly decrease the viability and migration ability of cancer cells. Also, the expression of E-cadherin, EpCAM and CD44 of cancer cells decreased. Conclusions: HSCs might promote HCC progression through IL-6 / STAT3 pathway.
BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells
Authors: Cigdem Atay, Taekyoung Kwak, Sergio Lavilla-Alonso, Laxminarasimha Donthireddy, Allison Richards, Valerie Moberg, Shari Pilon-Thomas, Michael Schell, Jane L. Messina, Vito W. Rebecca, Min Xiao, Jiufeng Tan, Gao Zhang, Jeffrey S. Weber, Meenhard Herlyn, Amod A. Sarnaik, Dmitry I. Gabrilovich
Journal: Clinical Cancer Research (2019)

BRAF and MEK inhibitors (BRAFi and MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAFV600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study, we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T-cell therapy (ACT) in melanoma resistant to BRAFi.Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as patient-derived xenografts (PDX) derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT.Herein we report that in human melanoma cell lines, senstitive and resistant to BRAFi and in PDX from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient upregulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TILs. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TILs demonstrated a significant increase of M6PR expression on tumors during vemurafenib treatment.BRAF-targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.See related commentary by Goff and Rosenberg, p. 2682.
Targeting Oncoprotein Translation with Rocaglates in MYC-Driven Lymphoma
Authors: Xuan Zhang, Chengfeng Bi, Ting Lu, Ting Yue, Weiwei Zhang, Xiaoyan Zhang, Wang Cheng, Tian Tian, Matthew A. Lunning, Julie M. Vose, Jerry Pelletier, John A Porco, Jianguo Tao, Kai Fu
Journal: Blood (2018)
S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes
Authors: Pinyang Cheng, Erika A. Eksioglu, Xianghong Chen, Wendy Kandell, Thu Le Trinh, Ling Cen, Jin Qi, David A. Sallman, Yu Zhang, Nhan Tu, William A. Adams, Chunze Zhang, Jinhong Liu, John L. Cleveland, Alan F. List, Sheng Wei
Journal: Leukemia (2019)

Myelodysplastic syndromes (MDS) are characterized by dysplastic and ineffective hematopoiesis that can result from aberrant expansion and activation of myeloid-derived suppressor cells (MDSCs) within the bone marrow (BM) niche. MDSCs produce S100A9, which mediates premature death of hematopoietic stem and progenitor cells (HSPCs). The PD-1/PD-L1 immune checkpoint impairs immune responses by inducing T-cell exhaustion and apoptosis, but its role in MDS is uncharacterized. Here we report an increased expression of PD-1 on HSPCs and PD-L1 on MDSCs in MDS versus healthy donors, and that this checkpoint is also activated in S100A9 transgenic (S100A9Tg) mice, and by treatment of BM mononuclear cells (BM-MNC) with S100A9. Further, MDS BM-MNC treated with recombinant PD-L1 underwent cell death, suggesting that the PD-1/PD-L1 interaction contributes to HSPC death in MDS. In accordance with this notion, PD-1/PD-L1 blockade restores effective hematopoiesis and improves colony-forming capacity in BM-MNC from MDS patients. Similar findings were observed in aged S100A9Tg mice. Finally, we demonstrate that c-Myc is required for S100A9-induced upregulation of PD-1/PD-L1, and that treatment of MDS HSPCs with anti-PD-1 antibody suppresses the expression of Myc target genes and increases the expression of hematopoietic pathway genes. We conclude anti-PD-1/anti-PD-L1 blocking strategies offer therapeutic promise in MDS in restoring effective hematopoiesis.
Efficacy and Safety of Romiplostim in Patients with Acquired Aplastic Anemia Ineligible or Refractory to Immunosuppressive Therapy: Interim Analysis of Phase 2/3 Clinical Trial
Authors: Yoshiaki Tomiyama, Jun Ho Jang, Jong-Wook Lee, Koji Miyazaki, Koji Nagafuji, Kensuke Usuki, Nobuhiko Uoshima, Tomoaki Fujisaki, Hiroshi Kosugi, Itaru Matsumura, Ko Sasaki, Masahiro Kizaki, Masashi Sawa, Michihiro Hidaka, Naoki Kobayashi, Satoshi Ichikawa, Yuji Yonemura, Hiroyuki Keta, Akira Matsuda, Keiya Ozawa, Kinuko Mitani, Shinji Nakao
Journal: Blood (2018)
Integrated population pharmacokinetic (PopPK) modeling of cabozantinib (C) in patients (pts) with various cancer types including hepatocellular carcinoma (HCC).
Authors: Linh Thuy Nguyen, Sunny Chapel, Tim Meyer, Ann-Lii Cheng, Anthony B. El-Khoueiry, Robin Kate Kelley, Ghassan K. Abou-Alfa, Steven Lacy
Journal: Journal of Clinical Oncology (2019)

305 Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and &lt;1% had severe hepatic dysfunction. A 2-compartment model with first-order elimination and dual first- and zero-order absorption processes adequately described the data. As in the previous model, the MTC population was the only cancer type to have a notable difference in C PK, with ~90% increase in apparent clearance (CL/F) versus HV and pts with other cancers including HCC. For a White male, CL/F was estimated as 2.48 L/hr and apparent volume of the central compartment (Vc/F) as 212 L. Inter-individual variability was ~46% for CL/F and ~67% for Vc/F. Other demographic covariates were predicted to have a small to moderate impact on C CL/F. Liver dysfunction, per NCI-ODWG criteria, had no discernable effect on C CL/F. Conclusions: C exposure at an equivalent daily dose is predicted to be similar in pts with several cancer types including advanced HCC with mild liver dysfunction.
The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3
Authors: Giovanni Gambi, Elisabetta Di Simone, Veronica Basso, Luisa Ricci, Rui Wang, Akanksha Verma, Olivier Elemento, Maurilio Ponzoni, Giorgio Inghirami, Laura Icardi, Anna Mondino
Journal: Cancer Research (2019)

Epigenetic silencing of promoter and enhancer regions is a common phenomenon in malignant cells. The transcription factor STAT3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repression of a number of tumor suppressor genes (TSG) via molecular mechanisms that remain to be understood. Using nucleophosmin-anaplastic lymphoma kinase-positive (NPM-ALK+) anaplastic large-cell lymphoma (ALCL) as model system, we found in cells and patient-derived tumor xenografts that STAT3 is constitutively acetylated as a result of ALK activity. STAT3 acetylation relied on intact ALK-induced PI3K- and mTORC1-dependent signaling and was sensitive to resveratrol. Resveratrol lowered STAT3 acetylation, rescued TSG expression, and induced ALCL apoptotic cell death. STAT3 constitutively bound the Sin3A transcriptional repressor complex, and both STAT3 and Sin3A bound the promoter region of silenced TSG via a resveratrol-sensitive mechanism. Silencing SIN3A caused reexpression of TSG, induced ALCL apoptotic cell death in vitro, and hindered ALCL tumorigenic potential in vivo. A constitutive STAT3-Sin3A interaction was also found in breast adenocarcinoma cells and proved critical for TSG silencing and cell survival. Collectively, these results suggest that oncogene-driven STAT3 acetylation and its constitutive association with Sin3A represent novel and concomitant events contributing to STAT3 oncogenic potential. SIGNIFICANCE: This study delineates the transcriptional regulatory complex Sin3A as a mediator of STAT3 transcriptional repressor activity and identifies the STAT3/Sin3A axis as a druggable target to antagonize STAT3-addicted tumors. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3076/F1.large.jpg.See related commentary by Monteleone and Poli, p. 3031.
In vitro activity of carbapenems (imipenem and meropenem) against Gram-negative pathogenes isolated from Brazilian intensive care units
Authors: Caio Marcio Figueiredo Mendes, S. Sinto, C. Oplustil, A. Hsiung, Antônio Carlos Nicodemo, C. Kiffer
Journal: Clinical Microbiology and Infection (2001)
Abstract 20151: Sympathetic Overactivation Predicts Body Weight Loss in Patients With Chronic Heart Failure
Authors: Shuji Joho, Ryuichi Ushijima, Takashi Akabane, Masaki Nakagaito, Makiko Nakamura, Koichiro Kinugawa
Journal: Circulation (2017)

Introduction: Cardiac cachexia is associated with poor prognosis in patients with heart failure (HF). Sympathetic overactivation might be implicated in the development of muscle wasting, considerin...
Safety and Efficacy of Ibrutinib in Combination with Rituximab and Lenalidomide in Previously Untreated Subjects with Follicular and Marginal Zone Lymphoma: An Open Label, Phase II Study
Authors: Loretta J. Nastoupil, Hun Ju Lee, F. B. Hagemeister, Jason R. Westin, Felipe Samaniego, Lei Feng, Jiffin John, Sheryl G Forbes, Luis E. Fayad, Michael R Green, R. Eric Davis, Sattva S. Neelapu, Nathan H. Fowler
Journal: Blood (2018)
Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome
Authors: Meijiao Wang, Dan Zhao, Liangzhi Xu, Wenjing Guo, Li Nie, Yi Lei, Yun Long, Min Liu, Yichen Wang, Xueqin Zhang, Li Zhang, Hanna Li, Jinhu Zhang, Dongzhi Yuan, Limin Yue
Journal: Metabolism (2019)
Variety Is the Spice of Life, but Maybe Not in Gastroesophageal Adenocarcinomas
Authors: Samuel J. Klempner, Daniel V.T. Catenacci
Journal: Cancer Discovery (2019)

Sanchez-Vega and colleagues prospectively demonstrate that both intra- and intertumoral differential expression of the receptor tyrosine kinases HER2, EGFR, and MET dictate sensitivity to the pan-HER inhibitor afatinib in a phase II trial of trastuzumab-refractory HER2-amplified gastroesophageal adenocarcinomas. Rapid autopsy, tissue-based genomic characterization, and molecular imaging provide complementary information and may aid in selecting optimal patients for targeted monotherapy versus combination approaches in gastroesophageal adenocarcinomas.See related article by Sanchez-Vega et al., p. 199.
Prognostic Role of CMR and Conventional Risk Factors in Myocardial Infarction With Nonobstructed Coronary Arteries
Authors: Amardeep Ghosh Dastidar, Anna Baritussio, Estefania De Garate, Zsofia Drobni, Giovanni Biglino, Priyanka Singhal, Elena G. Milano, Gianni D. Angelini, Stephen Dorman, Julian Strange, Thomas Johnson, Chiara Bucciarelli-Ducci
Journal: JACC. Cardiovascular imaging (2019)
EXPERT study: Randomized phase III trial of radical surgery and postoperative mFOLFOX6 versus perioperative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases (CLMs).
Authors: Yoshihiro Mise, Kiyoshi Hasegawa, Masaru Oba, Kensei Yamaguchi, Hiroyuki Uetake, Takayuki Yoshino, Satoshi Morita, Keiichi Takahashi, Michiaki Unno, Yasuhiro Shimada, Kei Muro, Kazuhiro Yoshida, Masaki Mori, Hideo Baba, Mitsuo Shimada, Akio Saiura, Masaru Matsumura, Kiyoshi Ishigure, Kenichi Sugihara, Norihiro Kokudo
Journal: Journal of Clinical Oncology (2019)

652 Background: Up-front radical surgery and adjuvant chemotherapy were regarded as one of the standard-of-care (SOC) in patients with resectablecolorectal liver metastases (CLMs), while perioperative chemotherapy plus surgery is also accepted. We conducted a multicenter randomized phase III trial to compare radical surgery and post-operative mFOLFOX6 with peri-operative mFOLFOX6 plus cetuximab in patients with KRAS wild-type resectable CLMs. Methods: Patients who had KRAS wild-type resectable CLMs having one to eight liver nodules without extrahepatic disease, were randomly assigned to groups: Group A (reference), hepatectomy and 12 cycles of post-operative mFOLFOX6: Group B (experimental), six cycles of preoperative mFOLFOX6 plus cetuximab (loading dose with 400mg/m 2 and thereafter 250mg/m 2 weekly), hepatectomy and six cycles of postoperative mFOLFOX6 plus cetuximab. Primary endpoint was progression-free survival (PFS). We hypothesized that 3-year PFS in Group B would be 25% with the hazard ratio (HR) being 0.75. Considering 3 year follow-up period with 5% of two-sided alpha error and 80% of power, target number were set as 500 (250 each). Study was registered in the University Hospital Medical Information Network (UMIN000007787). Results: This study was initiated since June 2012. However, the enrollment was terminated according to the recommendation from the monitoring committee on 2015 due to a slow accrual. A total of 77 patients (Group A 37 vs. Group B 40) were analyzed. Baseline characteristics were well-balanced between groups. Median numbers of liver mets were two each, ranging from one to eight. The HRs for PFS and overall survival (OS) showed no significant difference (PFS, HR = 1.18 [0.69-2.01], p = 0.54: OS, HR = 1.03 [0.46 – 2.29], p = 0.95). There were 3-year PFS of 35% in Group A vs. 30% in Group B, and 3-year OS: 86% vs. 74%, respectively. Conclusions: No additional survival benefits adding on peri-operative cetuximab were indicated, of which findings is consistent with the previous clinical studies, although there were small number of enrolled patients. Clinical trial information: UMIN000007787.