tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of Hu5F9-G4, a first-in-class anti-CD47 antibody, in patients with solid tumors and lymphomas.
Authors: Balaji Agoram, Bing Wang, Branimir I. Sikic, Nehal J. Lakhani, Amita Patnaik, Jie Liu, Rochelle Secreto, Mark Chao, Chris H.M. Takimoto
Journal: Journal of Clinical Oncology (2018)

2525 Background: Hu5F9-G4 is a humanized monoclonal antibody targeting CD47, a "don't eat me" signal on cancer cells, that stimulates tumor cell phagocytosis and activates an anti-tumor T-cell response. The objectives of this analysis were to characterize the pharmacokinetics (PK) and anti-drug antibody (ADA) incidence of Hu5F9-G4 after single and multiple doses in patients with solid tumors and lymphomas. Methods: Data from a first-in-human Phase 1 study in 58 patients with advanced solid tumors and lymphomas (NCT02216409) were used for this analysis. Multiple intravenous (IV) doses in the range 0.1 – 30 mg/kg were given at once or twice weekly frequencies. Serum samples were collected in all subjects at various timepoints after first and subsequent doses. PK data were analyzed by a noncompartmental approach using the PKNCA package in R; population modelling analysis was done with NONMEM software. Presence of ADA was analyzed using a 3-tiered - screening, confirmatory, titre - approach. Results: At doses of 0.1 – 10mg/kg increases in maximum serum concentration (Cmax) and area under concentration curve (AUC) of Hu5F9-G4 were greater than dose-proportional indicating nonlinearity in PK. The PK parameters were consistent with the presence of a CD47 antigen sink, which was saturated at doses ≥ 10 mg/kg. Above this dose level, increases in Cmax and AUC were dose proportional and the half-life of the antibody was ~14 days – typical of human IgG4. Simulations with the model predicted that a maintenance dosing regimen of 30 mg/kg every other week from cycle 2 onwards would result in serum concentrations ≥200 µg/mL, a level where full CD47 receptor occupancy on blood cells was observed in this study and where preclinical efficacy has also been previously reported. ADA were confirmed in 2 subjects (3.4%) in this study but had no observable impact on the PK parameters. Conclusions: Hu5F9-G4 has PK properties typical of antibodies directed towards cell-surface receptors. Hu5F9-G4 exhibits nonlinear PK, typical of a receptor-targeted antibody, with doses ≥10 mg/kg saturating the antigen sink. The PK profile of Hu5F9-G4 is suitable for every other week maintenance dosing in solid tumor and lymphoma patients in Phase 2.
The initial results for a phase III study of short-term radiotherapy plus chemotherapy vs long-term chemoradiotherapy in locally advanced rectal cancer (STELLAR trial).
Authors: Jing Jin, Jing Jin, Y Tang, S Li, N Li, H Ren, H-Z Zhang, Z-X Zhou, J-W Liang, Z-X Zheng, D-B Zhao, H-M Zhang, S-M Zou, H Fang, Y-H-B-L Chi, L Yang, W-H Wang, Y-W Song, Y-P Liu, S-L Wang
Journal: Journal of Clinical Oncology (2016)

e15000 Background: To present an initial results of a phase III trial of Short Term radiotherapy (SCRT) followed by chEmotherapy (experimental group) versus Long-term chemoradiotherapy (CRT) (control group) in Locally Advanced Rectal cancer (LARC)(STELLAR trial). Methods: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinomas diagnosed by magnetic resonance imaging, were randomly assigned to experimental group or control group. In experimental group, patients will receive a SCRT (25 Gy/ 5 fractions/ 5 days), followed by 4 courses of CAPOX. In control group, patients will receive a long-term CRT (50Gy/ 25 fractions/35 days with concurrent capecitabine). TME surgery in both groups was performed 4 and 6 or 8 weeks in experimental group and control group, respectively, and 2 or 6 courses of CAPOX was prescribed as the postoperative adjuvant chemotherapy in experimental group and control group, respectively. The hypothesis is 3-year disease-free survival in experimental group was non-inferior to that in control group. The estimated enrolled number of patients is 552. Results: Until January 23, 2016, ninety-three eligible patients from 7 Chinese hospitals were enrolled: 48 in experimental group and 45 in control group, with median distances from tumor edge to anal verge were 3 cm and 5 cm respectively. Sixty-four patients, who had finished neoadjuvant treatment, were eligible for toxicity analysis. Grade 3+ acute toxicity was observed 26.6% of patients in experimental group and 5.9% in control group. As to thirty-four patients who had received TME surgery (15 in experimental group and 19 in control group), R0 resection rates and pathological complete response (pCR) rates were 93.3%, 46.7% (7/15) and 94.7%, 10.5% (2/19), respectively in experimental group and in control group. Conclusions: The initial analysis revealed the acute toxicity was tolerable in both groups, and the experimental group showed a surprising pCR rate. Clinical trial information: NCT02533271.
Enteral feeding during preoperative chemotherapy for patients with local advanced esophageal cancer: A feasibility study.
Authors: Takashi Ogata, Hiroaki Osakabe, Shinsuke Nagasawa, Masato Nakazono, Yuta Kumazu, Kentaro Hara, Tsutomu Hayashi, Takanobu Yamada, Takaki Yoshikawa
Journal: Journal of Clinical Oncology (2018)

e16012 Background: During preoperative chemotherapy, appropriate nutritional support is necessary. Especially advanced esophageal cancer patients sometimes have a difficulty of oral ingestion. In Japan, standard treatment for resectable advanced esophageal cancer is surgery after 2 course preoperative chemotherapy of CDDP-5-FU, and we usually use naso-gastric ED tube with difficulty of oral injestion during preoperative chemotherapy to administrate adequate nutrition. Methods: The aim of this study is to clarify the safety of preoperative enteral feeding for patients with esophageal cancer using ED tube during preoperative chemotherapy and compare the nutritional status between using enteral feeding or not. From Jan 2012 to June 2017, consecutive 160 cases undergone esophagectomy with 2 course of preoperative chemotherapy were enrolled this study. 14 patients were treated with ED for nutrition(Group A) and 146 patients without ED(Group B). We evaluated the changes of nutritional status and postoperative complication as an indicator of safety. Results: The stage(1b/2a/2b/3a): 0/4/1/9 at Group A, and 33/39/28/46 at Group B (p < 0.05). The nutritional status before treatment, there was no significant difference between two groups. Changes before and after preoperative chemotherapy(GroupA/B): BMI:21.1→20.3/21.9→21.6, TP:7.4→6.9/7.2→6.7, alb:4.0→3.8/4.3→4.0, pre-alb:21.7→24.3/24.5→24.5, RBP:2.87→3.65/3.09→3.30. Adverse events: Grade 3 or more at hematological toxicity(GroupA/B): 7 cases(50.0%)/24 cases(16.4)(p < 0.01), and Grade 2 or more at non hematological toxicity: 7 cases(50.0%)/30 cases(20.1%)(p < 0.05). Postoperative complications (CD classification, Grade3 or more): 4 cases at Group A(28.5%), and 35 cases at Group B(23.9%)(N.S.), operating time: 425min vs 402min(N.S.), blood loss: 468ml vs 487ml(N.S.), and postoperative stay: 29.5days vs 20.4days(N.S.). Conclusions: Preoperative chemotherapy for esophageal cancer patients with difficulty of oral injestion, ED tube for nutrition was effective to maintain the preoperative nutritional status and there was no increase of postoperative complication.
The Trem2 R47H Alzheimer’s risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans
Authors: Xianyuan Xiang, Thomas M. Piers, Benedikt Wefers, Kaichuan Zhu, Anna Mallach, Bettina Brunner, Gernot Kleinberger, Wilbur Song, Marco Colonna, Jochen Herms, Wolfgang Wurst, Jennifer M. Pocock, Christian Haass
Journal: Molecular Neurodegeneration (2018)

The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer's disease. Mouse models accurately reproducing phenotypes observed in Alzheimer' disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer's disease. A CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice. Trem2 mRNA and protein levels as well as Trem2 splicing patterns were assessed in these mice, in iPSC-derived human microglia-like cells, and in human brains from Alzheimer's patients carrying the TREM2 R47H risk factor. Two independent Trem2 R47H knock-in mouse models show reduced Trem2 mRNA and protein production. In both mouse models Trem2 haploinsufficiency was due to atypical splicing of mouse Trem2 R47H, which introduced a premature stop codon. Cellular splicing assays using minigene constructs demonstrate that the R47H variant induced abnormal splicing only occurs in mice but not in humans. TREM2 mRNA levels and splicing patterns were both normal in iPSC-derived human microglia-like cells and patient brains with the TREM2 R47H variant. The Trem2 R47H variant activates a cryptic splice site that generates miss-spliced transcripts leading to Trem2 haploinsufficiency only in mice but not in humans. Since Trem2 R47H related phenotypes are mouse specific and do not occur in humans, humanized TREM2 R47H knock-in mice should be generated to study the cellular consequences caused by the human TREM2 R47H coding variant. Currently described phenotypes of Trem2 R47H knock-in mice can therefore not be translated to humans.
Continuation of trastuzumab beyond disease progression in patients with metastatic gastric cancer: A retrospective analysis of 25 cases—The MD Anderson experience.
Authors: Humaid Obaid Al-Shamsi, Jane Rogers, Jeannette Elizabeth Mares, Mariela A. Blum, Ibrahim Dahbour, Yazan Fahmawi, Quan Lin, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2016)

e15560 Background: Despite the widespread use of trastuzumab in the management of patients with Human Epidermal growth factor receptors (HER2) - overexpressing metastatic gastric cancer, its optimal duration of administration is unknown. Continuation of trastuzumab beyond disease progression post 1st line of treatment in HER2-overexpressing metastatic breast cancer has been shown to improve time to progression without increased risk of treatment related toxicity. Continuation of bevacizumab beyond disease progression in metastatic colon cancer has been shown to improve survival. Methods: The gastric cancer HER2-overexpressing metastatic gastric cancer patients were identified from our database between 2010 to 2014 , We retrospectively reviewed the medical records of 25 patients who received trastuzumab in combination with chemotherapy as first line and continued trastuzumab beyond disease progression in order to register their clinical course and toxicity. Results: 25 cases were identified, 18 males (72%), median age of the patients was 55 years. 23 (92%) presented with stage 4 as their initial presentation. Eighty percent had 3+ HER2 overexpression and 20% had 2+ HER2 overexpression confirmed by FISH.13 (52%) were moderately differentiated ,10 (40%) were poorly differentiated .The most common sites of metastasis were liver 18 (72%) and lung 9 (36%). The most commonly used combinations in first line was Oxaliplatin, 5 FU and trastuzumab in 18 (72%) of patients. 14(56%) of patients received irinotecan, 5 FU and trastuzumab in the second line . Median time to progression (TTP) on the first line was 6.5 months (m) (range 1.5 – 14 m) , while TTP on the second line was 4.5 m (range 1- 14 m) . 5 patients are still alive and excluded from calculating the median OS which was 15 m (range 5- 53 ) for the remaining 20 subjects.Trastuzumab was not discontinued due to side effects in any of the study population. Conclusions: This retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic gastric cancer is feasible and safe. Randomized studies are warranted.
E3508: Randomized trial of carboplatin (C), paclitaxel (P), bevacizumab (B) with or without cixutumumab (Cx) in patients (pts) with advanced non-squamous, non-small cell lung cancer (NSCLC).
Authors: Athanassios Argiris, Ju-Whei Lee, James Stevenson, Matthew Gerard Sulecki, Vladimir Hugec, Nicholas W. Choong, Joel N. Saltzman, Wei Song, Richard M. Hansen, Tracey L. Evans, Suresh S. Ramalingam, Joan H. Schiller
Journal: Journal of Clinical Oncology (2016)

9091 Background: Cx is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type receptor 1 (IGF1R) that can potentially reverse resistance and enhance the efficacy of chemotherapy. E3508 was designed to evaluate the addition of Cx to CPB, a reference ECOG-ACRIN regimen. Methods: B-eligible pts with stage IV or recurrent non-squamous NSCLC and ECOG performance status (PS) of 0-1 were randomized to receive either IV P 200 mg/m² ; C AUC = 6.0; B 15 mg/kg, every 21 days to a maximum of 6 cycles followed by B maintenance until progression or unacceptable toxicity (arm A) or CPB plus Cx 6 mg/kg IV over 1 hour, days 1, 8, and 15 during CPB and B maintenance (arm B). The primary endpoint was progression-free survival (PFS). Results: Of 175 pts randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). ECOG PS 0, 56% in arm A and 55% in arm B; adenocarcinoma, 94% in arm A and 87% in arm B. The median PFS was 5.8 months (95% CI, 5.4-7.1) in arm A vs. 7 mo (95% CI, 5.7-7.6) in arm B (p = 0.65, stratified logrank); hazard ratio 0.92 (95% CI, 0.65-1.31). Objective response was 46.2% vs. 58.7% in arm A vs. arm B (p = 0.15). The median overall survival was 16.2 mo (95% CI, 9.9-18.6) in arm A vs. 16.1 mo (95% CI, 12.3-19.4) in arm B (p = 0.95). Common treatment-related grade 3/4 (%) events in arm A vs. arm B were: febrile neutropenia, 0/0 vs. 9/0 (p = 0.007); neutropenia, 16/17 vs. 17/38 (p = 0.005); thrombocytopenia, 5/5 vs. 17/9 (p = 0.008); anemia, 7/0 vs. 12/0 (p = 0.31); fatigue, 6/0 vs. 20/1 (p = 0.006); nausea, 5/0 vs. 11/0 (p = 0.16); hyperglycemia, 0/0 vs. 10/1 (p = 0.002); peripheral sensory neuropathy, 5/0 vs. 5/0 (p = 1.00); hypertension, 14/0 vs. 21/0 (p = 0.31); thromboembolic event, 7/1 vs. 6/0 (p = 0.77). There was 1 grade 5 event in each arm (intracranial hemorrhage in arm A and lung hemorrhage in arm B). Conclusions: The addition of Cx to CPB increased toxicity without improving efficacy and is not recommended for further development in NSCLC. Both arms had longer OS than a historical control (E4599) which emphasizes the importance of a comparator arm in phase II trials. Clinical trial information: NCT00955305.
Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis.
Authors: Mohamad Bassam Sonbol, Belal Firwana, Zhen Wang, Daniel H. Ahn, Mitesh J. Borad, Issam Makhoul, Ramesh K. Ramanathan, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2017)

e15779 Background: There is paucity of data regarding the best available second-line treatment following progression on gemcitabine-based regimens in metastatic pancreatic ductal adenocarcinoma (PDAC). While a Nanoliposomal formulation of irinotecan (MM398) is considered a standard of care, there is conflicting data relating to the use of oxaliplatin in this setting. We performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan (IRI) formulations to a fluoropyrimidine (FP) as a second-line in PDAC patients. Methods: We searched different databases, including PubMed, Embase and Cochrane, to identify randomized controlled trials comparing FP monotherapy to FP combination therapy that includes either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in PDAC patients who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared to FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random effects models. Results: Five studies (2 with FPIRI and 3 with FPOX) with 895 patients were identified. Patients randomized to FPIRI/FPOX had a significantly improved PFS (HR = 0.74, CI 0.62 to 0.89) and a trend towards an improved OS compared to FP monotherapy (HR = 0.88, CI 0.65 to 1.19). When comparing FPIRI to FP, there was an improvement in both PFS (HR = 0.64, CI 0.47 to 0.87) and OS (HR = 0.70, CI 0.55 to 0.89) in patients treated with the combination. Conversely, FPOX showed only a modest improvement in PFS (HR = 0.81, CI 0.67, 0.97) with no improvement in OS (HR = 1.03, CI 0.64 to 1.67). Conclusions: Combination chemotherapy with oxaliplatin or various irinotecan formulations seem to improve PFS vs. single agent FP. FPIRI, but not FPOX seem to confer an OS advantage. Oxaliplatin with FP following gemcitabine failure may need further confirmatory studies to establish its role in refractory pancreas cancer.
Clinico-pathologic and molecular characteristics of patients with resected lung adenocarcinoma.
Authors: Mihaela Mates, Shuo Xu, Alexander Boag, Wilma M Hopman, Harriet Feilotter
Journal: Journal of Clinical Oncology (2016)

e23134 Background: Lung adenocarcinoma (LA) is the most common lung malignancy. Recently, a novel histologic classification was recognized as a stage-independent predictor of survival. Furthermore, important molecular discoveries in the lung cancer genome have identified targetable driver mutations that led to new therapeutic interventions. The purpose of this study was to assess clinico-pathologic and molecular characteristics of patients with resected LA at our centre. Methods: Through pathology records we identified patients with resected LA between January 2005 - December 2008. We collected demographic, treatment, pathologic tumor characteristics and disease outcomes. Molecular analysis was undertaken to investigate genomic profile by next generation sequencing assays (NGS). Data were analyzed to determine associations between clinico-pathologic and molecular characteristics and disease outcomes (chi-square tests, independent samples t-tests and Mann-Whitney U). Results: We identified 121 eligible patients. Mean age: 65; 58% female; 7% nonsmokers; 81% lobectomy. Stage distribution: I – 64%, II – 20%, III – 16%. Histologic subtype: mucinous 9%; lepidic 11%; acinar 46%; solid 27%; micro/papillary 7%. Neo/adjuvant therapy – 35%. Of these patients we obtained DNA and RNA from 36 tumors and molecular analysis was successful on all samples. Genomic alterations results: KRAS – 55%; EGFR – 11%; p53 – 51%; MET 8%; RET – 6%; HER 2 – 3% BRAF – 3%; ALK and ROS – 0%. Five-year overall survival (OS) was 69%; by stage: I – 79%; II – 37%; III – 65%; by neo/adjuvant therapy (yes vs no): stage I – 85 vs 78%; II – 41 vs 29%; III – 50 vs 87%; by histologic subtype: mucinous – 82%; lepidic – 92%; acinar – 70%; solid/micro/papillary – 56%; by KRAS status: wild-type 75%, mutated 74%. Conclusions: In this predominantly smoking population with resected LA the most common histologic subtype was acinar; the proportion of KRAS-mutations was higher than the national average, and the incidence of RET rearrangements was higher than expected. In this small study significant OS benefit with neo/adjuvant therapy was seen in stage I and II LA but not stage III; no significant associations were found between histological subtypes and KRAS mutation status.
Immunohistochemical Expression of Angiogenesis and cell-adhesion Markers in Surgical and Autopsy NSCLC Tissue samples: Correlation with Clinicopathologic parameters and survival.
Authors: Konstantinos N. Syrigos, Kyriaki Soldatou, Dimitra Grapsa, Dimitrios Sfairopoulos, Andriani Charpidou, Rodoula Trigidou, Antigoni Mitselou
Journal: Journal of Clinical Oncology (2016)

e20556 Background: The prognostic significance of angiogenesis and cell adhesion markers, including vascular endothelial growth factor (VEGF), E-cadherin and CD44, in non-small cell lung cancer (NSCLC) remains controversial. The primary aim of this study was to further investigate the value of these candidate biomarkers as predictors of overall survival (OS) in NSCLC. Methods: Formalin-fixed and paraffin-embedded tissue specimens from 77 surgical and 41 autopsy cases, were retrieved and evaluated by immunohistochemistry (IHC) for the expression of VEGF, E-cadherin, CD44, p53, Ki-67 and thyroid transcription factor -1 (TTF-1); Immunohistochemical findings were correlated with gender, age, primary tumor location/side, tumor histology and grade and disease stage at diagnosis. The association of clinicopathologic variables and IHC results with overall survival (OS) was assessed –only in the surgical subgroup- by univariate and multivariate Cox regression analysis. Results: Mean age of all cases (N = 118) was 64.8 years (SD = 11.1 years), while the majority were men (104/118, 88.1%). Adenocarcinoma was the predominant histological type (38.1%), while most cases (62.6%) had stage II disease at diagnosis. E-cadherin and CD44 expression were significantly correlated with lower tumor grade and disease stage at diagnosis, both in the total sample and in the surgical and autopsy subgroups. Positive VEGF expression was also correlated with lower grade and stage, in the total sample and the autopsy subgroup, but not in the surgical subset of cases. Positive E-cadherin and CD44 expression were associated with improved OS, both in univariate analysis (p = 0.006 and p = 0.011, respectively), as well as in the multivariate model, after adjusting for sex, age, tumor location, histology, grade and stage (HR = 0.08, 95% CI: 0.09-0.65, p = 0.019 and HR = 0.07, 95% CI: 0.09-0.63, p = 0.017, respectively). Conclusions: Our results suggest that E-cadherin and CD44 positiveimmunostaining may independently predict an improved survival in NSCLC.Validation of these findings in larger prospective studies is nevertheless warranted.
Antitumor effect of the combination of proteasome inhibitor (Pi) and histone deacytelase inhibitor (HDACi) in breast cancer (BC).
Authors: Joseph Kannarkatt, Omar Abed Alkharabsheh, Burra V Madhukar, Cheryl Leece, Deimante Tamkus
Journal: Journal of Clinical Oncology (2017)

e23156 Background: Previous studies demonstrated the efficacy of HDACi and Pi as single agents in BC. The synergistic combination of HDACi and Pi has been shown to be effective in clinical studies in other tumor types, including multiple myeloma, non-small cell lung cancer, and pancreatic cancer. In this in vitro study, we explored the hypothesis that combination of these two agents may improve overall antitumor effect in BC. Methods: In the experiment, we used 3 BC cell lines: MCF7 (ER+), MDA-MB-231 (ER-), and BCSV (isolated from metastatic ER+ tumor which lost ER expression with disease progression). The cells were treated with carfilzomib (Pi) and scriptaid (HDACi) as single agents and in combination. Cell viability was determined using MTT assay, and combination indexes were determined using CalcuSyn software. Additionally, cells were cultured in 3D tumor spheroid model, and response to treatment was assessed on day 5, 10, 15 and 20. Results: In comparison with control, single agent HDACi, single agent Pi and combination HDACi/Pi increased cell viability by 6%, decreased cell viability by 60% and by 69% respectively (p &lt; 0.0001) in MCF7 cells; and decreased cell viability by 25%, 59% and 66% respectively (p = 0.0061) in BCSV cells. The combination indexes for most HDACi and Pi combinations were lower than 1.0, indicating synergistic effects in MCF-7 and BCSV cells but not in MDA-MB-231 cells. In 3D cultures, the combination of carfilzomib 1µM and scriptaid 10µM led to significant reduction of tumor spheroid size as compared to single agent. By day 20, BCSV tumor spheroid size increased by 258% in control group and by 50% in Pi, decreased by 17% in HDACi and by 30% in HDACi/Pi combination group (p &lt; 0.0001). Conclusions: Combination of HDACi and Pi exhibited synergistic activity in both MCF7 and BCSV monolayer cultures. Additionally, combination HDACi and Pi significantly decreased 3D tumor spheroid size as compared to either single agent alone. Further study is needed to evaluate the mechanisms of Pi/HDACi combination in estrogen-mediated BC tumorigenesis.