tbuckley/cabot-search huggingface dataset:
Early discharge after induction chemotherapy for acute myeloid leukemia: Safety outcomes and hospital readmissions.
Authors: Nikita V. Baclig, Sarah A. Buckley, Anna B. Halpern, Paul C. Hendrie, Mary-Elizabeth M. Percival, Pamela Sue Becker, Elihu Estey, Roland B. Walter
Journal: Journal of Clinical Oncology (2018)

6532 Background: Adults with acute myeloid leukemia (AML) typically remain hospitalized after induction chemotherapy for the duration of pancytopenia. Several studies have suggested that outpatient management following completion of chemotherapy is safe and associated with lower resource utilization. This has become standard practice at our institution if logistics allow. Here, we examine outcomes of adults ≥18 years of age with newly-diagnosed AML (acute promyelocytic leukemia excluded) or high-grade myeloid neoplasms (i.e. ≥10% blasts) who received AML-like induction chemotherapy with a regimen as or more intense than 7+3 between 8/2014 and 7/2017 and who were discharged early (ED) or remained hospitalized based on individual provider assessment. Methods: Patients were identified via institutional electronic medical records. Clinical information was collected through manual patient record review from the day after chemotherapy until count recovery (absolute neutrophil count ≥0.5×109/L and self-sustained platelet count ≥20×109/L), receipt of further chemotherapy, transfer to a different institution, or completion of 45 days on study. Patients were considered ED if discharge occurred within 3 calendar days of study start and control if not. Results: 260 patients (median: 61 [range 20-90] years) underwent induction chemotherapy, 168 of whom (64.6%) were ED. Age and gender distribution were similar between ED and control patients. Mean time on study was similar between ED and controls (25.6 vs. 25.2 days; p = 0.73). There was no difference in death rate (5.6% vs. 4.3%; p = 0.59), rate of febrile neutropenia (69.6% vs. 67.4%; p = 0.71), or proportion of patients requiring ICU-level care (8.9% vs. 15.2%, p = 0.12) between groups during the study period. In the ED group, 71.4% were readmitted with 0.95 readmissions on average per patient. Mean length of time between discharge and readmission among ED patients was 7.2 days. Overall, ED patients spent fewer days in the hospital than control patients (7.1 vs. 16.0; p < 0.0001). Conclusions: ED appears safe outside a clinical trial setting. Despite high readmission rates among ED patients, total hospital stay was shorter than for controls.
A Cancer Research UK phase I/IIa trial of BT1718 (a first in class Bicycle Drug Conjugate) given intravenously in patients with advanced solid tumours.
Authors: Udai Banerji, Natalie Cook, T.R. Jeffry Evans, Irene Moreno Candilejo, Patricia Roxburgh, Claire L. S. Kelly, Narmatha Sabaratnam, Rashmi Passi, Sawretse Leslie, Sidath Katugampola, Lisa Godfrey, Neil Tremayne, Gavin Bennett, Maria Koehler, Gillian Langford, Stefan N. Symeonides, Marc Pittman
Journal: Journal of Clinical Oncology (2018)

TPS2610 Background: Membrane type I matrix metalloproteinase (MT1-MMP) is a member of the matrix metalloproteinase (MMP) family which are involved in tissue remodelling through proteolysis of extracellular matrix components. Overexpression of MT1-MMP is seen in multiple tumour types including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) and sarcoma. BT1718 is a novel first in class bicyclic targeting peptide that binds MT1-MMP and is linked to the maytansinoid tubulin inhibitor DM1 by a cleavable disulfide linker. Bicyclic peptides have a low molecular weight in comparison to other conjugated toxin approaches enabling rapid penetration and a short systemic half-life, potentially reducing toxicity. Methods: This is an open label first in human phase I/IIa study. The primary objective is to propose a recommended phase 2 dose (RP2D) and schedule of BT1718. Secondary objectives include pharmacokinetic (PK) parameters and preliminary clinical responses in biomarker pre-defined cohorts of patients. Tertiary objectives include correlative studies related to predictive biomarkers of response. Dose escalation (phase I) Stage 1: In keeping with preclinical PK and safety studies, initial cohorts of patients will be dosed twice a week. There will be single patient cohorts until either Grade 2 drug related toxicity occurs or the dose exceeds 6 mg/m2 twice a week. A 3+3 design will then be followed until the RP2D has been established. Stage 2: Once a RP2D is established in Stage 1, Stage 2 will commence in a once weekly schedule using a 3+3 design until the RP2D has been established for this schedule. Dose expansion (phase IIa) Part A: 14 patients with MT1-MMP expressing NSCLC or TNBC will be treated with BT1718 in the twice a week schedule at the RP2D. At least 6 patients will have pre & post treatment biopsies. Part B: 14 patients with MT1-MMP expressing NSCLC or TNBC will be treated with BT1718 at the RP2D in the once weekly schedule. At least 6 patients will have pre & post treatment biopsies. Part C/D: following parts A & B a decision will be made to explore the selected schedule in tumour-specific cohort(s) of around 15 patients, with refined MT1-MMP biomarker selection. Clinical trial information: 2016-004633-24.
Risk of venous thromboembolism, survival, and expression of procoagulant genes in neuroendocrine versus castration-resistant prostate cancer.
Authors: Panagiotis J. Vlachostergios, Christopher D. Jakubowski, Linda Lam, Paul J. Christos, David M. Nanus, Andrea Sboner, Francesca Khani, Himisha Beltran, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2018)

e17039 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive form of PC thought to carry a higher risk of VTE than standard castration resistant prostate cancer (CRPC), though it is unclear if this is due to inherent procoagulant properties or effect of stage or systemic therapy. Methods: Information was collected from an IRB-approved data/tissue registry. Khorana VTE risk score, sites of metastatic disease, systemic therapy, and date of death or last follow up were collected. The Chi-square test was used to compare characteristics and outcome; Kaplan Meier was used to calculate OS. Multivariable logistic regression was used to control for clinical variables on the effect of NEPC status and VTE risk. RNA was isolated and next generation paired-end mRNA sequencing was performed in 3 tumor subsets: PC adenocarcinoma (PCa), CRPC, and NEPC. Prothrombin (F2), tissue factor (F3), carboxypeptidase (CPB2), fibrinogen (FGG, FGA), PAR-1 (F2R), and PAR-2 (F2RL1) expression were compared by Wilcoxon tests. Results: The clinical cohort included 195 with NEPC (148 met clinical criteria, 47 histologic) and 189 with CRPC. Overall, 66 (17.2%) experienced a VTE during follow up. VTE was significantly more common with NEPC than CRPC (21.0% vs 13.2%, p = 0.04). VTE was more common with any chemotherapy (p = 0.003), taxane (p = 0.002), and platinum chemo (p = 0.001). Median OS was shorter for NEPC vs CRPC (p < 0.0001). On multivariate analysis, trends for higher VTE risk with NEPC remained (controlling for Khorana OR = 1.68, p = 0.08; controlling for chemo OR 1.46, p = 0.19). Both advanced disease tumor samples had differential expression of coagulant genes: F2, FGA, FGB, CPB2 higher and F3, F2RL1 lower in NEPC and CRPC than PCa (all p < 0.001). In metastatic samples, F2 had significantly higher expression in NEPC (N = 21) vs CRPC (N = 32) tumors (p < 0.001). Trends for higher expression of CPB2 (p = 0.1) and lower expression of F3 (p = 0.23) in NEPC vs CRPC were observed. Conclusions: Our study suggests that patients with NEPC have a higher risk of VTE compared to CRPC, which may be explained by higher inherent F2 gene expression in addition to exogenous risk factors such as chemotherapy.
Pulmonary embolism prophylaxis in solid tumors: Exploring a paradigm shift.
Authors: Nausheen Naila Hakim, Luiz Antonio Liarte Marconcini, Mariola A. Vazquez Martinez, Doris Maria Rivas, Christina Trotta, Jordan Spencer Carter, Stuthi Perimbeti, William May Lee, Seema Niphadkar, Neilanjan Nandi, Kristine Marie Ward, Maneesh Rajiv Jain, Michael Styler
Journal: Journal of Clinical Oncology (2017)

e18252 Background: Studies have found higher risk of development of pulmonary embolism (PE) in those with metastatic disease within the first year of diagnosis, predominantly in pancreatic cancer. Therapeutic anticoagulation is consequently recommended in pancreatic cancer. We thus hypothesized that the rate of PE would be highest in pancreatic cancer compared to other solid tumors. Methods: We queried the Nationwide Inpatient Sample between 1999-2014 using the ICD-9 codes for PE in association with the following solid tumor types: esophageal, colorectal, lung, stomach, breast, pancreatic, liver and small intestine. The primary diagnosis was the type of solid tumor and the secondary diagnosis was PE. Chi-square analysis was used to to analyze for the independence of two variables. Results: From 1999-2014 there was a total of 16,473 cases of PE in solid tumors. 1.9% of the pancreatic cancer admissions developed a PE, followed by 1.7%, 0.9% and 0.8% for lung, liver, and colorectal, respectively (p &gt; 0.05). Overall mortality rate for PE in pancreatic, lung, and colorectal cancers decreased from 32% in 1999 to 15% in 2014. Conclusions: Earlier detection due to improved diagnostic modalities may have contributed to the decrease in overall mortality rate observed in lung, liver, and colorectal cancers diagnosed with PE from 1999-2014. The highest rate of admissions associated with PE was seen in pancreatic cancer: however the differences between the four cancers were not statistically significant. Future studies should focus on observational prospective data monitoring solid malignancies for PE. If the prevalence of PE is indeed similar in different types of cancers, we should consider the addition of therapeutic anticoagulation to the current recommendations.
Roles of an immune-check point inhibitor (nivolumab) in heavily pretreated and platinum-resistant gynecologic cancers.
Authors: Yoshihiro Kikuchi, Hiroko Kouta, Takayoshi Asakawa, Miyuki Horikoshi, Tomoyuki Yoshikawa, Masashi Takano, Kenichi Furuya
Journal: Journal of Clinical Oncology (2018)

e17562 Background: Although most of gynecologic cancers receive platinum-containing chemotherapy after the first surgical procedure, the most cases eventually relapse and develop to platinum-resistance. Therefore, strategies to platinum-resistance are urgently necessary. The present study was performed to elucidate the differential effects of nivolumab on the heavily pretreated and platinum-resistant gynecologic cancers by measuring serum IL-6 and mutant P53 protein (mP53). Methods: All of 37 cases with gynecologic cancers received treatment by more than 3 regimens containing platinum and thereafter treatment by nivolumab (100 mg/body/ 3 week, more than 3 times) was performed. Serum IL-6 and mP53 was determined by CLEIA and ELISA methods, respectively. Response and adverse effect (AE) were assessed by the response evaluation criteria in solid tumors (RECIST) v1.1 and common terminology criteria for adverse events (CTCAE) v4.0, respectively. Results: Response rate (RR) and clinical benefit rates (CBR) by nivolumab were observed in order of uterine endometrial cancer (26% and 53%), ovarian cancer (15% and 39%) and uterine cervical cancer (11% and 22%), respectively. Intriguingly, in 7 cases with elevation of mP53 response by nivolumab was not observed, while in all 5 cases with lowering effects of IL-6 by nivolumab the positive tumor response was observed and 1 case with uterine endometrial cancer had complete response after 6 courses of nivolumab. In 1 case with ovarian cancer fulminant type I diabetes occurred after 3 courses of nivolumab and treatment was stopped. Except for this case, AE with more than grade 3 was not observed and the toxicity was almost manageable. Conclusions: In this preliminary study, we confirmed that the effect of nivolumab was obtained in the order of uterine endometrial cancer, ovarian cancer and uterine cervical cancer. Interestingly, elevation of mP53 in serum can predict non-responsive to nivolumab, while IL-6 lowering effect by nivolumab suggests clinical improvement. These results warrant further prospective studies with more large cases.
Association of EGFR and HER-2 exon 20 mutations with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
Authors: Marcelo Vailati Negrao, Alexandre Reuben, Jacqulyne Ponville Robichaux, Xiuning Le, Monique B. Nilsson, Chang-jiun Wu, Jianhua Zhang, Lara C.A. Landry, Emily Roarty, Waree Rinsurongkawong, Stephen Swisher, George R. Simon, Andrew Futreal, Bonnie S. Glisson, Jianjun Zhang, John Heymach
Journal: Journal of Clinical Oncology (2018)

9052 Background: Immune checkpoint blockade has led to unprecedented durable clinical benefit in metastatic non-small cell lung cancer (NSCLC), but response rates are low for patients with targetable driver mutations. EGFR and HER-2 exon 20 mutations account for ~4% of NSCLC, but outcomes for these patients when treated with immune checkpoint blockade have not been previously reported. Methods: We queried GEMINI, a MD Anderson Lung Cancer Moon Shot funded database for prospective collection of clinical information for patients with NSCLC, for patients with driver mutations in EGFR exon 19, 20, 21 and HER-2 exon 20 and treated with immune checkpoint inhibitors. We assessed overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Results: From 2014 to 2018, 90 patients with classic EGFR mutations (exon 19 del + exon 21 L858R, n = 38), EGFR exon 20 mutations (n = 36; no T790M included) and HER-2 exon 20 mutations (n = 16) had been treated with checkpoint inhibitors. Compared to classic EGFR mutants, EGFR exon 20 mutants demonstrated a higher disease control rate at 6 and 12 months as well as higher ORR. Also, EGFR exon 20 mutants demonstrated significantly higher PFS (HR 0.45, p = 0.002) and OS (HR 0.2, p < 0.001) (Table). These differences remained significant in multivariate analysis after adjusting for age, smoking status, radiation prior to treatment initiation and treatment with concurrent agents such as chemotherapy and/or radiation. HER-2 exon 20 mutants had similar ORR and PFS compared to classic EGFR mutants (HR 1.1, p = 0.8) (Table). Conclusions: EGFR exon 20 mutations are associated with superior outcome from immune checkpoint inhibitors compared to classic EGFR and HER-2 exon 20 mutations. Further studies on PD-L1 status and tumor mutation burden in these molecularly-defined groups are ongoing to address potential underlying mechanisms associated with these findings. EGFR exon 20 N = 36 Classic EGFR N = 38 HER-2 exon 20 N = 16 Disease control – N (%) 6 months 13 (36) 6 (16) 0 (0) 12 months 4 (11) 0 (0) 0 (0) Response rate – N (%) CR 1 (3) 0 (0) 0 (0) PR 8 (22) 0 (0) 1 (6) SD 9 (25) 6 (16) 2 (13) PD 15 (42) 32 (84) 13 (81) NA 3 (8) 0 (0) 0 (0) Survival – median PFS 2.9 1.9 1.8 OS NR 11.5 17.1
Abstract A097: Regulation of immunophenotype modulation of monocytes-macrophages from M1 to M2 by prostate cancer cell culture supernatant via the transcription factor STAT3
Authors: Raul Solis, Alejandro Bravo, Georgina Hernandez, Alejandro Bravo
Journal: Cancer Research (2018)

Abstract Background: The transcription factor STAT3 has a prominent innate immunity effect on cancer progression. We determined the regulation of STAT3 in the immunophenotype modulation of macrophages from M1 to M2 induced by the cell culture supernatant of the prostate cancer line PC3. Methods: Monocyte-macrophages from healthy donors were cultured in the supernatant of PC3 cells, membrane proteins and intracytoplasmic and phosphorylated STAT3 were measured using flow cytometry, and cytokines and growth factors were studied using luminescence. Cytotoxicity and nitric oxide were evaluated via colorimetric assays. Results: The supernatant of prostate tumor PC3 cells effectively induced macrophages toward an M2 profile, and the expression of phosphorylated STAT3 in the monocytes-macrophages notably increased. In the group of monocytes-macrophages treated with an STAT3 inhibitor, the macrophages were induced towards an M1 phenotype. Conclusions: In this study, we show that the secretion profile of PC3 prostate cancer cells induces a change in macrophage phenotype from M1 to M2, and this phenomenon is related to phosphorylation of the transcription factor STAT3. Citation Format: Raul Solis, Alejandro Bravo, Jr., Georgina Hernandez, Alejandro Bravo. Regulation of immunophenotype modulation of monocytes-macrophages from M1 to M2 by prostate cancer cell culture supernatant via the transcription factor STAT3 [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A097.
Apatinib to enhance chemosensitivity of gastric cancer to paciltaxel and 5-fluorouracil.
Authors: Xiangdong Cheng, Zhiyuan Xu, Jiahui Chen, Chunli Zhang, Jianfa Yu, Fei Teng, Guowei Zheng, Hang Lv
Journal: Journal of Clinical Oncology (2017)

e15545 Background: Patients (pts) with late-stage gastric cancer (GC) have a poor prognosis. Targeted agent combined with chemotherapy is expected to yield clinical benefits. Apatinib, a novel tyrosine kinase inhibitor targeting VEGFR-2, improves outcomes in patients with metastatic GC as a third line of treatment. Hence, we aimed to assess the efficacy and safety of apatinib plus chemotherapy in vivo and in vitro. Methods: The MGC803 cell viability was assessed by CCK-8 assay, and the interactions between apatinib and conventional cytotoxic agents revealed by combined index (CI) values were calculated using Calcusyn 2.0 software. We also used a zebrafish embryo xenograft model to validate the synergistic interactions. Furthermore, 4 pts with late-stage GC were enrolled to receive paclitaxel (PTX)/S1 chemotherapy plus apatinib in conversion surgery. Apatinib was administered 500 mg once a day continuously, PTX 130 mg/m 2 was given on day 1, and S-1 was administered at 80 mg/m 2 for 14 consecutive days, followed by 7 days of rest. Treatment was administered for 3-5 cycles, but the last cycle did not include apatinib. Results: Apatinib showed synergistic interactions with both PTX and 5-Fu in vivo (CIs &lt; 1). The zebrafish embryo xenograft model also demonstrated that addition of 0.25 µg/mL apatinib significantly enhanced the tumor growth inhibition effects of 25 (38.39% vs. 11.77%, P &lt; 0.001) and 50 ng/fish (43.58% vs. 17.88%, P &lt; 0.05) 5-Fu, as well as those of 0.75 ng/fish (53.62% vs. 35.22%, P &lt; 0.001) and 1.5 ng/fish (59.71% vs.46.73%, P &lt; 0.01) PTX. Apatinib plus S1/paclitaxel chemotherapy was well tolerable before surgery. Objective response to preoperative SPA treatment was achieved in all pts. No posteroperative bleeding event or wound-healing complication was observed. No postoperative mortality occurred and morbidity was encountered. Pathological examination showed that all pts had grade Ib pathological response. Conclusions: The experimental data suggested that apatinib improves the efficacy of PTX and 5-Fu both in vitro and in vivo. Clinical evidence showed that combination of PTX/S1 chemotherapy with apatinib has promising efficacy and acceptable safety profile in late-stage GC, especially in the conversion surgery.
Molecular analyses of left- and right-sided tumors in adolescents and young adults (AYA) with colorectal cancer (CRC).
Authors: Megan Jagosky, Richard M. Goldberg, Derek Raghavan, Alberto Puccini, Anthony Frank Shields, David Arguello, Wolfgang Michael Korn, Andreas Seeber, Jimmy J. Hwang, Philip Agop Philip, John Marshall, Edward S. Kim, Heinz-Josef Lenz, Mohamed E. Salem
Journal: Journal of Clinical Oncology (2018)

3577 Background: The incidence of CRC, particularly left sided tumors, in AYA is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in AYA. We compared molecular features of left-sided colorectal tumors (LT) in AYA to right-sided tumors (RT) in AYA and to LT in older patients. Methods: Primary tumors annotated by site of origin were examined by NextGen Sequencing (592 genes), protein expression, and gene amplification. Tumor mutation load (TML) was calculated by enumerating somatic missense mutations. Chi-square testing was used for comparisons. Results: In total, 1,064 primary CRCs were examined. Comparing LT (n = 220) with RT (n = 47) in AYA (≤ 40 years; see table), RT had higher mutation rates in RNF43 (33.3% vs. 3.4%, P < 0.001), PIK3CA (31% vs. 11.1%, P = 0.005), KMT2D (29.6% vs. 4.1%, P < 0.001), MSH6 (14.8% vs. 2%, P = 0.002), PTEN (13.8% vs. 2%, P = 0.003), BRCA2 (13.3% vs. 3.9%, P = 0.038), MLH1 (10.3% vs. 2%, P = 0.022) and MSH2 (10% vs. 1.3%, P = 0.009). MSI-H was seen in 25% of RT compared to 5.5% of LT (P = 0.001). RT had a higher frequency of TML-high compared to LT (32% vs. 6.9%, P < 0.001). When we compared LT from AYA (≤ 40 years; n = 220) with LT from older pts (≥ 65 years; n = 589), AYA exhibited higher mutation rates of BRCA2 (3.9% vs. 0.8%, P = 0.014), MSH2 (1.3% vs. 0%, P = 0.031), and TSC2 (1.4% vs. 0%, P = 0.031). Genes responsible for histone modification were significantly more frequently mutated in AYA than older pts: KMT2A (1.5% vs. 0%, P = 0.027), KMT2C (4.5% vs. 0%, P = 0.003), and KMT2D (4.1% vs. 0.4%, P = 0.004). High TML was seen more frequently in AYA (6.9% vs. 2.8%, P = 0.031) Conclusions: LT in AYA carry genetic alterations that are different from RT in AYA, as well as LT in older pts. Our data suggest that histone modification warrants further exploration and may be a promising target in treatment of CRC in AYA. Molecular differences between lt and rt in aya. Gene RT % LT % P-value APC 50 75.7 0.006 TP53 50 77 0.002 ARID1A 54.5 22.2 0.04 POLE 7.7 0.7 0.01 BRCA1 6.9 0 0.01 EGFR 3.3 0 0.02 NOTCH1 3.7 0 0.02 NF2 3.4 0 0.02 MEN1 3.4 0 0.02 RAD50 20 1.3 0.002 HNF1A 11.1 2.1 0.01 CDH1 4.3 0 0.02 AMER1 7.1 0.7 0.0 PALB2 6.7 0 0.02 BMPR1A 6.9 0 0.00 PRKDC 3.7 0 0.02 SMAD2 3.7 13.3 0.01