tbuckley/cabot-search huggingface dataset:
Expansion study of ADI-PEG 20, pemetrexed and cisplatin in patients with ASS1-deficient malignant pleural mesothelioma (TRAP).
Authors: Melissa Phillips, Teresa Szyszko, Peter Hall, Gary J. R. Cook, Ramsay Khadeir, Jeremy P. C. Steele, James F. Spicer, Xiaoxing Feng, Mirela Hategan, Sukaina Rashid, Amanda Johnston, John S. Bomalaski, Jonathan Shamash, Simon Pacey, Michael Sheaff, Peter Wojciech Szlosarek
Journal: Journal of Clinical Oncology (2017)

8553 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation with pegylated arginine deiminase (ADI-PEG20), which also potentiates the cytotoxic effect of pemetrexed (PEM). In the phase I dose-escalation TRAP study (NCT02029690) we showed that ADI-PEG20 with first-line PEM and cisplatin (CIS) chemotherapy (ADIPEMCIS) produced a 100% disease control rate (DCR) in patients (pts; n = 9) with ASS1-deficient thoracic cancers, with no additional toxicity (Beddowes et al 2017). Here, we present the TRAP expansion cohort experience in MPM. Methods: Good performance (ECOG 0-1) MPM pts with non-resectable disease and measurable by modified RECIST, were enrolled in a phase I TRAP expansion cohort at the maximum tolerated dose (MTD) of ADIPEMCIS, using tumoral ASS1 loss as a selection biomarker. PEM (500mg/m2) and CIS (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for a maximum of 6 cycles with maintenance ADI-PEG20 in responding pts. Primary endpoint was tumor response rate (modified RECIST), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We measured plasma arginine and citrulline concentrations, ADI-PEG20 antibodies, and biopsied patients on progression to explore resistance mechanisms. Results: 31 ASS1-deficient MPM pts (median age 67) were enrolled (11 epithelioid, 10 biphasic and 10 sarcomatoid) out of 92 screened pts. Plasma arginine decreased with a reciprocal increase in plasma citrulline. The partial response rate was 35.5% (95% CI 19.2%-54.6%) with a DCR of 93.5% (95% CI 78.6%-99.2%). Median PFS was 5.6 months (95% CI 4-6) and median OS was 10.1 months (95% CI 6.7-17.7). 10/31 pts (32.3%) experienced grade 3/4 treatment-related toxicities, the most common being neutropenia (16.1%). Upregulation of ASS1 expression was observed in 2/3 biopsies on progression. Conclusions: The ADIPEMCIS regimen is active in ASS1-deficient MPM pts, including non-epithelioid disease. Based on these data the ATOMIC-meso phase 2/3 trial has opened comparing ADIPEMCIS versus PEMCISPlacebo, focusing on pts with non-epithelioid MPM. Clinical trial information: NCT02029690.
Comparison of two different neoadjuvant chemoradiatiotherapy regimens for locally advanced rectal cancer: Results of a phase II, multicenter, randomized trial.
Authors: Ji Zhu, Yun Guan, Senxiang Yan, Ye Xu, Xinxiang Li, Sanjun Cai, Zhen Zhang
Journal: Journal of Clinical Oncology (2017)

3614 Background: The aim of this study is to compare clinical outcomes between two groups of different chemoradiation Regimens. Methods: Eligible patients were randomly assigned to Patients received either IMRT to the pelvis of 50 Gy/25Fxs concurrent with oxaliplatin 50 mg/m2 weekly and capecitabine 625 mg/m2 bid d1–5 weekly (Arm A), or IMRT to the pelvis of 50 Gy/25Fxs and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, followed by a cycle of XELOX two weeks after the completion of chemoradiotherapy (Arm B). Surgery was scheduled eight weeks after the completion of CRT. All patients were recommended to receive adjuvant CT regardless of pathological stages. A total of six cycles of XELOX chemotherapy was recommended including neoadjuvant and adjuvant period. The primary end point was pCR. Results: From February 2010 to December 2011, a total of 120 patients were randomly assigned to Arm A (n = 60) or Arm B (n = 60). One hundred and ten patients (Arm A = 53, Arm B = 57) underwent surgery, the other 10 patients didn’t receive surgery because of unresectable disease. Eight and 14 cases were evaluated as pCR in two groups respectively ( p= .157). Tumor response was further classified into good response and poor response, the former was defined as ypT0N0, ypT1-2N0 and ypT0N1a. The rate of good responses were 30.0% and 55% ( p= .006). No significant differences were found in grade 3 or 4 acute adverse events during the treatment between the two groups. However, number of patients who had delayed incision healing was 13 and 3 patients ( p= .007). There were no statistical differences in OS ( p= .553), DFS ( p= .349) and local-regional control ( p= .856) between the two groups. In the univariate analysis, N stage, MRF involvement and tumor response had significant impacts on OS, DFS and LC. In the multivariate analysis, MRF involvement had significant impacts on OS ( p= .02), DFS ( p= .01) and LC ( p= .01). Conclusions: A dose-intensified radiotherapy in neoadjuvant chemoradiotherapy demonstrated contribution to tumor regression with acceptable toxicity, but led delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigation. Clinical trial information: NCT01064999.
Clinical outcomes of EGFR exon 20 insertion in advanced NSCLC in Korea.
Authors: Seonggyu Byeon, Youjin Kim, Jiyun Lee, Jong-Mu Sun, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2018)

e21136 Background: The most common EGFR mutations in non-small cell lung cancer (NSCLC) include exon 19 deletion and L858R in exon 21 which account for 90% of EGFR mutation and are associated with high response rate to EGFR tyrosine kinase inhibitors (TKIs). Give the rarity of exon 20 insertion mutation, the clinical outcomes are not fully established. Here we present the clinical outcomes of exon 20 insertion mutation in advanced NSCLC patients in Korea. Methods: Between Jan 2009 and Dec 2017, NSCLC patients who underwent EGFR mutation test by direct sequencing or PNA Clamp and showed exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes including response to chemotherapy or targeted therapy. Results: Of 3,539 NSCLC patients who harbored activating EGFR mutation, 56 patients (1.6%) had exon 20 insertion mutation. Only for advanced NSCLC patients, 27 of 1,479 (1.8%) patients have exon 20 insertion. The median age was 60, 59% male, and 77% never smoker. The median overall survival (OS) was 29.4 months (95% Confidence Interval, CI 9.3-49.6) for 27 patients. 22 patients who received systemic chemotherapy achieved 50.0% of response rate and 77.2% of disease control rate with 4.2 months of median progression free survival (PFS). Among 6 patients who were treated with EGFR tyrosine kinase inhibitor (TKI), 3 of 4 patients with exon 20 insertion only showed progressive disease and one stable disease. Other 2 patients with combined mutation of exon 20 insertion with other activating EGFR mutation patients achieved partial response. Brain metastasis was associated with poor OS (p = 0.043). Conclusions: The incidence of exon 20 insertion mutation is rare in Korea and occasionally accompanied with common EGFR mutations. Although the response to systemic chemotherapy in patients with exon 20 insertion is comparable to other mutation, response to first or second generation EGFR TKIs is quite low, suggesting development of more efficient novel agent is urgently warranted. Further analysis will be updated.
Immunogenicity of tisagenlecleucel in relapsed/ refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) patients.
Authors: Karen Thudium Mueller, Stephan A. Grupp, Shannon L. Maude, John E. Levine, Michael Pulsipher, Michael W. Boyer, Keith Jason August, Gary Douglas Myers, Rakesh Awasthi, Edward K Waldron, Lida Bubuteishvili-Pacaud, Tanya Taran, Mariana Cota, Constantine Si Lun Tam, Ulrich Jäger, Ronan Foley, Peter Borchmann, Stephen J. Schuster, Edmund K. Waller, Theodore Willis Laetsch
Journal: Journal of Clinical Oncology (2018)

3044 Background: Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy, contains a murine single chain variable fragment (mCAR19) binding domain. Humoral immunity to anti-mCAR19 had no impact on safety or efficacy in pediatric r/r B-ALL patients (pts) (Mueller ASH 2017); immunogenicity in r/r DLBCL has not been studied. Methods: Tisagenlecleucel immunogenicity was measured in r/r B-ALL (ELIANA [NCT02435849, n = 75]; ENSIGN [NCT02228096, n = 29]) and r/r DLBCL (JULIET [NCT02445248, n = 99]) ≤ 12 months after infusion. Cellular immunity was measured in PBMCs and tested for mCAR19 peptide-activated T cell responses by stimulated intracellular interferon-gamma production. Anti-mCAR19 antibodies (Ig) were measured by flow cytometry at baseline and after treatment. Treatment-induced Ig was defined as the ratio of postbaseline Ig levels to baseline. The impact of preexisting and treatment-induced Ig and T-cell activation on cellular kinetics, efficacy and safety were determined. Results: 84.6% of r/r B-ALL and 91.4% of r/r DLBCL pts had preexisting humoral immunogenicity. Treatment-induced humoral immunogenicity occurred in 34.6% of r/r B-ALL and 5% of r/r DLBCL pts. No relationship was found between tisagenlecleucel expansion (AUC0-28d) and preexisting humoral responses in r/r B-ALL (r2= 0.002) or r/r DLBCL (r2= 0.008), or treatment-induced humoral responses in r/r B-ALL (r2= 0.006). Results for Cmax were similar. Treatment induced humoral responses did not impact expansion or persistence of CARs in B-ALL, but sample size prevented correlation analysis in DLBCL as only 5% of pts had treatment-induced Ig. Preexisting humoral immunity did not appear to impact transgene persistence, duration of response, event-free survival or safety in either indication. T-cell responses were consistent over time with net responses < 1% at baseline and postinfusion for the majority of pts. T-cell responses did not appear to impact transgene expansion or persistence or pt outcomes. Conclusions: Preexisting/treatment-induced humoral and antigen-specific cellular immunity did not impact tisagenlecleucel expansion, persistence, efficacy or safety. Clinical trial information: NCT02435849, NCT02228096, NCT02445248.
Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality
Authors: Merry L Lindsey, Mira Jung, Andriy Yabluchanskiy, Presley L Cannon, Rugmani Padmanabhan Iyer, Elizabeth R Flynn, Kristine Y DeLeon-Pennell, Fritz M Valerio, Courtney L Harrison, Crystal M Ripplinger, Michael E Hall, Yonggang Ma
Journal: Cardiovascular Research (2018)

Macrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI).CXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source. Adult male C57BL/6J mice were subjected to coronary artery occlusion, and MI mice were randomly infused with recombinant mouse CXCL4 or saline beginning at 24 h post-MI by mini-pump infusion. Compared with saline controls, CXCL4 infusion dramatically reduced 7 day post-MI survival [10% (3/30) for CXCL4 vs. 47% (7/15) for saline, P < 0.05] as a result of acute congestive heart failure. By echocardiography, CXCL4 significantly increased left ventricular (LV) volumes and dimensions at Day 5 post-MI (all P < 0.05), despite similar infarct areas compared with saline controls. While macrophage numbers were similar at Day 5 post-MI, CXCL4 infusion increased Ccr4 and Itgb4 and decreased Adamts8 gene levels in the infarct region, all of which linked to CXCL4-mediated cardiac dilation. Isolated Day 5 post-MI macrophages exhibited comparable levels of M1 and M4 markers between saline and CXCL4 groups. Interestingly, by both ex vivo and in vitro phagocytosis assays, CXCL4 reduced macrophage phagocytic capacity, which was connected to decreased levels of the phagocytosis receptor CD36. In vitro, a CD36 neutralizing antibody (CD36Ab) significantly inhibited macrophage phagocytic capacity. The combination of CXCL4 and CD36Ab did not have an additive effect, indicating that CXCL4 regulated phagocytosis through CD36 signalling. CXCL4 infusion significantly elevated infarct matrix metalloproteinase (MMP)-9 levels at Day 5 post-MI, and MMP-9 can cleave CD36 as a down-regulation mechanism.CXCL4 infusion impaired macrophage phagocytic capacity by reducing CD36 levels through MMP-9 dependent and independent signalling, leading to higher mortality and LV dilation.
Tumoral genetic variations of the homologous recombination (HR) reparation system in brain metastases in women with epithelial ovarian cancer (EOC).
Authors: Maxime Fontanilles, Laurent Castera, Nicolas Gouardon, Corinne Jeanne, Dominique Vaur, pierre-Emmanuel Brachet, Florence Joly
Journal: Journal of Clinical Oncology (2017)

e17048 Background: Brain metastases (BM) EOC are rare and late events. We explored tumoral genetic variations of HR system. We identify genomic alterations with NGS in both primary tumor and BM EOC Methods: Seven patients suffering from histologically proven EOC and BM, which underwent neurosurgery, were included in the study. Seven matched samples (primary tumor and BM) were analyzed by high throughput sequencing after enrichment by capture of the whole exome. After bioinformatics procedures (BWA, HaplotypeCaller, Varscan2, Outlyzer) the analysis was restricted firstly to a in silico panel of 69 genes involved in HR system. Results: Mean age was 56 years (47 to 71). Five had serous and 2 endometrioid carcinomas. All the patients had an initial FIGO stage ≥IIIA, were platine-sensitive. Median time from diagnosis of EOC to BM was 29 months (24 to 76). BM occurred after first line treatment in 5 cases and after at least 2 relapses in the 2 other cases. Median Overall survival (OS) from diagnosis of BM was 17 months (1 to 45). Five primary tumor showed a variation of at least one HR gene: pathogenic variants inactivating in BRCA2 (n = 2), CDK12 (n = 1) and probably pathogenic missenses in BRIP1 (n = 1) and TOPB1 (n = 1). These 5 variations have been also found in the BM tissues. Among the 2 patients without variations in the primary tumor, 2 probably pathogenic missenses were detected in the BM tumor (1 FANCD2 and 1 FANCM). Time to BM relapse and OS were longer among these 2 last patients compared to the remaining 5 patients (median 68 vs 29 months and 90 vs 56 months, respectively). Conclusions: Patients with BM presented HR somatic mutations and are susceptible to have high response to Parp inhibitors.
Role of adjuvant chemoradiation in treatment of elderly women with advanced high-grade endometrial cancer: A SEER-Medicare analysis.
Authors: Hyo K. Park, Julie J. Ruterbusch, Michele L. Cote
Journal: Journal of Clinical Oncology (2017)

5589 Background: Use of combined adjuvant chemoradiation (CRT) in treatment of advanced stage endometrial cancer is increasing, but the survival benefit over chemotherapy (CT) or radiation therapy (RT) alone remains unclear. We examined adjuvant treatment patterns and survival associated with CRT for Stage III-IV high-grade endometrial cancer using a large population-based database. Methods: Women 66 years of age or older who underwent primary surgical treatment for Stage III-IV high-grade endometrial cancer between 2000-2011 were identified from the SEER-Medicare database. Demographic and clinical predictors for receipt of adjuvant CRT vs. CT or RT alone were examined using multinomial logistic regression. In addition, overall survival (OS) by adjuvant treatment type, histology (endometrioid vs. non-endometrioid), stage, and age group were examined using Kaplan-Meier estimates and Cox proportional hazards regression. Results: Of the 2,735 eligible women, 13.1% received CRT vs. 42.5% CT alone vs. 13.2% RT alone, and 31.1% received no adjuvant treatment. Hispanic ethnicity, carcinosarcoma, serous histology, and Stage IV disease were significant predictors of receiving CRT over CT alone. Increasing age group, non-Hispanic black race/ethnicity, endometrioid histology, having 3+ comorbidities at the time of surgery, and not being partnered were associated with receiving RT alone over CRT. For Stage III disease, those who received CT (HR 1.30; 95% CI 1.09-1.55) or RT alone (HR 1.34; 95% CI 1.09-1.64) had poorer 5-year OS compared to CRT. In a subgroup analysis, the relative survival benefit of CRT vs. CT was only significant for women &lt; 75 years of age and was more pronounced for endometrioid (HR 1.72; 95% CI 1.22-2.41) vs. non-endometrioid histology (HR 1.22; 95% CI 0.99-1.49). For Stage IV disease, there was no survival difference among those who received CT or RT only compared to CRT regardless of histologic subtypes. Conclusions: Adjuvant CRT was associated with improved OS in elderly women with Stage III high-grade endometrial cancer. This survival benefit was more pronounced for endometrioid histology and women &lt; 75 years of age.
Abstract 16483: A New Cardiovascular Disease Risk Model using Historical Repeated Predictors in Electronic Health Records
Authors: Ellie Paige, Jessica Barrett, Irwin Nazareth, Irene Petersen, Angela Wood
Journal: Circulation (2016)

Introduction: GP-embedded pre-screening to identify high-risk patients for formal risk assessment could be improved by utilizing historical repeated risk predictors. The aim of this study was to de...
Incidence of venous thromboembolism in the gynecologic cancer patient population at a single institution after implementation of pre-operative venous thromboembolism prophylaxis.
Authors: Elizabeth Hopp, Lauren Martin, Jennifer Kumar, John Nakayama
Journal: Journal of Clinical Oncology (2018)

e17529 Background: Venous thromboembolism (VTE) is a significant risk for women with gynecologic cancer. As the risk of VTE is increased along with morbidity and mortality in the gynecologic oncologic population undergoing major surgery, the focus of prophylaxis has shifted to also providing pre-operative prophylactic anticoagulation. Yet, there remains controversy in the optimal prophylactic regimen for the major surgical gynecologic cancer patient. The objective of this study was to define the incidence of VTE in gynecologic cancer patients prior to and after the institutional implementation of pre-operative heparin in the VTE prophylaxis regimen. Methods: A retrospective cohort study was performed in patients with gynecologic cancer who underwent a major surgical procedure from January 2010 to December 2016 at a single institution. The incidence of post-operative VTE was compared between patients who received post-operative mechanical and chemical prophylaxis and those who received a single dose of pre-operative heparin in addition starting in 2015. Factors including estimated surgical blood loss, amount and location of disease at time of surgery, and route of surgery were examined in those diagnosed with a VTE post-operatively. Results: Of the 609 surgical patients with gynecologic cancer prior to the initiation of a single dose of preoperative heparin, 42 (6.90%) were diagnosed with a post-operative VTE. After initiation of pre-operative heparin, 17 (3.27%) of 520 patients experienced VTE postoperatively. There was a significant difference between the incidence of VTE after the practice change (p < 0.006, 95% CI 1.03-6.23%). Surgical blood loss was similar in both groups. Those diagnosed with a VTE tended to have a heavy burden of disease at time of surgery and underwent laparotomy. Conclusions: A significant decrease in the incidence of VTE in patients with gynecologic malignancy undergoing surgery was seen with the initiation of a single dose of pre-operative heparin. This shift in the standard of care has had a meaningful impact at an institutional level and has potential to be impactful at a national level.
Educational level and outcome in small-cell lung cancer (SCLC): A population-based study.
Authors: Salomon Tendler, Marit Holmqvist, Gunnar Wagenius, Rolf Lewensohn, Kristina Viktorsson, Mats Lambe, Luigi De Petris
Journal: Journal of Clinical Oncology (2016)

e20096 Background: To examine possible associations between educational status and outcome in patients with SCLC. Methods: The present study was based on information in LcBaSe, a lung cancer research database generated by record linkages between the Swedish National Lung Cancer Register and several other population-based registers. Educational level was categorized according to number of years of schooling; low ( ≤ 9 years), middle (10-12 year) and high ( ≥ 13 years). Stage was classified into two groups: limited disease (LD) and extensive disease (ED). Risk of death expressed as hazard ratios (HR) with 95 % confidence interval (CI) were computed in multi-variable analyses adjusted for age, gender, disease stage at diagnosis, number of persons/household and performance status (PS). In additional steps, separate multivariable analyses stratified by gender and stage were performed. Results: The study population encompassed4256 patients with a SCLC diagnosis between 2002-2011. Median age was 69 years. 3174 (74 %) patients were diagnosed with extensive disease. One fifth of patients had a poor performance score (PS 3-4). Fifty percent had a low educational level (middle 37 %; high 11 %). Slightly less than half of patients (46%) lived in a one-person household. Compared to men with a low level of education, the risk of death was significantly lower in men with high education (HR 0.84; 95 % CI 0.73-0.98). The corresponding comparison between women with low and high education yielded an estimate of 0.92(95% CI 0.78-1.09). A statistically significant gradient in outcome was observed in patients with LD (high vs low education, HR 0.76; 95 % CI 0.58-0.98), but not in the ED subgroup (HR 0.92; 95 % CI 0.82-1.04). Conclusions: In Swedish men diagnosed with SCLC, and among patients with limited disease SCLC, a low education was associated with a poorer prognosiscompared to patients with a high education.The origins of these differences in outcome between educational groups are unknown, but may reflect differences in access to care, treatment intensity, general health status, social support and lifestyle factors.