tbuckley/cabot-search huggingface dataset:
Abstract 12118: Risk of Thrombotic Events After Discontinuation of Aspirin in Perioperative Period in Patients With Established or at Risk of Coronary Artery Disease: A Systematic Review and Meta-analysis
Authors: Faraz Khan Luni, Haris Riaz, Abdur R Khan, Sadik Khuder, Yusuf Kanjwal
Journal: Circulation (2015)

Introduction: Aspirin for prolonged duration is commonly prescribed to patients with a history of cardiovascular events who are at continued risk for occlusive vascular events (secondary prevention). Patients in the peri-operative period are not only at an increased risk of bleeding but also for thrombotic vascular events because of the pro-thrombotic milieu. Hypothesis: The objective of our study was to do a systematic review and meta-analysis to compare the risk of thrombotic events and the risk of bleeding in patients with early (3-5 days) versus late discontinuation/no discontinuation of aspirin. Methods: PubMed and Embase were searched to identify the studies that report discontinuation or non-adherence of aspirin in patients undergoing surgery. The studies were included if they reported thrombotic events (stroke, all-cause mortality, MI, stent thrombosis &amp; restenosis, stroke, heart failure, VTE, acute limb ischemia, perioperative cardiovascular complications) and perioperative bleeding. Odds ratio was calculated for the measured outcomes. The outcomes were pooled by generic inverse variance method in a random effects model and corresponding forest plots were made. Quality assessment was done as per Newcastle-Ottawa scale. Results: Our search strategy revealed 1018 studies out of which 6 observational studies (3 evaluating cardiac and 3 non-cardiac surgeries) met the inclusion criteria. There was no difference in the risk of thrombotic events both in early or late discontinuation of aspirin (OR 1.17, 95% CI= 0.74-1.84, p =0.50; I2 = 56%) (Figure 1). Early discontinuation of aspirin showed a decreased risk of peri-operative bleeding (OR 0.82, 95% CI= 0.67-0.99; p =0.04; I2 = 42%) (Figure 2). Conclusion: Planned discontinuation of aspirin is acceptable with no increased risk of thrombotic events and with a decreased risk of bleeding. Moreover the decreased risk of peri-operative complications may help reduce the length of stay and associated co-morbidities.
Adjuvant chemotherapy in high-risk liposarcomas.
Authors: Philipp Loehmer, Alessandro Gronchi, Thomas Brodowicz, Eberhard Stoeckle, Dario Callegaro, Jean-Michel Coindre, Lars Podleska, Wolfgang Lamm, Marco Fiore, Sophie Cousin, Juergen Treckmann, Sophie Schur, Stefano Radaelli, Maud Toulmonde, Anna-Carinna Reis, Chiara Colombo, Christoph Pöttgen, Lewin Eisele, Antoine Italiano, Sebastian Bauer
Journal: Journal of Clinical Oncology (2016)

11036 Background: Stage III soft tissue sarcomas are associated with a high risk of metastatic spread. Adjuvant chemotherapy (ACTX) may provide a small survival benefit, especially in sarcomas with large size ( > 10cm), G3 differentiation and extremity location when analyzed in pooled cohorts of randomized trials. Very little is known how these findings apply to different histological subtypes. Methods: We have conducted a retrospective analysis of 400 UICC stage III LPS that were treated consecutively in 4 European countries (I, FR, AT, D). Covariates were size (5-10cm, 10-15cm, > 15cm), grading (G2/G3), subtype (dedifferentiated [DDLPS], myxoid [MLPS], pleomorphic [PLPS]), location and the use of CTX. Univariate and multivariate analyses were performed for metastasis-free (MFS) and overall survival (OS). Results: Patient characteristics were: male/female ratio 61:39, median age 58y, 53% DDLPS; 35% MLPS; 12% PLPS. Extremity was the major primary location (47%; retroperitoneal: 30%). 65% of patients (pts) had tumors ≥ 10cm. Five and 10y OS was 64% and 50% for the entire cohort. 5yOS was 70% for the ACTX and 61% for pts without CTX. 40% of pts received CTX (majority MLPS 59%; neoadjuvant CTX: 17%; ACTX 26). Univariate analyses of MFS showed better MFS for CTX in G3 (HR: 0.549; p = 0.023) and a positive trend for CTX in extremity LPS (HR: 0.723; p = 0.223) and MLPS (HR: 0.785; p = 0,482). For OS we observed HRs of 1.367 (DDLPS; p = 0.237), 1,739 (MLPS; p = 0.232) and 0.491 (PLPS; p = 0.12) for the use of CTX. OS was better with CTX in pts with extremity primaries (HR 0.894, p = 0.705) and G3 tumors (HR: 0.523; p = 0.010). Multivariate analyses (OS) revealed grade 3 (HR: 1.716; p = 0.006), size > 15cm (HR: 2.346; p = 0.000) and MLPS (HR: 0.37; p = 0.000) as prognostic factors. Perioperative CTX (OS) was not associated with a survival benefit (HR of 0,804 (p = 0,291) in the entire LPS cohort nor in DDLPS and MLPS subgroups. Conclusions: This largest analysis for stage III LPS provides evidence for a survival benefit for pts with PLPS but not for patients with DDLPS or MLPS when treated with traditional adjuvant protocols. Despite its limitations, this study provides a reference for future LPS studies and underscores that future adjuvant trials in STS require stratification for exact histological subtypes.
Induction chemoradiotherapy for esophageal cancer: Comparing CROSS regimen with cisplatin/5-FU.
Authors: Abraham Geller, Ashok Muniappan, Hui Zheng, Henning A Gaissert, Cameron D Wright, Douglas J Mathisen, Michael Lanuti
Journal: Journal of Clinical Oncology (2018)

4070 Background: While trimodal therapy with neoadjuvant carboplatin/paclitaxel (CP) has demonstrated superiority over surgery alone for treatment of locally advanced esophageal cancer (LAEC), its superiority to alternative regimens is yet unproven. Here we directly compare CP against cisplatin/5-FU (CF), the historical standard, as a component of trimodal therapy for LAEC. Methods: Patients receiving trimodal therapy with either CP or CF for LAEC at a single institution from 2002 to 2017 were included in this retrospective study. Clinical data, treatment regimen, and tumor response were obtained from medical records. The primary outcome was pathologic complete response (pCR). Secondary outcomes were overall (OS) and disease–free survival (DFS), calculated from the date of surgery until death (OS & DFS) or first recurrence (DFS only). Primary outcomes were measured with logistic regression; survival was estimated with Kaplan–Meier and Cox Proportional Hazards models. Patient characteristics were compared with Student’s T and chi square tests. Results: 326 patients were included in this study. 187 patients (57%) received CP; 139 patients (43%) received CF. Mean follow-up was 36 months. The CP group was older (mean age 64 vs. 62, P < .01) and had a higher rate of hypertension (49% vs. 35%, P = .02) than the CF group. Distribution of tumor stages was similar between groups (P = .3). CF was associated with improved pCR compared to CP in both univariate (OR 1.8, P = .02) and multivariate (OR 2.2, P = .01) analysis. CF showed improved median OS compared to CP (42 vs. 29 months, P = .04), and trended toward improved DFS (27 vs. 17 months, P = .08). In multivariate analysis controlling for age, performance status, and comorbidities, CF was associated with improved OS (HR .68, P = .03) and DFS (HR .67, P = .02) compared to CP. Conclusions: Trimodal therapy with CP has become the standard of care for curative treatment of LAEC, yet most studies compare it against surgery alone rather than trimodal therapy with an alternative regimen. Here we directly compare CP to the historical standard regimen (CF), finding that CP is associated with worse tumor response and survival. These findings warrant further investigation with prospective studies.
Implementation of active pharmaceutical search for adverse drug reactions.
Authors: Marcos Coelho Simões Travassos Soares, Nathalia Fonseca Gamboa, Karoline Conceição Alvellos, Carina Brasiliense, Bruna Camillo, Lucyana Carvalho, Marcio Borella, Fabiano Hosken Pombo
Journal: Journal of Clinical Oncology (2018)

e18825 Background: Adverse Drug Reactions (ADRs) are any responses to a drug that is harmful, unintended and that occurs at doses normally used in humans for prophylaxis, diagnosis and treatment of diseases or for modifying a physiological function. Monitoriment of reactions is essential to ensure the quality and safety of medicinal products after they are placed on the market. Pharmacovigilance is a science that performs this function by identifying, evaluating, understanding and preventing these drug-related reactions. The objective of this study is to describe the implementation and demonstrate the importance of Pharmacovigilance by the active search for ADR in a private cancer reference center in the state of Rio de Janeiro. Methods: The evaluation period was 2012 to 2017. Until 2012, the Pharmacovigilance tool used was voluntary notification by filling out a specific form. From 2013 until today the pharmacists used the methodology of active search of the report of intercurrences completed automatically by the nursing team in the medical record. Results: In 2012, the monthly average of treatments that was voluntarily notified due to ADR by nursing was 10.58 notifications (0.34%). After the implantation of the new methodology of active search by the pharmacy team, a significant increase in the number of ADR identified was observed. In 2013 the monthly average increased to 67.50 notifications (2.12%); in 2014 were 88.58 (2.74%); in 2015 there were 97.83 (2.85%); in 2016 were 149.17 (3.42%) and in 2017 the average was 140.75 (2.27%). Conclusions: The active search methodology proved to be superior to the voluntary notification method. The results demonstrate that, in addition to mitigating possible underreporting, they indirectly emphasize the importance of the pharmacist as an integral part of the multidisciplinary team in order to increase safety in the use of drugs in our institution.
Associations of anticoagulant use with outcome in newly diagnosed glioblastoma.
Authors: Emilie Le Rhun, Els Genbrugge, Roger Stupp, Olivier L. Chinot, Louis B. Nabors, Timothy Francis Cloughesy, David A. Reardon, Wolfgang Wick, Thierry Gorlia, Michael Weller
Journal: Journal of Clinical Oncology (2018)

e14070 Background: To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. Methods: We assessed survival associations of anticoagulant use from baseline up to start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomized clinical trials in newly diagnosed glioblastoma including 1,273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with: anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents, versus neither nor. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. Results: Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS compared to no use on multivariate analysis (p = 0.001, HR = 1.52, 95% CI: 1.18-1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. Conclusions: Anticoagulant use was not associated with improved OS. Our analysis does not support the notion that anticoagulants exert relevant anti-tumor properties in glioblastoma.
Phase 1 study of cemiplimab, a human monoclonal anti-PD-1, in patients with unresectable locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC): Final efficacy and safety data.
Authors: Taofeek Kunle Owonikoko, Kyriakos P. Papadopoulos, Melissa Lynne Johnson, Marta Gil Martin, Victor Moreno, April K.S. Salama, Emiliano Calvo, Nelson S Yee, Howard Safran, Antonio González-Martín, Raid Aljumaily, Daruka Mahadevan, Jiaxin Niu, Kosalai Kal Mohan, Jingjin Li, Elizabeth Stankevich, Israel Lowy, Matthew G. Fury, Hani M. Babiker
Journal: Journal of Clinical Oncology (2018)

9557 Background: Initial analysis of expansion cohorts (ECs) patients in a phase 1 study showed that cemiplimab (REGN2810) demonstrated a positive risk/benefit profile and produced antitumor activity in patients (pts) with advanced CSCC. We now report mature final data from the CSCC ECs of the phase 1 study (NCT02383212). Methods: Pts with distantly metastatic and locally advanced CSCC were enrolled in EC 7 and 8, respectively. All pts received cemiplimab 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks for up to 48 weeks. Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate (ORR; complete response [CR] + partial response [PR]). The data cutoff date was Oct 02, 2017. Tumor response was assessed by an independent central review committee. Results: A total of 26 pts were enrolled (21 M/ 5 F; 10 in EC 7, 16 in EC 8; median age: 72.5 years [range, 55–88]; ECOG performance status 1 in 16 pts and 0 in 10 pts). Median duration of cemiplimab exposure was 36.0 weeks. The most common treatment-related adverse event (TRAE) of any grade was fatigue (26.9%). The following ≥Grade 3 TRAEs occurred once: asthenia, maculopapular rash, increased alanine aminotransferase, increased aspartate aminotransferase, adrenal insufficiency, and myalgia. ORR was 50.0% (95% CI: 29.9–70.1); 0 CR and 13 PRs. Disease control rate (DCR; ORR + stable disease [SD] + non-CR + non-progressive disease [PD]) was 76.9% (95% CI: 56.4–91.0); 6 SD and 1 non-CR/non-PD. Durable DCR (SD/non-CR/non-PD or response for ≥105 days) was 65.4% (95% CI: 44.3–82.8). 3 pts were not evaluable for response. The median duration of response has not been reached; however, for pts with PR, the duration of response exceeded 6 months in 7 pts and 12 months in 2 pts. Median time to response was 2.3 months (range, 1.7–7.3). Median duration of follow-up was 11.0 months (range: 1.1–17.0). Conclusions: In this study, cemiplimab demonstrated a positive risk/benefit profile and produced substantial antitumor activity as well as durable responses in pts with advanced CSCC. Clinical trial information: NCT02383212.
SWOG S0905: A randomized phase II study of cediranib versus placebo in combination with cisplatin and pemetrexed in chemonaive patients with malignant pleural mesothelioma.
Authors: Anne S. Tsao, Jieling Miao, Ignacio Ivan Wistuba, Nicholas J. Vogelzang, John Heymach, Frank V. Fossella, Charles Lu, Mario R. Velasco, Brandy Box-Noriega, James Gilbert Hueftle, Shirish M. Gadgeel, Mary Weber Redman, David R. Gandara, Karen Kelly
Journal: Journal of Clinical Oncology (2018)

8514 Background: Anti-angiogenic inhibitors combined with cisplatin-pemetrexed (CP) have shown efficacy in unresectable malignant pleural mesothelioma (MPM). Cediranib, a vascular endothelial growth factor receptor and platelet derived growth factor receptor inhibitor, showed preliminary efficacy in SWOG 0905 phase I. Methods: S0905 phase II randomized MPM patients to CP with cediranib/placebo followed by maintenance cediranib/placebo (CPC v CPP). Randomization was stratified by PS (0-1 vs 2) and histology [epithelioid (E) vs biphasic or sarcomatoid (B/S)].The primary endpoint was RECIST PFS. The trial was designed to detect a difference in PFS at the 1-sided 0.10 level, using a stratified log-rank test. Results: Ninety-two eligible patients were enrolled (2011-2016). Median age was 72, 85% men, 75% E and 25% B/S histology. The trial met its primary objective: PFS was significantly prolonged by CPC (HR 0.69, p = 0.096, median PFS 7.2 vs 5.6 months). CPC did not increase RECIST RR (26% vs 18%, p = 0.48), but did prolong the duration of response (median 6 vs 1.7 months). By modified RECIST, CPC increased RR (53% vs 20%, p = 0.01). CPC numerically improved OS (HR 0.84, p = 0.44; median OS 10 vs. 8.5 months). E patients had a markedly improved survival compared to B/S patients (median PFS 7.1 vs 3.4 months, HR 0.61, p = 0.047 and median OS 10.9 vs 6.4 months, HR 0.605, p = 0.045). B/S patients may derive less benefit from cediranib than E patients in terms of OS (HR 0.83 for E v HR 1.03 for B/S) despite a similar RECIST PFS (B/S HR 0.71 and E HR 0.72). Grade 3-4 toxicities were 64% versus 54% for CPC vs. CPP (p = 0.273). The most common toxicities (any grade) associated with CPC were diarrhea (46.7% vs. 17%) and hypertension (44% vs. 15%). Conclusions: The addition of cediranib to CP improves RECIST PFS in patients with MPM. E patients may benefit more with anti-angiogenic agents. Clinical trial information: NCT01064648.Outcome CPC (median in months) CPP (median in months) HR [95% CI], p-value ITT PFS (RECIST) 7.2 5.6 0.69 [0.45-1.07], 0.096 ITT PFS (modified RECIST) 6.9 5.6 0.84 [0.55 – 1.23], 0.42 ITT OS 10 8.5 0.84 [0.54 – 1.32], 0.44 E PFS (RECIST) 7.4 6.1 0.72 [0.44-1.17], 0.18 B/S PFS (RECIST) 3.4 3 0.71 [0.29-1.7], 0.44
Molecular testing of gliomas
Authors: D. Konvalinka, R. Mech, I. Urbanovska, O. Motyka, M. Smolikova, J. Simova, S. Pitronova, J. Zmolikova, M. Uvirova, J. Dvorackova
Journal: Annals of Oncology (2018)

Background: Gliomas are the most frequent CNS primary tumours, which account for up to 80 % of brain malignancies. Important diagnostic and prognostic factor, and recently significant WHO glioma classification marker as well, is mutational status of IDH1/2 genes. Moreover, search for another markers with predictive character is needed. Methylation status of MGMT gene promoter is one of relevant predictive markers, connected with therapeutic response to chemotherapy. Methods: 260 glioma samples were biopted or surgically resected at Neurosurgery Clinics within Moravian – Silesian Region, Czech Republic. DNA was extracted from native tissue samples. IDH1/2 gene mutation detection was performed with extension primer method – SnaPshot® assay. MGMT gene promoter methylation status was tested by nested methylation-specific PCR and real-time PCR, preceded by bisulfite conversion of DNA samples. Results: Analysis of 260 glioma samples was performed. Out of this, 218 samples were histopatologically diagnosed as high-grade (HG) gliomas and 42 samples were classified as low-grade (LG) gliomas. Median age of all patients was 60 years (range 24 – 82 years) at the time of diagnosis. 55 % of patients were men. IDH1 gene mutations were detected in 29, 2 % (76/260) of patients, MGMT gene promoter methylation was detected in 60, 8 % (158/260) of patients. IDH2 gene mutations were not detected. Median overall survival (mOS) was 9 months longer in patients with HG glioma and IDH1 gene mutation than in patients without mutation. If complete set of HG and LG gliomas was included, 11 months difference of mOS has been reached. Furthermore, statistically significant difference of mOS among the group of patients with IDH1 gene mutations and without mutations has been reached (p value < 0.001 and p < 0.001, respectively). Conclusions: Observed relationship of IDH1 gene occurrence to median OS in patients with primary glioma was statistically significant. MGMT gene promoter methylation did not have any statistically significant influence to OS in observed HG glioma patients. Legal entity responsible for the study: CGB Laborator a.s. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Characterization and similarity assessment of a pegfilgrastim biosimilar MYL-1401H.
Authors: Praveen Kallamvalliillam Sankaran, Dinesh V. Palanivelu, Reshmi Nair, Preethy S.E. Nair, Harish V. Pai, Praveen Reddy Moole, Rajesh Ullanat, Parag Goyal, Daniel Ranayhossaini, Jeffrey Smith, Gopinath Ranganna
Journal: Journal of Clinical Oncology (2018)

e19028 Background: MYL-1401H is a proposed biosimilar of pegfilgrastim (Neulasta [peg-GCSF]), a long-acting granulocyte colony-stimulating factor (GCSF) indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy. Methods: Structural and physicochemical characterization of MYL-1401H and US-licensed and EU-approved peg-GCSF (US- and EU-peg-GCSF) were performed. GCSF receptor binding was assessed by surface plasmon resonance and potency measured by in vitro stimulated proliferation in the murine myelogenous leukemia cell line M-NFS-60. In vivo rodent studies included a pharmacodynamic study (single dose up to 3 mg/kg) using a validated chemically induced neutropenic rat assay and a 28-day repeat-dose toxicology study (up to 1.5 mg/kg/day). Results: MYL-1401H, US-, and EU-peg-GCSF demonstrated high similarity in structure, molecular mass, impurities, and functional activity. Similar GCSF receptor binding was observed for MYL-1401H, US-, and EU-peg-GCSF: mean (SD) KD, 394 (40), 380 (49), and 397 (51) pM, respectively. Equivalent relative potency was observed in in vitro cell proliferation: mean (SD), 1.05 (0.08), 1.05 (0.05), and 1.01 (0.07). Neutrophil (Table) and leucocyte counts were comparably increased in neutropenic rats. Toxicology findings and drug kinetics were comparable between MYL-1401H and EU-peg-GCSF. Conclusions: MYL-1401H, US-, and EU-peg-GCSF demonstrated high analytical and functional similarity. Table. Pharmacodynamic Analysis of Neutrophil Response in Neutropenic Rats Dose (mg/kg) Emax, cells × 109/L blood tmax, h AUEC0-t last, h*cells × 109/L blood AUECeff 0-t last, h*cells × 109/L blood Vehicle (non-neutropenic) 2.6 103 483.8 — Vehicle 2.6 226 305.9 — US-peg-GCSF 0.1 8.1 38 929.6 623.7 0.3 8.0 72 971.8 665.8 1.0 22.7 118 2358.3 2052.4 3.0 39.3 122 3404.2 3098.3 EU-peg-GCSF 0.1 7.6 67 834.5 528.6 0.3 7.5 89 866.3 560.4 1.0 19.6 113 1932.5 1626.6 3.0 40.2 122 3566.7 3260.8 MYL-1401H 0.1 10.6 113 1097.3 791.4 0.3 8.7 72 1008.5 702.5 1.0 21.2 132 2258.9 1953.0 3.0 48.6 125 4224.8 3918.9 ANC, absolute neutrophil count; AUEC, area under effect-time curve; AUECeff, effective AUEC; Emax, maximum ANC response; tmax, time of Emax.Mean values are shown. N = 10/group.