tbuckley/cabot-search huggingface dataset:
Technical validation of the electric field-induced release and measurement (EFIRM) assay for the detection of <i>EGFR</i> mutations in circulating cell free DNA in plasma and saliva.
Authors: Fang Wei, Charles Strom, Rena Xian, Wei Liao, Jordan Cheng, Michael Tu, David Chia, Yong Kim, Feng Li, Chien-chung Lin, Wu-Chou Su, Wayne Grody, David T. Wong
Journal: Journal of Clinical Oncology (2018)

e24172 Background: Electric Field-Induced Released and Measurement (EFRIM) is a signal amplification platform capable of directly detecting minute amounts of circulating mutant tumor DNA without amplification or sequencing. Two published studies have demonstrated near perfect correlation between biopsy and EFIRM CF DNA results in advanced NSCLC. The assay can be performed directly on 40 mcl of plasma or saliva without DNA isolation or amplification. EFIRM is plate based, easily automatable, and analysis can be completed within 2 hours, making it ideal for screening purposes. We have begun the technical validation of a laboratory developed EFIRM assay for 3 actionable EGFR mutations in a CLIA laboratory, the UCLA Molecular Pathology Laboratory. Methods: An EFIRM assay was developed to detect 3 common actionable mutations (Exon 19 del, p.L858R, p.T790M) commonly seen in NSCLC. Sensitivity of the EFIRM assay was assessed using reference standards obtained from Horizon Dx containing concentrations of the 3 mutations at 10%, 1% and 0.1% levels. Stability studies were also conducted. Results: The EFIRM assay was easily able to detect the p.T790M mutation at a level of 0.1% , the p.L858R at a level of 0.5% and the Exon 19 del at a level of 1% . The variance in detection for the 3 mutations is likely due to differences in the capture probe affinity for the target. Work is ongoing to improve the performance. The observed sensitivities represents improved performance in comparison to a popular IVD assay, which are 2.0% - 3.0%, 1.4% – 7.2%, and 4.0 – 5.3% for p.T790M, Exon 19 del and L858R respectively. Initial experiments demonstrated linearity and stability over several logs of mutant concentration using synthetic oligonucleotides. Conclusions: We have found the EFIRM platform to be sensitive, robust, and easy to use. We are in the process of completing a technical validation of an EFIRM based laboratory developed CLIA test for plasma and saliva for 3 mutations in EGFR and will report on the performance characteristics.
GAPVAC-101: First-in-human trial of a highly personalized peptide vaccination approach for patients with newly diagnosed glioblastoma.
Authors: Wolfgang Wick, Pierre-Yves Dietrich, Sabrina Kuttruff, Norbert Hilf, Katrin Frenzel, Arie Admon, Sjoerd H. van der Burg, Andreas von Deimling, Cecile Gouttefangeas, Judith R. Kroep, Francisco Martinez-Ricarte, Hideho Okada, Christian H.H Ottensmeier, Berta Ponsati, Hans Skovgaard Poulsen, Stefan Stevanovic, Ghazaleh Tabatabai, Hans-Georg Rammensee, Ugur Sahin, Harpreet Singh
Journal: Journal of Clinical Oncology (2018)

2000 Background: The need for treatment personalization is obvious as every cancer is molecularly unique. In addition glioblastoma (GB) are immunologically regarded as resistant, "cold" tumor with few targetable antigens available from mutations, thus demanding new personalized immunotherapies. Methods: The GAPVAC consortium realized an immunotherapy, for which personalized selection of 2 peptide-based actively personalized vaccines (APVAC) per patient for treatment of newly diagnosed GB was based not only on whole-exome sequencing but also on human leukocyte antigen (HLA)-ligandome analyses providing insight into the actual presentation of relevant epitopes in the tumor. GAPVAC-101 (NCT02149225) enrolled 16 patients in a European phase I feasibility, safety and immunogenicity trial integrated into standard of care. For APVAC1, up to 7 peptides were selected from a trial specific warehouse based on individual biomarker data. Vaccination (i.d.) with GM-CSF and poly-ICLC in 15 patients started with the 1st adjuvant cycle of temozolomide (TMZ). For APVAC2, analyses revealed a median of 36 somatic, non-synonymous mutations in the patients' tumors. From the 4th TMZ cycle, 11 patients received APVAC2 with usually 2 de novo antigens per patient selected according to mutation, actual or putative HLA presentation and immunogenicity. Overall 20 APVAC2 antigens incl. 14 mutated were vaccinated. Results: Adverse events were largely reversible injection site reactions but also 2 anaphylactic reactions and one increase in cerebral edema. Short, non-mutated APVAC1 antigens induced sustained CD8 responses with memory phenotype, being with regard to CD8 immunogenicity rate (51%, ex vivo readout) numerically at least not inferior to long mutated antigens (45%, readout after in vitro culture). Mutated APVAC2 antigens induced predominantly CD4 responses of favorable TH1 type. Median PFS and OS were 14.2 and 29 months from diagnosis, respectively, in patients that received ≥1 APVAC vaccination (N = 15). Conclusions: Overall, the GAPVAC approach displayed expected safety profiles and high biological activity warranting further development. Clinical trial information: NCT02149225.
Time to treatment failure (TTF) as a potential clinical endpoint in real-world evidence (RWE) studies of melanoma.
Authors: Rajeshwari Sridhara, Jiaxi Zhou, Marc Robert Theoret, Pallavi Shruti Mishra-Kalyani
Journal: Journal of Clinical Oncology (2018)

9578 Background: Time to treatment failure (TTF) has been suggested as a practical clinical endpoint for studies of oncologic agents using real-world evidence (RWE). However, TTF is rarely studied as an endpoint in the clinical trial setting; thus, little is known about its association with commonly used endpoints such as progression-free survival (PFS) or overall survival (OS). Methods: All studies submitted to CDER as part of a marketing application between 2010 and 2016 for treatment of patients with advanced melanoma were considered. 11 phase 3, randomized, and active-controlled trials were included in this analysis; 3 studies had 3 arms, resulting in a total of 25 randomized arms. Therapeutic agents were categorized as chemotherapy (CT), single agent PD-1 inhibitors (PD1), all immunotherapy (IT), and targeted therapy (TT). Patient-level association between TTF and PFS or OS was determined using correlation coefficients (corr) for each trial and for each therapeutic category. Additionally, to determine associations of trial-level comparative efficacy measures, pair-wise analyses were performed of hazard ratios (HR) for TTF, PFS, and OS using a weighted linear regression model. Results: 6021 patients from 11 clinical trials were included in the analysis. Patient-level corr for each trial ranged from 0.62 to 0.93 for TTF and PFS and from 0.53 to 0.82 for TTF and OS. Corr between TTF and PFS, and TTF and OS by therapeutic category are listed in the Table below. Trial-level associations between TTF HR & PFS HR and TTF HR & OS HR in all patients were poor. However, in TT these associations were much stronger (TTF & PFS: R2 = 0.56 and TTF & OS: R2 = 0.80). Conclusions: Though these analyses indicate a clear association of TTF & PFS for all categories, the association of TTF & OS may only exist for a few therapeutic categories. Extension of this work to other disease types and therapeutic categories would benefit the discussion of clinical endpoints for RWE. Therapeutic Category N mTTF mPFS mOS Corr of TTF & PFS Corr of TTF & OS All patients 6021 5.1 5.1 18.7 0.80 0.60 CT 786 2.3 2.1 11.2 0.65 0.35 PD1 1354 8.4 6.2 28.2 0.86 0.67 IT 2937 3.2 3.5 18.7 0.79 0.58 TT 2298 7.5 7.4 19.8 0.79 0.72
Pilot trial of epidermal growth factor (EGF) ointment for the patients with epidermal growth factor receptor (EGFR) inhibitor related skin side effects.
Authors: Sung Yong Oh, Suee Lee, Jung Hun Kang, Seung Tae Kim, Chan Kyu Kim, Joung Soon Jang, In Gyu Hwang, Young Saing Kim, Hee Kyung Ahn, Lee Chun Park, Jun Ho Ji, So Yeon Oh, Seong-Geun Kim, Soonil Lee, Sang-Cheol Lee, Jeeyun Lee
Journal: Journal of Clinical Oncology (2018)

10054 Background: The efficacy of the EGFR inhibitors has been demonstrated in non-small cell lung cancer (NSCLC), pancreatic cancer (PC) and colorectal cancer (CRC). Dermatological reactions can cause significant physical and psycho-social discomfort to patients. In present study, we evaluated the efficacy of EGF ointment on EGFR inhibitor related skin side effects (ERSEs) Methods: this was placebo-controlled double blind, multicenter, phase III trial. The patients diagnosed as NSCLC, PC, or CRC who were treated with EGFR inhibitors (e.g. erlotinib, gefitinib, cetuximab). Only patients with Grade ≥2 ERSEs according to the NCI-CTCAE v. 4.03 were enrolled. The patients were randomized to 3 groups; A (placebo) group, B (1ppm concentration of EGF ointment), or C (20ppm of EGF ointment). The response to study drug was defined as follows: (1) Grade 2, 3, or 4 ERSEs downgraded to ≤Grade 1 or (2) Grade 3 or 4 ERSEs downgraded to Grade 2 and persisting for at least two weeks. The quality of life (QoL) was evaluated with SKINDEX-16. Results: Between Jun 2015 and Sep 2017, final efficacy evaluation included 80 patients. Palmar plantar erythrodysesthesia was main symptomatic ERSEs of PC, Rash/Acne was main symptomatic ERSEs of NSCLC and CRC. According to the definition of effectiveness, response to EGF study drug of A (placebo), B (1ppm), or C (20ppm) were 44.4%, 61.5%, and 77.8%, respectively (P= 0.0424). They had been observed linear correlation between different EGF concentration groups (P= 0.0119). The QoL results of the SKINDEX-16 were analyzed as an overall score and three domain scores (including symptoms, emotions and functioning), and reported as mean value. Mean ± standard deviation (SD) score change from baseline to maximum response of A (placebo), B (1ppm), or C (20ppm) were -5.16 ± 8.62, -11.74 ± 14.16, and -18.58 ± 17.70, respectively (P= 0.0078). Comparing with placebo group, emotions (P= 0.005) and functions (P= 0.044) score domains were much improved by EGF containing group. Conclusions: Based on the results, the EGF ointment is effective for ERSEs compared with placebo. The EGF ointment evenly improved all kinds of symptoms and QoL of patients with ERSEs. Clinical trial information: NCT02284139.
Relationship between checkpoint molecule B7-H3 and refractoriness to anti-PD-1 therapy in non-small cell lung cancer.
Authors: Kimio Yonesaka, Keita Kudo, Shiki Takamura, Hitomi Sakai, Ryoji Kato, Koji Haratani, Takayuki Takahama, Kaoru Tanaka, Hidetoshi Hayashi, Hiroyuki Kaneda, Masayuki Takeda, Osamu Maenishi, Michiko Yamato, Masaaki Miyazawa, Kazuto Nishio, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2018)

3023 Background: While anti-PD-1 therapy improves survival in non-small cell lung cancer (NSCLC), some patients do not respond, indicating the need for alternative strategies. Some cancers express B7-H3, an immune checkpoint molecule. Herein, we evaluated B7-H3 expression and analyzed its relationship with anti-PD-1 therapy efficacy in NSCLC. Methods: Eighty-two patients with advanced NSCLC were enrolled in this retrospective study; 50 had been treated with anti-PD-1 therapy. The response rate (RR) and progression-free survival (PFS) were assessed by RECIST v 1.1. B7-H3, PD-L1, and CD8 expression were evaluated by immunohistochemistry; PD-L1 expression levels were scored by tumor proportion score (TPS). For statistical tests, the unpaired t-test was used for continuous variables; Fisher’s exact test, categorical variables; and Cox regression and log-rank tests, time to event (two-sided p-values were obtained). Results: B7-H3 was positive in 74% of patients and correlated with responsiveness to anti-PD-1 therapy (p = 0.0007). The RR was 88% for B7-H3-negative patients and 29% for B7-H3-positive patients. Multivariate analysis for PFS revealed that PD-L1 expression favorably correlated with PFS [TPS < 50 vs. ≥50; HR 3.559, p = 0.006]. In contrast, B7-H3 unfavorably correlated with PFS [negative vs. positive; HR 0.082, p = 0.003]. The median PFS was 427 days for B7-H3-negative patients, but 148 days for B7-H3-positive patients [p = 0.024]. There was no correlation between PD-L1 and B7-H3 expression, indicating these biomarkers were independent. CD8+ T cells were greater in tumors with PD-L1 TPS ≥50% than in those with < 50% [median 104 vs. 11/mm2; p = 0.0038]. However, among patients with PD-L1 TPS < 50%, B7-H3-negative tumors still had more CD8+ T cells than B7-H3-positive tumors [median 47 vs. 8/mm2; p = 0.0103]. Consistently, patients with PD-L1 TPS < 50% and B7-H3 negativity demonstrated 86% RR. Conclusions: NSCLCs lacking B7-H3 had inflammatory microenvironments and responded to anti-PD-1 therapy, despite low PD-L1 expression. Although our sample size was small, our results encouragingly suggest that B7-H3-targeting therapies will enhance the anti-tumor efficacy of anti-PD-1 antibodies.
Factors Associated With Long-term Benzodiazepine Use Among Older Adults
Authors: Lauren B. Gerlach, Donovan T. Maust, Shirley H. Leong, Shahrzad Mavandadi, David W. Oslin
Journal: JAMA Internal Medicine (2018)

This cohort study evaluates factors associated with the transition to long-term benzodiazepine use among older adults newly prescribed this drug by a nonpsychiatric clinician.
Impact of Ga-68 DOTATATE scan on clinical management of neuroendocrine tumor patients (NET): A single center review of 200 Scans.
Authors: Aman Chauhan, Timothy Waits, Ravi Jayavarapu, Elizabeth Oates, Heidi Weiss, Riham Khouli, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2018)

e16187 Background: Gallium 68 dotatate (DOTA) scanning provides physiologic imaging and assists in the localization of disease in somatostatin receptor positive NET patients (pts). Questions regarding the utility of Ga-68 DOTA scanning in the FDA post-approval era in NET pts include: usefulness in disease monitoring, correlating DOTA avidity to Ki-67 index and its impact on clinical decision making. Methods: Retrospective review of the first 200 pts who had undergone Ga-68 DOTA scanning at the Markey Cancer Center from Dec 2016 to Dec 2017 was conducted. Results: Of these 200 patients, 59.5% were females and the median age was 62 (30-84 years). The study cohort was comprised of following primary tumor sites: small bowel 37.5%, pancreas 18.5%, bronchial 14%, colon 3.5%, rectum 2%, appendix 1.5%, adrenal 0.5%, prostate 0.5%, others 3% and unknown primary 19%. Ga-68 DOTA scan influenced clinical decisions in 39% (n = 78) pts. Table 1 reports specific changes noted in the management pre-and post-gallium scan. Ga-68 DOTA scanning was able to locate primary tumors in 17 of 38 pts who were classified as NET of unknown primary based on CT imaging. Seventeen patients had comparative Ga-68 DOTA scans. Ten of 17 (58%) patients had discordant results between Ga-68 DOTA vs IV contrasted CT scan. Five progressed on CT but had stable disease or no evidence of disease on Ga-68 DOTA scan. Two demonstrated stable disease on CT but had progression on Ga-68 DOTA scanning. Subgroup analysis of mean SUV for hepatic metastatic lesions revealed 37.3 for G1 (n = 20) as compared to 32.3 for G2 (n = 37) and 17.46 for G3 (n = 4) Mean hepatic SUV of the hottest lesion in 96 patients was similar irrespective of exposure to SSA LAR. 31.3 vs 27.8 for SSA vs no SSA cohorts. Conclusions: Ga-68 DOTA scanning impacted clinical decision making in 39% of NET pts (n = 200), identified the primary site in 38 pts and assisted with differentiating G3 NET from G1/G2 based on mean SUV in a subgroup analysis (n = 61). Serial Ga-68 DOTA monitoring disease progression in our subset analysis (n = 17) revealed a 58% discordancy between anatomical vs physiologic imaging. Systemic exposure to long acting SSA does not seem to impact quality of Ga-68 DOTA scan.
Testicular germ cell tumors with malignant somatic component: A single-center experience.
Authors: Caleb Scheckel, Heidi E. Kosiorek, Richard Butterfield, Thai Huu Ho, Talal Hilal
Journal: Journal of Clinical Oncology (2018)

e16544 Background: Germ cell tumors (GCT) with a malignant somatic component (MSC) represent an uncommon variant of what is typically a curable neoplasm. Histologic subtypes of the somatic component vary widely, with previous studies suggesting sarcomas being the most common. Because this phenomenon only occurs in 3-6% of GCTs, there is a paucity of data on outcomes in different somatic subtypes. Methods: After obtaining IRB approval, we searched our institutional database from 1982 to 2017 and identified patients with GCTs with a MSC. Patient characteristics, pathologic description, treatment, and clinical outcomes were extracted from the medical records. The probabilities of overall survival (OS) and progression-free survival (PFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients with differing somatic subtypes. Results: We identified 26 cases of GCTs with MSC; the MSC was adenocarcinoma in 50% (13/26) of cases and sarcoma in 50%. Median age at diagnosis was 27 (3-66). TNM stage at presentation was 80%, 8%, and 12% for stages III, II, and I, respectively. Alpha-fetoprotein (AFP) and b-hCG were undetectable in 38% (10/26), both were elevated in 27% (7/26), only AFP was elevated in 27% (7/26), and only b-hCG was elevated in 8% (2/26). Median follow-up was 3.5 years (10 mos – 28 years); 61.5 % (8/13) with an adenocarcinoma subtype and 53.8% (7/13) with a sarcomatous subtype were still living. Those with an adenocarcinoma subtype had a median survival of 245 (186-NR) months compared with 89 (22-230) months in the sarcomatous subtype (hazard ratio (HR) 0.21, 95% CI 0.05-0.8; p = 0.015). PFS for the adenocarcinoma and sarcoma subtypes were 111 (80-292) and 56 (7-222) months, respectively (HR 0.47; CI 95%, 0.17-1.30; p = 0.133). Conclusions: Allowing for the small number of cases and the retrospective nature of the study, in this single-center experience, patients with GCT with an adenocarcinoma component appear to have improved OS compared to GCTs with a sarcomatous component.
Pembrolizumab (P) monotherapy in patients with previously treated metastatic high grade neuroendocrine neoplasms (HG-NENs).
Authors: Namrata Vijayvergia, A. Dasari, Eric A. Ross, Efrat Dotan, Daniel M. Halperin, Igor A. Astsaturov, Michael J. Hall, Nicole Marie Ross, Daniel McClean, Crystal S. Denlinger, Steven J. Cohen, Paul F. Engstrom
Journal: Journal of Clinical Oncology (2018)

4104 Background: There is currently no standard therapy for metastatic HG-NENs after progression on platinum based therapy and available chemotherapy is of limited benefit. Given the promising activity of checkpoint inhibitors in small cell lung cancer, we initiated a phase II trial of P (PD-1 inhibitor) in pts with previously treated metastatic HG-NENs. Methods: A prospective, open-label, phase 2 trial, for which pts with metastatic, histologically confirmed HG-NENs (Ki67 > 20%), excluding lung/thymus origin, were eligible after prior platinum based therapy. Other eligibility criteria included ECOG PS 0–1, adequate hematological, hepatic, and renal function. Pt selection was not based on PD-L1 expression but archival tissue was mandated for correlative testing of immunophenotype. P was administered at a dose of 200 mg every 3 weeks intravenously with and radiographic evaluation was conducted every 9 weeks. The primary endpoint was overall response rate. Results: Between 11/ 2016 and 1/ 2018, 21 pts (11 males/ 10 females) were enrolled from two institutions and received at least one dose of P, thus completing accrual. Grade 3 toxicities were observed in 6 pts (28%) with 4 (19%) at least possibly related to P (elevated liver enzymes, fatigue, hypercalcemia and hyperkalemia). Other common grade 1-2 toxicities observed include fatigue (32%), diarrhea (26%) and nausea/vomiting (37%). Efficacy analyses and correlative studies are underway and will be presented at the meeting. Conclusions: P as a single agent can be safely administered to pts with advanced HG-NENs with similar toxicity profile as described previously for this agent. Efficacy data and correlative analysis will be presented at the annual meeting. Clinical trial information: NCT02939651.
Importance of pharmacovigilance in the analysis of the profile of hospitalized patients for treatment toxicity.
Authors: Nathalia Fonseca Gamboa, Karoline Conceição Alvellos, Carina Brasiliense, Bruna Camillo, Lucyana Carvalho, Fabiano Hosken Pombo, Marcos Coelho Simões Travassos Soares
Journal: Journal of Clinical Oncology (2018)

e18846 Background: Patients undergoing oncologic outpatient treatment may present severe toxicity to medications, requiring hospitalization to control adverse reactions. Due to the risk of complications in this period, it is important to know the profile of the patients in each institution, in order to implement preventive measures. The objective was to analyze the patients profile of a clinic in Rio de Janeiro hospitalized related with toxic effects in 2017. Methods: Inpatients were followed by physicians from the institution who performed a report of hospitalization after discharge. This report was used for the initiation of the Pharmacovigilance investigation. Results: A total of 70 investigations were carried out in 2017 involving 38 drugs, with the main drugs being Doxorubicin (10), Cyclophosphamide (13), Bevacizumab (11), Carboplatin (12), Irinotecan (12) and Fluorouracil (15); and the main protocols R-CHOP, AC, Folfox, Folfiri, Carboplatin / Paclitaxel and Carboplatin / Pemetrexed. Febrile neutropenia was the main cause of hospitalization (49 - 70%), followed by gastrointestinal toxicity (18 - 25.7%). The most present CIDs were C34 (11-15.7%) and C50 (20-28.5%). Regarding age, 32 patients were 68 years of age or older (45.7%), and 23 patients were between 50 and 67 years (32.8%), being 21 men (30%) and 49 women (70%). Conclusions: A predominance of female patients over 50 years of age and of drugs that have been on the market for more than 10 years was observed. New medications seem to cause fewer hospitalizations, as they are not present in the treatment of most hospitalized patients. The Pharmacovigilance service is essential to ensure the specialized monitoring of these patients, leading to the most efficient support and prevention treatments. The decrease in hospitalizations improves patients' quality of life, in addition to reducing cost to public and supplementary health.
TCT-403 The Surgery after Stent (SAS) Registry: a gender-based analysis on clinical outcomes in women undergoing cardiac and non-cardiac surgery
Authors: Daniela Trabattoni, Elona Collaku, Stefano Savonitto, Giuseppe Musumeci, Ivan Calchera, Maddalena Lettino, Maria Molfese, Luigi Piatti, Giuseppe Tarantini, Emanuela Piccaluga, Luigi Oltrona Visconti, Marco Ferlini, Roberto Caporale, Roberta Rossini
Journal: Journal of the American College of Cardiology (2018)
Need for Reassessment of Early Transpyloric Feeding in Preterm Infants
Authors: Matthew B. Wallenstein, David K. Stevenson
Journal: JAMA Pediatrics (2018)

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