tbuckley/cabot-search huggingface dataset:
Detection of low abundant mutants from circulating tumor DNA of plasma, pleural effusion, and cerebrospinal fluid of lung cancer patients using a novel mutant-capture enrichment approach.
Authors: Rui Lin, Yue Pu, Li Mao
Journal: Journal of Clinical Oncology (2019)

e14520 Background: In the era of precision medicine, liquid biopsy analysis is well accepted based on advantages including availability, non-invasiveness, and non-heterogeneity. However, the circulating tumor DNA (ctDNA) in liquid biopsy is diluted by a large excess of wild-type alleles, which necessitates high sensitivity approach for ctDNA detection. In addition, ctDNA analysis from different liquid biopsy samples need to be evaluated. Methods: We have developed a novel mutant-capture based method, termed PErsonalized Analysis of Cancer (PEAC), for high sensitivity detection of cancer driver mutants at abundance as low as 0.01-0.1% for circulating free DNA (cfDNA) standards. ctDNA samples were extracted from body fluids of lung cancer patients including plasma, pleural effusion and cerebrospinal fluid. EGFR mutants predictive of EGFR tyrosine kinase activity were enriched using PEAC technology, and analyzed using Sanger sequencing. Results: Plasma ctDNA samples B7110003, B7110010, and B7112012 had no or barely detectable L858R mutation, which was enriched to 50-90% after PEAC and readily detected by Sanger. T790M was undetectable before PEAC in plasma sample B7112052 and became 50% after PEAC enrichment. Pleural effusion samples E8106029 and E8111305 had dominated L858R and T790M peaks, respectively, in Sanger chromatograms after PEAC, which was almost to the background levels prior to PEAC. Interestingly, both EGFR L858R and T790M mutants were detected in pleural effusion sample E8106029 after PEAC; the sample was from a patient who had previously treated with an EGFR tyrosine kinase inhibitor (TKI), suggestive of resistance developed after target therapy and the utility of PEAC in monitoring patient’s response to EGFR TKI. In addition to enriching point mutations, we also established enrichment of the most frequently occurred EGFR 19 deletion, E746_A750del (c. 2235_2249 del15), which were dominant after PEAC enrichment of ctDNA from plasma samples (B8101186 and B8101241), pleural effusion (E8108088) and cerebrospinal fluid (C8108095); the mutants were undetectable without PEAC enrichment. Conclusions: PEAC technology can enrich ctDNA from body fluids in lung cancer patients and allow detection of low abundant mutants predictive for EGFR TKI therapy. With further validation, the technology may improve current detection methods used in clinical practice.
Family history of cancer as surrogate predictor for immunotherapy with anti-PD-1/PD-L1 immune checkpoint inhibitors: The FAMI-L1 study.
Authors: Alessio Cortellini, Sebastiano Buti, Daniele Santini, Raffaele Giusti, Marcello Tiseo, Federica Zoratto, Paolo Marchetti, Melissa Bersanelli, Federica De Galitiis, Maria Giuseppa Vitale, Francesca Rastelli, Rossana Berardi, Marianna Tudini, Francesco Atzori, Daniela Iacono, Alessandro Inno, Sergio Bracarda, Clara Natoli, Paolo Antonio Ascierto, Corrado Ficorella
Journal: Journal of Clinical Oncology (2019)

2559 Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.
Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.
Authors: Xianbao Zhan, Bin Wang, Zonghai Li, Jie Li, Huamao Wang, Longpei Chen, Hua Jiang, Meihong Wu, Jun Xiao, Xiaobo Peng, Hong Ma, Dan Feng, Dakun Wang, Qiang Fu, Mei Wang, Fengping Shen, Qiang Hao, Linli Zhang, Jing Xu, Yingyi Zhang
Journal: Journal of Clinical Oncology (2019)

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 10 8 ) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.
Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: Nong Xu, Kejing Ying, Ziping Wang, Yunpeng Liu, Haiping Jiang, Hui Zhou, Shuyan Wang
Journal: Journal of Clinical Oncology (2019)

e20546 Background: Anti-programmed death-1 antibodies (PD-1 Abs) have shown benefits in advanced NSCLC. The efficacy and safety of sintilimab, a PD-1 Ab, in combination with chemotherapy for 1L NSCLC is evaluated in this phase Ib study (NCT02937116). Methods: The study enrolled treatment-naïve unresectable locally advanced or metastatic non-squamous (nsq-) and squamous (sq-) NSCLC patients with neither EGFR mutations nor ALK rearrangements in cohort D and E respectively. Patients received sintilimab 200mg IV q3w in combination with pemetrexed 500mg/m 2 and cisplatin 75mg/m 2 IV q3w (4 cycles) in cohort D, or gemcitabine 1250mg/m 2 D1,8 and cisplatin 75mg/m 2 D1 IV q3W (6 cycles) in cohort E until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the efficacy and safety of the combination. Results: As data cutoff (15 Jan 2019), 21 and 20 patients were enrolled in cohort D and E respectively. ORR in nsq- and sq-NSCLC were 68.4% (95%CI, 43.4 to 87.4) and 64.7% (95%CI, 38.3 to 85.8) respectively based on data of 19 and 17 patients with at least one radiological assessment. Median PFS was 11.4 months (95%CI, 3.1 to NA) and 6.5 months (95%CI, 5.3 to 8.0) respectively (Table). Totally 38 (92.7%) patients experienced at least one treatment emergent adverse event (TEAE). Treatment-related AEs (TRAEs) occurred in 28 (68.3%) patients. TRAE ≥grade 3 occurred in 4 (9.8%) patients. Immune related AEs occurred in 10 patients (24.4%), the most common of which were skin rash (N = 5), pneumonitis (N = 3) and hypothyroidism (N = 2). There was no AEs leading to death. The biomarker analysis was ongoing. Conclusions: The combination of sintilimab and chemotherapy showed efficacy with an acceptable safety profile in 1L nsq- and sq-NSCLC. Two phase III trials are ongoing to evaluate the combination in 1L nsq- (NCT03607539) and sq-NSCLC (NCT03629925) respectively. Clinical trial information: NCT02937116. [Table: see text]
Latest research progress of marine microbiological corrosion and bio-fouling, and new approaches of marine anti-corrosion and anti-fouling
Authors: Yangfan Li, Chengyun Ning
Journal: Bioactive Materials (2019)

Marine resources and industry have become one of the most important pillars in economic development all over the world. However, corrosion of materials is always the most serious problem to the infrastructure and equipment served in marine environment. Researchers have found that microbiologically influenced corrosion (MIC) and marine bio-fouling are two main mechanisms of marine corrosions due to the complicated marine environment and marine organisms. This article summarized the latest research progress about these two mechanisms and indicated that both MIC and marine bio-fouling are closely related to the biofilms on material surfaces formed by the marine microorganisms and their metabolites. As a result, to prevent the occurrence of MIC and bio-fouling, it is important to control the microorganisms in biofilms or prevent the adhesion and formation of biofilms. The traditional method of using chemical bactericide or antifoulant faces the problems of pollution and microorganism resistance. This article introduced four research approaches about the new tendency of applying new materials and technologies to cooperate with traditional chemicals to achieve better and longer effects with lower environment pollution through synergistic actions. Finally, some future research tendencies were proposed for whole marine anti-corrosion and anti-fouling areas.
Implementing a web-based patient reported outcomes (PRO) assessment: Uptake, usability, and lessons learned.
Authors: Linda A. Jacobs, Abigail N. Blauch, Donna A. Pucci, Angela DeMichele, Steven C Palmer
Journal: Journal of Clinical Oncology (2019)

e23062 Background: PRO assessment has the potential to improve patient-provider communication, yet has been difficult to implement in practice. We developed and pilot-tested a web-based PRO assessment (Assessing Concerns at End of Treatment, ACE) within an existing cancer survivorship clinic to ascertain practicality, usability, and uptake by both patients and providers. Methods: ACE is a brief PRO assessment that interfaces with the patient-portal and delivers results into the electronic medical record (EMR). Prior to visit eligible patients were asked to complete a series of measures including a 19-item instrument assessing severity of physical and emotional difficulties and desire for assistance. These results were then made available to providers during the visit through the EMR. Patients were provided up to 3 reminder calls/emails to prompt completion. Eligibility included a breast cancer (BC) diagnosis up to 5 years prior to a scheduled survivorship visit, no current cancer treatment aside from hormonal therapies, and access to the internet. Results: Over 27-months 779 eligible BC survivors were approached and asked to participate, and 566 (73%) agreed. The ACE survey was completed by 332 (59%) of these patients prior to their visit. The most common difficulties reported were Fatigue (86.6%), Worry (75.4%), Difficulty Sleeping (74.8%), and Pain (72.2%). Patients most commonly requested assistance for Aching Joints (31.2%), Fatigue (29%), Difficulty Sleeping (28.6%), and Weight Gain (25.7%). Providers reported being burdened by the information provided and few referrals were made in response to ACE. Technical difficulties were encountered frequently and required more maintenance than initially anticipated. Conclusions: Most eligible patients agreed to complete ACE, however a minority actually did so despite repeated contacts. Lack of buy-in from providers was an obstacle, as were technical difficulties. Difficulties with physical and emotional issues were common, but desire for assistance was less so, and resulted in few referrals. Although practicable, questions remain about the cost vs. benefit of a web-based PRO assessment with survivors.
Survival after primary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (FFCD ACHBTH AURC 9002 trial and EORTC Intergroup trial 40983).
Authors: Carl Christoph Schimanski, Stefan Kasper, Susanna Hegewisch-Becker, Jan Schroeder, Friedrich Overkamp, Frank Kullmann, Wolf Otto Bechstein, Matthias Voehringer, Robert Oellinger, Florian Lordick, Volker Heinemann, Michael Geissler, Armin Schulz-Abelius, Bernhard Linz, Helga Bernhard, Karin Potthoff, Irene Schmidtmann, Markus Hermann Moehler
Journal: Journal of Clinical Oncology (2019)

e15019 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term survival and cure after hepatic metastasectomy. The optimal treatment after primary liver resection remains controversial. Here we compare results from the LICC trial with historical controls, the FFCD ACHBTH AURC 9002 trial (FFCD; Portier et al., 2006) and the EORTC Intergroup trial 40983 (EORTC; Nordlinger et al., 2008, 2013). The three trials investigated pts with mCRC LLD who underwent primary hepatic resection. Methods: LICC, FFCD and EORTC were compared regarding pts characteristics, treatment, surveillance and efficacy outcomes. LICC pts received the adjuvant antigen-specific cancer vaccine tecemotide (L-BLP25) or placebo after primary LLD resection for up to 2 years. The FFCD trial compared postoperative 5-FU/leucovorin and the EORTC trial perioperative FOLFOX versus surgery alone. Results: Primary resected pts in LICC (n = 80; R0 n = 76), FFCD (R0 n = 171; postoperative chemotherapy n = 86) and EORTC (n = 364) showed different pt characteristics concerning median age (60, 63 and 63 years) and rate of synchronous metastases (46.8%, 27.9% and 34.0%). In LICC, &gt; 5 liver metastases were resected in 11.6% of pts, in FFCD and EORTC all eligible pts had &lt; 5 liver metastases resected. In contrast to EORTC, LICC and FFCD had a close surveillance until recurrence or a maximum of 2 years. Median OS (mOS) in LICC was not yet estimable in primary resected pts (tecemotide arm: 62.8 months; placebo arm: not yet estimable). In the FFCD and the EORTC trial, mOS was 62.1 and 61.3 months, respectively. Further details will be presented. Conclusions: Despite unfavorable disease characteristic in LICC compared with the earlier EORTC and FFCD studies, primary liver resection without adjuvant chemotherapy led to surprisingly good survival outcomes. Improvements in imaging-based pt selection and liver resection techniques might in part explain our finding. Surgery alone appears to be an option for selected pts with resectable LLD. Better systemic chemo(immune-)therapy may have also contributed to the OS benefit. Clinical trial information: LICC: NCT01462513; EORTC: NCT00006479; FFCD: not registered.
Abstract 20282: Comparative Estimates of Heart Failure Hospitalization Between Simple and Multi-State Proportional Hazard Models in a Population With a High Rate of Competing Events
Authors: Jenica N Upshaw, Marvin A Konstam, David van Klaveren, David M Kent
Journal: Circulation (2016)

Background: Cox proportional hazard models using Kaplan-Meier estimates are often used in prediction models but may lead to biases in situations of competing or semi-competing risks due to informat...
Additional prognostic value of metabolic parameters measured by dual time point pretreatment F-18 FDG PET/CT in patients with intrahepatic cholangiocarcinoma.
Authors: Jae Pil Hwang, Seo Youn Choi, Hee Kyung Kim, Jong Ho Moon, Jung Mi Park
Journal: Journal of Clinical Oncology (2019)

e15598 Background: The aim of this retrospective study was to determine whether delayed glucose metabolism assessed by dual time point F-18 FDG PET/CT provides additional prognostic information independent of established prognostic factors in patients with intrahepatic cholangiocarcinoma (IHCC). Methods: We reviewed retrospectively the medical records of 96 patients (men 57, women 39, mean age 66 ± 10 years) with pathologically proven IHCC. They underwent dual time point F-18 FDG PET/CT as part of a pretreatment workup from July 2012 to December 2017. For the analysis, patients were classified by age, sex, stage, serum CA19-9, early SUVmax (eSUV), delayed SUVmax (dSUV), delta SUVmax (ΔSUV, difference between early and delayed SUVmax) and histopathology (pCEA, p53, Ki-67 index). The relationship between FDG uptake and survival was analyzed using the Kaplan-Meier with log-Rank test and Cox’s proportional-hazard regression methods. Results: Median survival for all 96 study subjects was 303 days and median SUVmax was 7.2 (range: 2.5 – 21.7). The survival was found to be significantly related to eSUV ( p &lt; 0.0001), age ( p = 0.017), LN metastasis ( p = 0.03) and p53 index ( p = 0.04) and multivariate analysis study revealed that the patients with a higher SUVmax ( p = 0.0001, 95%CI = 1.80 to 5.89, HR = 3.26), prescence of LN metastasis ( p = 0.031), higher age ( p = 0.044) and a higher p53 index ( p = 0.007) showed worse overall survival. In addition, we carried out a subgroup analysis targeting the 55 patients with delayed SUVmax to evaluate a prognostic value of delayed image parameter. In univariate analysis, dSUV (cut-offvalue 7.3, p = 0.0006) and ΔSUV (cut-off value 3.2, p = 0.035), age ( p &lt; 0.0001) and sCA19-9 ( p = 0.018) showed significant correlation and dSUV was an independent factor of overall survival in multivariate analysis. ( p = 0.014, 95%CI = 1.30 to 10.7, HR = 3.74) And then, we analyzed combinations of eSUV, dSUV and ΔSUV each other to evaluate additional prognostic information. The result revealed that higher dSUV ( p = 0.0001, AUC = 0.68) and ΔSUV ( p = 0.0002, AUC = 0.71) showed a poorer overall survival although the eSUV of IHCC was low. Conclusions: Higher delayed SUVmax and ΔSUVmax on pretreatment dual time point F-18 FDG PET/CT can predict poorer survival and additional information of risk stratification in patients with IHCC.
Impact of biopsy methodology on biomarker testing in NSCLC in EU5.
Authors: Christophe Homer
Journal: Journal of Clinical Oncology (2019)

e14264 Background: With the increasing number of drug treatments in NSCLC reliant on complementary or companion diagnostics and the evolution of testing methodologies that require larger sample volumes, biopsy remains a gatekeeper to providing adequate sample for biomarker testing and informing treatment decisions. Methods: The Ipsos Global MDx Monitor 2018 Q3 NSCLC EU5 (UK, France, Germany, Italy, Spain) Module: an online multi-stakeholder study involving drug treating physicians (225) and pathologists (81) who answer perceptual questions and report de-identified medical chart data on NSCLC patients (1257) / samples (516), that have undergone at least 1 biomarker test. Study fielded July-September 2018. This abstract reviews pathologist data only. Results: EU5 pathologists (n = 81) state that in 14% NSCLC cases there was not enough sample to carry out any biomarker tests, in 19% cases there was enough sample to carry out some requested biomarker tests and in 67% cases there was enough sample to carry out all biomarker tests. On analyzing NSCLC sample record forms, 83% (421/505) samples from unique patients were from solid samples (FFPE block /Fresh frozen), 14% liquid samples (fluid/cytology) (73/505). Of the 487 NSCLC sample records submitted, 39% biopsies were performed by bronchoscopy (190/487), 25% by Transthoracic Core Needle Biopsy (CNB) (126/487), 16% by Transthoracic Fine Needle Aspiration (FNA) (78/487), 8% by Open biopsy/resection (39/487). Sample sufficiency varies by biopsy methodology; 100% open biopsies/resection (39/39) provided enough sample to carry out all tests ordered - versus 87% for Transthoracic CNB (99/113), 84% for bronchoscopies (155/184), 67% for Transthoracic FNA (49/73). Sample sufficiency varies by sample type; 89% solid samples (357/399) provided enough sample to carry out all tests ordered, 75% liquid samples (49/65). Conclusions: Sample sufficiency and thus ability to test for biomarkers is affected by the biopsy method used to extract the sample, and sample type used for testing (i.e. liquid vs. solid). Sample insufficiency can necessitate a re-biopsy or lead to treatment decisions being taken without the tumour’s full genomic profile at the physician’s disposal.