tbuckley/cabot-search huggingface dataset:
Pulmonary Lymphatic Perfusion Syndrome
Authors: Taizou Hirano, Naoya Fujino, Kei Takase, Hideki Ota, Rie Tanaka, Ryota Saito, Ayumi Suzuki, Koji Okutomo, Teruyuki Sato, Sakiko Kageyama, Tsutomu Tamada, Hisatoshi Sugiura, Masakazu Ichinose
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Distant outcomes of chemoimmunotherapy with recombinant interferon-gamma for acinar-type adenocarcinoma of the lung.
Authors: Sergey P. Pyltsin, Yuriy N. Lazutin, Tamara G. Ayrapetova, Anna V. Chubaryan, Pavel A. Anistratov, Igor A. Leyman, A. S. Shogenov, M. A. Gappoeva, M. Kh. Afaunov
Journal: Journal of Clinical Oncology (2017)

e20090 Background: We performed a comparative analysis of disease-free survival (DFS) after adjuvant chemoimmunotherapy (ACIT) with recombinant interferon-gamma in combination therapy and standard adjuvant chemotherapy (ACT) of patients with acinar-type adenocarcinoma of the lung. Methods: The study included 63 patients who received radical surgery for stage I-IIIA adenocarcinoma in 2009-2012. Group 1: 33 patients with ACIT after radical pneumonectomy, carboplatin AUC = 5 on day 1 and etoposide 100 mg/m 2 on days 1, 3 and 5; i.v. ingaron 500 000 IU/m 2 but no more than 1 million IU for one injection on days 2, 4 and 6. Carboplatin was replaced by cisplatin 100 mg/m 2 in ACIT after lobectomy. Group 2: 30 patients with similar ACT without ingaron. The interval between courses was 21 days. Survival was estimated by Kaplan-Meier method, and differences were compared using log-rank test. Results: Group 1: 28 (84.8%) patients received 3 ACIT courses, 5 (15.2%) – 2 courses. Group 2: 27 (90%) patients received 3 ACT courses and 3 (10%) – 2 courses. Analysis of the Kaplan-Meier curves showed a tendency to a 8% increase in 5-year DFS that was 58% in Group 1 and 50% in Group 2 (p = 0.064). Conclusions: 5-year DFS increase by 8% demonstrates the expediency of further studies involving more patients which will allow revealing statistically significant differences in long-term results of treatment.
An ex vivo native environment precision medicine AML test and the correlation with responses to 1st line treatment.
Authors: Juan Ballesteros, Pau Montesinos, David Martinez Cuadron, Joaquin Martinez, Josefina Serrano, Jaime Perez de Oteyza, Pascual Fernandez, Gabriela Rodriguez-Macias, Maria Belen Vidriales, Pilar Herrera, Mar Tormo, Juan M Bergua, Raimundo Garcia-Boyero, Susana Vives, Maria Angeles Fernandez, Jesus Villoria, Federico Moscardo, Inaki F Troconiz, Miguel A. Sanz
Journal: Journal of Clinical Oncology (2016)

e18510 Background: The aim of this study is to determine the ability of Vivia's novel test (based on studying the ex-vivo sensitivity to drugs) to predict the complete remission (CR) rates after induction chemotherapy with cytarabine (Ara-C) and idarubicin (Ida) in 1st line AML Methods: Observational clinical trial collecting bone marrow samples from de novo AML adult patients in Spanish PETHEMA centers. Whole marrow samples maintaining their Native Environment were incubated for 48h in well plates containing Ara-C, Ida, or their combination. Pharmacological responses are calculated using population models. Induction response was assessed by Cheson criteria (2003). Patients attaining a CR/CRi were classified as responders and the remaining as resistant Results: 390 patient samples were used to calculate the dose response (DR) curves synergism. For clinical correlation we used 142 patients with median 56 years. The strongest clinical predictors were the Area Under the Curve of Ara-C (P = 1.34E-05) and IDA (P = 3.9E-05). The correlation models revealed a significant relationship (R2= 0.45 and deviance explained = 45%) between these predictors and higher probabilities of post-induction resistance. The test obtains a high 82% general correlation, with high Specificity (95%), lower sensitivity (50%), and high (81-82%) Positive & Negative Predictive Values. The lower sensitivity arises from 21/142 clinically resistant but predicted sensitive, probably due to a minority resistant clone present in a minority of leukemic cells. Consistent with this analysis, adding the cytogenetic risk factor to the regression analysis as a covariable significantly improves the correlation to 90% in 117 patient samples, achieving 72% sensitivity and 88-90% predictive values. Both approaches lead to substantial improvements in estimated overall survival Conclusions: This novel test is able to predict the clinical response to Ida + Ara-C induction with overall correlation and predictive values of 82% alone, or 90% adding the cytogenetic risk factors, significantly higher than the 70% standard response rate. Thus this novel test may be valuable information to guide 1st line patient therapy
Abstract 18587: Acute Flow Physiology in Arterial in-situ Grafts at CABG
Authors: Ashesh N Buch, Cheng Chen, Joseph A Babb, T. Bruce Ferguson
Journal: Circulation (2016)

Background: There is advocacy for multi-arterial grafting as a new CABG standard of care, based on assumed 10-20 yr graft patency and documented survival benefit. This standard emphasizes the techn...
Effects of FDA drug approvals on a thoracic oncology program’s clinical trial enrollment in 2015.
Authors: Alice Huai-Yu Li, Jonathan Wade Goldman, Marshall L. Spiegel, Carlos R. Adame, Courtney L. Wells, Aaron Elliott Lisberg, Jennifer L. Strunck, Sina Famenini, James M. Carroll, D. Andrew Tucker, Ariana R. Hardy, Karolyn K. Morris, Paulina J. Linares, Lauren Sauer, Deborah Jean Lee Wong, Blanca A. Ledezma, Melody A. Mendenhall, Meghan B. Brennan, Christina DiLauro Abaya, Edward B. Garon
Journal: Journal of Clinical Oncology (2016)

e20662 Background: The 6 FDA drug approvals for non-small cell lung cancer (NSCLC) in 2015 included 2 programmed cell death protein 1 (PD-1) inhibitors and a 3rd generation (gen) epidermal growth factor receptor (EGFR) inhibitor. For previously treated NSCLC, nivolumab (nivo) was approved for squamous (Mar 4) and non-squamous (Oct 2) disease (dz), and pembrolizumab (pembro) for PD-L1+ dz according to a companion diagnostic (Oct 9). Osimertinib was approved for previously treated EGFR T790M+ mutant dz (Nov 13). The National Comprehensive Cancer Network (NCCN) listed nivo as a category 2A recommendation in non-squamous dz on Jun 4. We assessed the impact of increased commercial access in a program in which just the trials requiring new biopsies enrolled ~4 patients / month (pts/m) in 2012-4 (Nameth et al. 2015). Methods: We reviewed trials at UCLA’s Jonsson Comprehensive Cancer Center for therapeutic studies that were specifically for NSCLC or included a NSCLC cohort, analyzing accrual from 1/1/15-12/31/15. Of 33 trials meeting these criteria, 7 tested a PD-1 inhibitor and 4 tested a 3rd gen EGFR inhibitor. Results: The accrual rate for PD-1 inhibitor trials dropped from 6.67 to 4.33 pts/m after nivo was approved for squamous dz, and then to 0.73 pts/m after nivo was also approved for non-squamous dz (table); 0 pts enrolled in Nov and Dec. The accrual rate for 3rd generation EGFR inhibitor trials decreased from1.62 to 0.67 pts/m after osimertinib was approved; 0 pts enrolled in Dec. Conclusions: Increased commercial access (particularly FDA approvals) was associated with decreased accrual rates. Although normal enrollment fluctuation could contribute to these accrual reductions, the potential impact of drug approvals on clinical trial enrollment should be considered in the design of new trials evaluating these classes of agents. Jan Feb Mar* Apr May Jun† Jul Aug Sep Oct** Nov*** Dec # Pts enrolled to PD-1 inhibitor trials 9 5 2 3 8 5 6 2 3 3 0 0 # Pts enrolled to 3rd gen EGFR inhibitor trials 2 1 2 1 0 2 3 2 1 2 2 0 *FDA approval of nivo for squamous dz (Mar 4) †NCCN recommendation of nivo including non-squamous dz (Jun 4) **FDA approvals of pembro for biomarker-restricted dz (Oct 2) and nivo for non-squamous dz (Oct 9) ***FDA approval of osimertinib (Nov 13)
Validation of an expanded neoantigen identification platform for therapeutic and diagnostic use in immuno-oncology.
Authors: Sean Michael Boyle, Jason Harris, Gabor Bartha, Ravi Alla, Patrick Jongeneel, Mirian Karbelashvili, Scott Kirk, Steve Chervitz, Eric Levy, Craig Rowell, Daryl Thomas, Robert McCord, Shujun Luo, John West, Richard Chen
Journal: Journal of Clinical Oncology (2017)

11589 Background: Neoantigen identification is increasingly critical for clinical immuno-oncology applications including predicting immunotherapy response and neoantigen-based personalized cancer vaccines. Although standard research pipelines have been developed to aid neoantigen identification, building a robust, validated neoantigen identification platform suitable for clinical applications has been challenging due to the complex processes involved. Methods: To improve neoantigen identification, we extended standard sequencing and informatics methods. We developed an augmented and content enhanced (ACE) exome sequenced at 200X to increase sensitivity to SNPs and indels used for neoantigen identification as well as HLA performance. To accurately identify fusions and variants from RNA, we optimized our ACE transcriptome for FFPE tissue. To improve neoantigen pipelines based on MHC binding algorithms, we developed peptide phasing, high accuracy HLA typing, TCR interaction predictors, and transcript isoform estimation tools to detect neoantigens from indel and fusion events. We performed comprehensive analytical validation of the platform including the ACE Exome, somatic SNV/indel calls, RNA based variant and fusion calls, and HLA typing. This was followed by an overall in silico validation of neoantigen identification using 23 experimentally validated immunogenic neoepitopes spiked into exome data. Results: Analytical validation of our ACE exome platform showed &gt; 97% sensitivity for small variants with a specificity of &gt; 98% at minor allele frequency &gt; 10%. From the ACE transcriptome we achieved a fusion sensitivity of &gt; 99% and RNA based variant calls sensitivity of &gt; 97%. Our ACE exome based HLA typing was 98% and 95% concordant with Class I and II HLA results (respectively) from clinical testing. Our in silico validation of neoantigen predictions resulted in identification of 22 out of 23 immunogenic neoepitopes. Conclusions: We developed sequencing and informatics improvements to standard approaches that can enhance neoantigen identification and demonstrated a comprehensive validation approach that may support neoantigen use in future clinical settings.
NHS long term plan must tackle current challenges to set realistic targets, says NHS Providers
Authors: Susan Mayor
Journal: BMJ (2018)

The new long term plan for the NHS, due out this autumn, must consider the challenges currently facing services including a deficit of nearly £1bn (€1.12bn; $1.29bn), ageing infrastructure, and a high staff vacancy rate, a briefing from NHS Providers has recommended.1

The organisation, which represents hospital and community services treating patients in the NHS, proposes five tests to apply to recommendations made in the 10 year plan, to help ensure that they are achievable.

Chris Hopson, chief executive of NHS Providers, said, …
Safety and efficacy of anti-CD20 immunotoxin MT-3724 in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in a phase I study.
Authors: Michelle A. Fanale, Paul A. Hamlin, Steven I. Park, Daniel Oscar Persky, Jack P. Higgins, Christine Burnett, Kristina Dabovic, Eric Poma, Nenad Sarapa, Anas Younes
Journal: Journal of Clinical Oncology (2018)

7580 Background: MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1. The SLT-I A1 forces MT-3724 internalization and irreversibly inactivates ribosomes triggering cell death. We present interim results from a Phase I study in patients (pts) with B-cell NHL who relapsed after prior response to anti-CD20 Mab and chemotherapy (NCT02361346). Methods: 24 pts were treated by 13FEB2018: 21 pts (12 DLBCL) at 5-100 µg/kg/dose in 6 dose escalation cohorts and 3 pts (all DLBCL) at 75 µg/kg/dose in MTD expansion cohort. MT-3724 was given as six 2-hr IV infusions on Days 1-12 of each cycle (C) for up to 5 cycles. Investigator assessed tumor response after C2, C4 and C5 using Cheson criteria. Results: Demographics in 24 evaluable pts were: 54% female, mean age 66 yrs (range 34-78); ≥4 prior NHL therapies in 67%; ECOG status 0 in 42%, 1 in 46%, 2 in 4% and unknown in 8%. All pts had ≥1 AE (59 G≥3; 13 related), and 15 pts (63%) had 33 SAEs (23 G≥3; 4 related). The most common AEs were peripheral edema (67%), fatigue (43%), diarrhea (38%), myalgia (38%) and cough (33%). MT-3724 was not tolerated at 100 µg/kg/dose (2 pts had 1 DLT each: G2 pneumonia and G2 ileus). In dose escalation, no pts had DLT at doses ≤MTD of 75 µg/kg/dose. In the MTD expansion, 2 of 3 pts had G2 capillary leak syndrome (CLS) leading to dose delay and reduction. The CLS events occurred in obese pts (96 and 154 kg = high total of 7208 and 11572 µg/dose) and were reversible, but MTD was reduced to 50 µg/kg/dose and capped at 6000 µg/dose. Five pts (all DLBCL) had clinical benefit at 5-75 µg/kg/dose [1 CR and 2 PR (ORR 12.5%)' 2 SD with large tumor reduction (48% and 49%; DCR 21%)]. All pts with benefit had undetectable serum rituximab (RTX) level at screening. No pts with detectable screening RTX level had benefit, likely due to competitive inhibition of CD20 binding by prior RTX. Conclusions: MT-3724 showed clinical anti-tumor activity in heavily pre-treated pts with R/R B-cell NHL. Consistent with mechanism of action, MT-3724 had the best activity in rapidly growing DLBCL. Safety and efficacy assessment is ongoing at the adjusted MTD of 50 µg/kg/dose in DLBCL pts with undetectable screening RTX level. Clinical trial information: NCT02361346.
Comparison between Ki-67 biomarker expression in primary breast cancer before and after neoadjuvant therapy.
Authors: Jamal Zidan
Journal: Journal of Clinical Oncology (2018)

e24311 Background: Core needle biopsy (CNB) is widely used not only to establish the histological type and histologic grade of the tumor, but also to assess immunohistochemical findings of predictive factors: estrogen receptor, progesterone receptor, HER2 and Ki67. Neoadjuvant treatment (NAT) followed by surgery has currently become a part of standard care for patients with locally advanced breast cancer. Postopeartive treatment is generally established on the same detective biomarkers evaluated in CNB before NAT. Breast cancer is a heterogeneous and genetically unstable disease. The aim of this study was to investigate whether NAT induces some selective changes in the breast biomarkers. Methods: we collected the appropriate data for about 52 patients that conform to the requirements from the personal hospital files, since 2007 until 2016. Formalin fixed paraffin embedded samples or fresh tissue samples were used. Followed by cutting the section into 4 microns thin and mounted on special charged slides that are appropriate for immuno staining. The antibody-antigen interaction is observed using chromogenic detection, an enzyme (DAB) conjugated to the antibody to produce a colored precipitate at the location of the antigen. Results: Mean age of patients was 52.3 ± 13.9. Ethnicity: 28 (53.8%) women were Jews and 24 (46.2) were Arabs. 56% of women were premenopausal , 44% postmenopausal. Lumpectomy was done in 39 (75%) of patients while the others (25%) had mastectomy. Mean level of Ki67 in the primary tumor was 34.8±26.1%, after NAT was 17.8±22.9% (p < 0.001). Conclusions: In this study we found significant changes in Ki67 expression between the pretreatment biopsy specimens and the resected specimens of breast cancer patients who underwent neoadjuvant therapy. This discordance in the expression of biomarkers may effect the choice of postoperative adjuvant treatment in clinical practice and may be a detective factor for prognosis.
4-year survival and outcomes after cessation of pembrolizumab (pembro) after 2-years in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in KEYNOTE-006.
Authors: Georgina V. Long, Jacob Schachter, Antoni Ribas, Ana M. Arance, Jean-Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona M. McNeil, Michal Lotem, James M. G. Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Teresa M. Petrella, Omid Hamid, James Anderson, Clemens Krepler, Nageatte Ibrahim, Caroline Robert
Journal: Journal of Clinical Oncology (2018)

9503 Background: KEYNOTE-006 (NCT01866319) established superiority of pembro over ipi in advanced melanoma. We provide 4-y outcomes, long-term data for pts who completed 2 y pembro, and data for second course. Methods: Eligible pts (N = 834) were randomly assigned 1:1:1 to receive pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 y (pembro only; completed defined as ≥94 weeks of pembro and discontinued with at least SD) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. End points were OS and ORR per irRC by investigator review. Upon PD, eligible pts could receive an additional 1 y pembro. Results: At data cutoff (Dec 4, 2017), median follow-up was 45.9 mo (range, 0.3-50.0). 4-y OS rate was 42% in the pooled pembro arms (n = 556) and 34% in the ipi arm (n = 278); ORR was 42% and 17%. Median DOR was NR for pembro (range, 1.0+ to 46.1+ mo) or ipi (1.1+ to 45.6+ mo); 62% pembro- and 59% ipi-treated pts had a response lasting ≥42 mo. In treatment-naive pts, 4-y OS rates were 44% in the pooled pembro arms (n = 368) and 36% in the ipi arm (n = 181); ORR was 47% and 17%. Median DOR was NR for pembro (range, 1.6+ to 46.0+ mo) or ipi (1.1+ to 42.2+ mo); 65% pembro- and 68% ipi-treated pts had a response lasting ≥42 mo. Of 556 pts, 103 (19%) completed the protocol-specified 2-y pembro (28 CR, 65 PR, 10 SD). Median follow-up was 20.3 mo after pembro completion; 89 (86%) pts did not progress and 14 pts had PD (prior response 2 CR, 9 PR, 3 SD). Eight pts (prior response 3 CR [including 1 pt who discontinued early with CR and then progressed], 4 PR, and 1 SD) received second-course pembro but 3 discontinued (1 each due to PD, interstitial pneumonia, and infection). Median duration of second-course pembro was 9.7 mo; BOR was 1 CR, 1 PR, 5 SD, and 1 PD. 1 pt with SD had subsequent PD. 5 pts had a TRAE during second-course pembro; there were no grade 3/4 TRAEs or deaths. Conclusions: Pembro provides durable antitumor activity in treatment-naive or -experienced pts with advanced melanoma. Of pts who completed 2 y pembro, 86% were progression free at 20 mo. Pembro is safe and provides additional antitumor activity as second-course treatment. Clinical trial information: NCT01866319.
Comprehensive genomic characterization of hepatocellular carcinoma to reveal novel therapeutic targets.
Authors: Yuewei Zhang, Yan Ding
Journal: Journal of Clinical Oncology (2016)

e15643 Background: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, which is particularly common in certain regions of Asia. Here we report the transcriptome and whole exome or targeted deep sequencing of 35 paired HCC cases and 3 metastatic tumors. Methods: We have collected and analyzed tumor tissue samples from patients diagnosed with hepatocellular carcinomas from the Affiliated Zhongshan Hospital of Dalian University with patient written consent. Whole exome, transcriptome and targeted deep sequencing were performed using Illumina Nextseq500 sequencer and sequence data were analyzed using OncoDecoder (Genomic Future, Inc.). Results: We identified novel significantly mutated genes such as FAT3, CSF1R, IKBKE, JAK3, PITCH1, TOR2A, ITGB2, and NF1 in addition to previously discovered ones (TP53, CTNNB1, ATM, APC, RB1, HNF1A and CCND1) in perimary HCC. Comparing to primary HCC, the cutaneous metastatic HCC harbors distinct somatic mutation signature in genes encoding ALK, BRAF, CDH1, ERBB2, JAK3, PIK3CA and VHL. Copy number analyses identified recurrent amplifications in MI1E, NCAM2, EGR1, ID1, PLIN2 and PPPIR3B genes, and deletions in PLA2G2A, IFI6, KRT1, JUN, PIGR, FGL1 and ITIH3. Pathway analyses show distinct dysregulation in alcoholic liver cirrhosis for tumors with alcohol as risk factor, Ras signaling for metastatic cases and a novel identified IL4-mediated signaling pathway in primary tumors infected with hepatitis B. Moreover, our study uncovered several potential druggable targets for HCC, and CDH1 was further explored as a therapeutic target since its mutation and gene expression dysregulation. Conclusions: In summary, our integrative approaches identified a number of novel genetic lesions in HCC and shed light on understanding hepatocellular carcinomas and developing therapeutic targets.
Improving metachronous cancer risk assessment using clinicopathological information in colorectal cancer patients.
Authors: Takaharu Kato, Sergio Alonso, Yuta Muto, Hiroshi Noda, Yasuyuki Miyakura, Koichi Suzuki, Shingo Tsujinaka, Masaaki Saito, Taro Fukui, Kosuke Ichida, Yuji Takayama, Fumiaki Watanabe, Nao Kakizawa, Manuel Perucho, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2016)

e15092 Background: Non-hereditary colorectal cancer (CRC) patients are at higher risk of developing metachronous cancers than cancer-naive individuals. The reason for this higher incidence remains an open question. We aimed to clarify the risk factors for developing metachronous CRC among patients who underwent surgery for CRC. Methods: One thousand five CRC patients were recruited. Relative hazard risk of clinicopathological factors was assessed by univariate and multivariate Cox’s proportional hazard regression analysis. Observed metachronous CRC incidence was compared with the expected cancer incidence of the general population in Japan. Results: Twenty-seven metachronous CRCs developed in 24 patients (2.4%) during a follow-up period of 3,676 person-years. The incidence of metachronous CRCs was significantly higher in CRC patients than in the general population (standardized incidence ratio (SIR) 2.55; 95% confidence intervals (CI) 1.61-3.6; p = 0.0001). In univariate analyses three factors associated with a higher risk of metachronous tumors: the presence of synchronous CRCs (hazard ratio (HR) 5.24; CI 2.17-12.65; p < 0.001), tumor size ≥ 65 mm (HR 4.17; CI 1.85-9.39; p < 0.001), and gender male (HR 3.08; CI 1.05-9.02; p = 0.04). In multivariate analysis, two factors retained statistical significance: synchronous CRC (HR 6.88; CI 2.79-16.97; p < 0.0001) and tumor size ≥ 65 mm (HR 5.22; CI 2.27-11.99; p < 0.0001). Patients with either synchronous or large solitary tumors exhibited much higher risk for metachronous CRC than patients with solitary small tumors (HR 7.3; CI = 3.13-17.1; p < 10-5). When compared with the general Japanese population, patients with synchronous or solitary large CRCs exhibited a significantly higher risk for a second independent CRC (SIR 7.01; CI 4.15-11.14; p < 10-8), while patients with solitary small tumors did not (SIR 1.07; CI 0.5-2.03; p = 0.8). Conclusions: Synchronous CRC is a well-established risk factor for metachronous CRC development. Our data reveals that primary tumor size is also a strong independent risk factor, providing new insights to assess the risk for metachronous CRCs that should improve the postoperative surveillance regimen in CRC patients.