tbuckley/cabot-search huggingface dataset:
Analysis of the relationship between ratio N/L and survival in lung cancer patients treated with immunotherapy.
Authors: Noemi De Dios Alvarez, Marinha Costa Rivas, Sara Agraso Busto, Diego Pereiro Corbacho, Ana Alonso Herrero, Carmé García Benito, Maria Jose Villanueva Silva, Gerardo Huidobro Vence, Martín Emilio Lázaro Quintela, Javier Castellanos Diez, Joaquín Casal Rubio
Journal: Journal of Clinical Oncology (2019)

e14247 Background: The neutrophil-lymphocyte (N / L) ratio is a marker of general immune response in different stress situations, having shown a relationship between the quotient and the evolution of patients treated with immunotherapy (IT), emphasizing the importance of inflammation in these patients. Methods: In order to evaluate this relationship in a context of usual clinical practice, we performed a retrospective review of patients with pulmonary neoplasia who received IT treatment in the first line or successive, between November 2015 and December 2018, excluding those who received treatment within of clinical trial. Data were collected from the clinical history of each patient, with special attention to baseline neutrophil and lymphocyte numbers, objective response to therapy by criteria iRECIST 1.1 after 3 months of treatment and overall survival (OS) defined from the beginning of treatment until death by progression of the disease. Results: 92 patients (29 women and 63 men) with a median age of 64 years (44-79) were analyzed. 15 (16,3%) patients (p) received immunotherapy as first line treatment, 65.2% (60 p) received it as 2nd line and 18,5% (17 p) as 3rd or succesive lines. The average number of cycles received was 14 (1-52). Regarding the type of IT, 54 p (58,7%) received treatment with Nivolumab, 33 patients (36%) with Pembrolizumab and 5 patients (5.3%) were treated with Atezolizumab. Two stretches of baseline N / L ratios ≤5 (low) and &gt; 5 (high) were defined. Low ratio N / L (≤5) was identified in 62p (67.4%) of the patients treated with IT and high ratio N/L ( &gt; 5) in 30p (32,6%). Of the 62 patients with a low ratio: 41p (66.1%) had some type of response or stabilization of their disease, 13 patients (21%) had progression and 8 patients (12.9%) received less than three months of treatment, 6 patients for PS deterioration and the other 2 patients continue with the treatment and are pending reevaluation. Among the 30 patients with high N / L quotient: 7p (23.3%) presented response or stabilization of the disease, 23 patients (76,7%) presented progression or treatment was interrupted due to deterioration of the ECOG. The average survival in the group with a low N / L ratio (≤5) was 213 weeks compared to the group with a high N / L ratio ( &gt; 5) 144 weeks (p &lt; 0.05). Conclusions: The N / L ratio has been identified in some studies as an adverse prognostic factor in patients treated with IT. Our data from the usual clinical practice support this theory. If these findings are confirmed in future studies, it could be used as a response biomarker for better patient selection.
Phase 1a study results investigating the safety and preliminary efficacy of ABL001 (NOV1501), a bispecific antibody targeting VEGF and DLL4 in metastatic gastrointestinal (GI) cancer.
Authors: Jeeyun Lee, Seung Kim, Su Jin Lee, Se Hoon Park, Joon Oh Park, Eunsin Ha, Doo-Hong Park, Neunggyu Park, Hoon-Kyo Kim, Sang Hoon Lee, Weon-Kyoo You, Ho Yeong Lim, Young Suk Park, Won Ki Kang
Journal: Journal of Clinical Oncology (2019)

3023 Background: Antiangiogenic therapy has been a successful clinical strategy for the treatment of various cancer types. To date, all approved antiangiogenic drugs primarily inhibit the VEGF/VEGFR pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis. A dual blockade of both VEGF and DLL4 could be a promising strategy to overcome anti-VEGF therapy resistance. ABL001 (NOV1501) has been developed as a bispecific antibody to bind and inhibit both DLL4 and VEGF thereby significantly suppressing tumor angiogenesis. Methods: In a classical 3+3 dose-escalation design, ABL001 was administered IV at doses ranging from 0.3, 1, 2.5, 5, and 7.5 mg/kg biweekly (NCT03292783: the next doses of ABL001 are 10 and 12.5 mg/kg). After the first administration of ABL001 in each cohort, DLT (dose limiting toxicity) was observed for 3 weeks. Tumor assessments were performed every 6 weeks and cardiac assessments were performed every cycle. Results: From 2017 November to February 2019, 18 patients were enrolled on this trial. All patients were heavily pre-treated with at least 3 prior lines of chemotherapy. All patients in cohort 4 and 5 were either metastatic colorectal cancer or gastric cancer. Of the 5 cohorts, there was no DLT observed during dose escalation. In addition, there was no maximum tolerated dose identified up to 7.5 mg/kg dose. The most common treatment-related adverse events (AEs) (including all dose levels and all grades) occurred were hypertension, anorexia, general weakness, headache and anemia. Preliminary results of pharmacokinetic (PK) analysis demonstrated slightly shorter mean half-life than conventional monoclonal tantibodies due to the bispecific nature of the ABL-001. In addition, preliminary pharmacodynamic (PD) biomarker analysis using PBMC and plasma samples showed engagement of both VEGF/VEGFR and DLL4/Notch1 pathway modulation after ABL001 administration. One gastric cancer patient at 7.5 mg/kg achieved unconfirmed partial response at the time of this writing. Conclusions: ABL001 therapy has been well tolerated up to 7.5 mg/kg with no significant treatment related adverse events and showed preliminary anti-tumor activity in heavily pre-treated cancer patients. After completion of this ongoing phase 1a study, phase 1b/2a study is planned in combination of ABL001 with chemotherapy or anti-PD-1 antibody. Clinical trial information: 03292783.
Impact of Zika virus infection in human glioblastoma cell lines.
Authors: Andre P. Fay
Journal: Journal of Clinical Oncology (2019)

e13563 Background: Glioblastoma (GBM) is the most common central nervous system (CNS) tumor. Despite available therapies survival remains poor, and new treatment strategies are needed. Oncolytic viral therapy is under investigation in GBM. Zika virus (ZV) infection has demonstrated inhibition of neuronal precursor cells proliferation in preclinical studies. This study aims to evaluate the effects of ZV infection on human glioblastoma cell lines survival. Methods: Two GBM cell lines (U138 and U 251) were infected by 2 hours with ZV using the titer of PFU/ml diluted in 1:100, 1:1000, 1: 10000. Cell. We performed tests to evaluate cell viability by MTT and protease active assay, cell migration trough a wound healing assay and cell infiltration using insert culture method. Also the cell lines were tested by cell adhesion capacity, apoptosis (Caspase 3/7), interleukins levels and cell surface markers for CD 14 and CD73.These results were compared to controls. Results: Our study has demonstrated a reduction in cell viability in U138 lineage trough MTT assay. In the U251 lineage and in the others tests for cytotoxicity/viability, ZK did not altered cell viability neither cell migration compared to controls. We showed that ZV caused reduction in cell invasion and resulted in increased rates of apoptosis in both cell lines. We observed that infection of ZV caused increased rates of cell adhesion and CD73 marker. Conclusions: These findings suggest that ZV infection may be associated with increased CD 73 Expression thus increasing cell adhesion and cell infiltration. The ZV may be cause an increase rates of apoptosis and influencing cell cytotoxicity and viability. Further investigations to explore the role of ZV in GBM treatment are warranted.
A digital pathology demonstration of an "immune hot" ICOS+/CD45RO+ immunephenotype and the impact on survival in patients with esophageal adenocarcinoma.
Authors: Matthew Philip Humphries, Natalie Fisher, Rafal Kacprzyk, Stephanie G Craig, Victoria Bingham, Stephen McQuaid, Richard C. Turkington, Graeme I Murray, Jacqueline James, Manuel Salto-Tellez
Journal: Journal of Clinical Oncology (2019)

4062 Background: Therapies targeting immune checkpoints are changing our understanding of the biology and treatment of cancer. Analysing the immune landscape in esophageal adenocarcinoma (EA) may help future prognostication and therapeutic decision-making. Methods: We assembled 310 EA cases in a tissue microarray format with associated clinicopathological information, including a discovery cohort of 156 EA from Northern Ireland and a 154 EA validation cohort from Aberdeen. We carried out validated immunohistochemistry (IHC), stained for range of adaptive immune (CD3, CD4, CD8 and CD45RO) and immune checkpoint biomarkers (ICOS and IDO-1). Slides were digitised and assessed using QuPath image analysis software program to quantify their expression and correlate them with outcome. Results: In the discovery cohort we identified a group of patients highly expressing several immune biomarkers, conferring a significant positive survival advantage (p = 0.022). CD3, CD4, CD8, CD45RO, and ICOS were individually prognostic for better overall survival (Log rank p = 0.0003; p = 0.0292; p = 0.0015; p = 0.0008; p = 0.0051 and p = 0.0264 respectively). Multivariate and correlation analysis identified a subgroup of CD45RO+/ICOS+ patients with significantly improved overall survival (p = 0.0002). The co-expression of CD45RO+/ICOS+ immunophenotype was investigated in the validation cohort and a confirmed survival advantage was seen (p = 0.042). Additionally, the Opal Multiplex IHC technology revealed the much higher frequency of single-cell, dual labelling of CD45RO+/ICOS+ in immune hot cases. Conclusions: These data demonstrate the advantage of immune markers other than the traditional CD3/CD4/CD8 in EA prognostication. The fact that one of these biomarkers is an immune checkpoint inhibitor may have therapeutic implications.
Phase II trial of pembrolizumab (MK-3475) in metastatic cutaneous squamous cell carcinoma: An updated analysis.
Authors: Melinda Lynne Yushak, David H. Lawson, Monica Goings, Marjorie Mckellar, Necia Maynard, Kristin Sieja Woodruff, Caroline Gorgoglione, Stephanie McBrien, Keith A. Delman, Michael C. Lowe, Ragini Reiney Kudchadkar
Journal: Journal of Clinical Oncology (2019)

e21015 Background: Cutaneous squamous cell carcinomas (cSCC) are generally curable with surgery and/or radiation. Unfortunately, some patients develop locally advanced or metastatic disease, with an estimated 3900 to 8700 patients dying of cSCC in 2012. Aggressive disease is often associated with immunosuppression, and no treatment has shown an improvement in overall survival (OS). Recently the FDA has approved cemiplimab-rwlc which targets PD-1. This abstract provides an updated analysis and additional followup for patients treated with pembrolizumab which also targets PD-1. Methods: Clinical activity of pembrolizumab in cSCC patients was evaluated in patients who were not curable by surgery and/or radiation. Patients were treated with pembrolizumab 200mg IV every 3 weeks for up to 2 years. Tumor response was measured every 12 weeks using RECIST version 1.1. Response rate (RR) of pembrolizumab in metastatic cSCC was the primary objective. 6-month progression-free survival (PFS) and 1 year OS were secondary objectives. Results: 11 subjects have been enrolled thus far with a median age of 70.3 years. Two were female and all were Caucasian. ORR per RECIST criteria was 64% with 18% (2) having a complete response, 36% (4) a partial response, 36% (4) progressive disease (PD), and 9% (1) stable disease. The patient with stable disease had a clinical response and was eventually able to undergo surgery that rendered him without any evidence of disease. 6 month PFS for evaluable patients was 72%. Of those patients with a response, 50% had a durable response of 18 months or greater at the time of data cut-off. No subject deaths have occurred on study. Three grade 3 related-adverse events were noted (hepatitis and pneumonitis). Conclusions: Pembrolizumab is active in advanced cSCC. Responses appear durable and comparable to what has been seen in previous studies with the FDA-approved agent, cemiplimab. No new safety concerns were noted. Additional follow up is needed in order to establish an OS benefit. Clinical trial information: NCT02964559.
Case 45-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, J.D. Rutherford, D.C. Sgroi
Journal: New England Journal of Medicine (1992)

Presentation of CaseA 75-year-old man was admitted to the hospital because of a colonic carcinoma, right ventricular mass, and pleuritic chest pains.The patient was in vigorous health three months earlier, when a physical examination was normal; he continued to play tennis doubles regularly and to take part in ballroom dancing. A stool specimen gave a negative test for occult blood. One month later he had a "boring," nonpleuritic pain in the left scapular region. His physician heard a Grade 2 apical systolic murmur for the first time; the lungs were clear. Radiographs of the chest revealed slight prominence . . .
Integration of radiomic, genomic and clinical data to support decision making for lung cancer.
Authors: Thierry Colin
Journal: Journal of Clinical Oncology (2019)

e14607 Background: Medical imaging techniques play a central role in the evaluation of lung cancer and proper images analysis is essential for determining the location and stage of tumors, for diagnosis and prognosis assessment, guiding therapeutic decisions and for monitoring tumor response during and after treatment. It also supports interventional radiology acts (i.e. biopsies, thermo-ablations or embolization). Yet, this source of information, which is critical for the decision-making process, is not being used to its full potential. Besides, NGS technics allow the precise characterization of the genomic profile of a tumor by detecting mutations, evaluating the TMB and providing additional information such as the PD-L1 status. Methods: We have used an AI-based strategy to improve the stratification of cohorts of patients suffering from lung cancer. Using an advanced segmentation technology, we were able to quickly and precisely extract 3D Radiomic characteristics from the images. We then combined extracted heterogeneity and texture indicators with the biology information thanks to a machine learning based methodology. Results: We have applied this strategy to stage 4 NSCLC with EGFR mutation treated with TKI and have shown that stratification of the cohort with respect to the OS can be delivered using the base-line CT-scan and the first two exams used for the evaluation of the early response to the treatment. The same strategy was developed for the monitoring of lung metastases in order to help scheduling thermo-ablation by providing a prediction of the growth of the lesion in oligo-metastatic cases. Conclusions: This study paves the way to a near future when Artificial Intelligence will provide precise evaluation of lung tumors and full integration of all the medical information available for each patient to support the decision making within the tumor board.
Ramucirumab (RAM) for sorafenib intolerant patients with hepatocellular carcinoma (HCC) and elevated baseline alpha fetoprotein (AFP): Outcomes from two randomized phase 3 studies (REACH, REACH2).
Authors: Josep M Llovet, Chia-Jui Yen, Richard S. Finn, Yoon-Koo Kang, Masatoshi Kudo, Peter R. Galle, Eric Assenat, Marc Pracht, Ho Yeong Lim, Kun-Ming Rau, Christophe Borg, Jean-Baptiste Hiriart, Bruno Daniele, Thomas Berg, Hyun Cheol Chung, Nathalie Godinot, Chunxiao Wang, Yanzhi Hsu, William R. Schelman, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2019)

4073 Background: Oral multikinase inhibitors that have shown improvements in overall survival (OS) in HCC are associated with clinically important toxicities that commonly require dose adjustment or discontinuation (D/C) due to intolerance. REACH and REACH-2 studied RAM in patients (pts) with HCC who progressed on or were intolerant to sorafenib (SOR), and REACH-2 only enrolled pts with baseline AFP ≥400 ng/mL. In REACH-2 RAM treatment (trt) improved OS compared to placebo (P), supporting findings in REACH pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by reason for D/C of SOR was performed. Methods: Pts had advanced HCC, Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or P Q2W. A pooled independent pt data analysis (stratified by study) of REACH-2 and REACH pts (AFP ≥400 mg/mL) was performed. Results are reported by reason for SOR D/C (intolerance or disease progression). OS and PFS were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR) and safety are reported. Results: Baseline characteristics in the pooled population were generally balanced between trt arms in each subgroup. Median durations of prior SOR were 2.5 mo for SOR intolerant (n = 70) and 4.0 mo for SOR progressors (n = 472). Median OS (RAM v P) was 10.2 v 6.7 mo for SOR intolerant and 8.0 v 4.7 mo for SOR progressors (Table). Rates of D/C due to trt-related adverse events (AEs) (Table) (7% in each subgroup), and Grade ≥3 AEs (most frequently hypertension) were consistent with those observed in each study. Conclusions: Acknowledging limitations of sample size, the RAM trt benefit in SOR intolerant pts was consistent with that in the ITT population. RAM was well tolerated in SOR intolerant pts with low rates of D/C due to related-AEs. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]
Abstract 9042: Left Ventricular End Systolic Cross-Sectional Area Shows Strong Correlation with Short Axis Untwisting Rate
Authors: Michael Tee, Muhammad Ashraf, David J Sahn
Journal: Circulation (2012)

Background: The untwisting rate of the left ventricle (LV) has been related to early diastolic filling and is proposed as a sensitive index of diastolic function of the heart. In this investigation, we examined the LV segmental untwisting rate (specifically at the lateral and septal walls) with relation to the efficiency of systolic contraction computed as end-systolic short axis area. Methods: We analyzed high-resolution image data acquired from the LV of 15 open chest pigs using a 10MHz probe on a GE Vivid 7 Dimension ultrasound system. Apical short axis views were exported to EchoPac PC. With this software, end systolic area was measured by tracing the endocardium at maximum contraction. Using 2D speckle tracking, untwisting rate was recorded at the septal wall and the opposing lateral wall of the heart at the mid cavity level just above the papillary muscles. Results: The septal untwisting rate (102.9 ± 23.5 deg/s) was significantly greater than the lateral untwisting rate (25.0 ± 13.9 deg/s). Although both showed a strong negative correlation with end systolic area, our results indicate that the septal wall untwisting rate showed a stronger correlation (R = -0.85, p &lt; 0.05) with end systolic area than lateral wall untwisting rate (R = -0.79, p &lt; 0.05). Conclusions: Septal untwisting rate showed a stronger negative correlation with the end systolic LV cavity area at the mid level than the lateral wall untwisting rate.
PULMONARY METASTASES IN RECURRENT, TREATMENT-RESISTANT MENINGIOMA: PROGNOSIS AND IDENTIFICATION BY IN-OCTREOTIDE IMAGING
Authors: Daniela Alexandru, Michael J Glantz, Lyndon Kim, Marc C Chamberlain, Daniela A Bota
Journal: Neuro-Oncology (2010)

Author(s): Alexandru, Daniela; Glantz, Michael J; Kim, Lyndon; Chamberlain, Marc C; Bota, Daniela A
NTRK1 fusion identified by capture-based next-generation sequencing in non-small-cell lung cancer.
Authors: Ruiying Zhao, Chan Xiang, Nan Dong, Lianying Guo, Shengji Ma, Yuchen Han
Journal: Journal of Clinical Oncology (2019)

e20664 Background: The clinicopathological features and genomic rearrangements of neurotrophic tyrosine kinase receptors (NTRKs) fusion in non-small-cell lung cancer (NSCLC) have not been fully identified. To explore NTRK1 fusion in non-small-cell lung cancer (NSCLC) specimens, and to explore the relationships between the NTRK1 fusion and the clinicopathological features and to identify genomic rearrangements by multiple molecular methods. Methods: In total, 3947 NSCLC specimens were tested for NTRK1 fusion using genomic DNA capture-based NGS. Then, these NTRK1 fusion cases were identified by Oncomine Focus Assay and FISH. The clinicopathological features were analyzed. Results: In total, five specimens (0.13%) were detected NTRK1 fusion. All these five specimens were adenocarcinoma (0.15%, 5/3423), while no NTRK1 fusions were found in 496 squamous cell carcinoma (SCC) cases and 28 adenosquamous carcinoma (ASC) cases. The ages of patients carried NTRK fusion were range from 31-year to 64-year-old. These five NTRK1 fusion cases were two females and three males, four non-smokers and one with 30 years smoking history, three surgical specimens and two small biopsies. Among these three surgical specimens, one was minimally invasive adenocarcinoma and two were invasive adenocarcinoma. One canonical fusion (TPM3-NTRK1) was detected, the other four were noncanonical fusion type (C14orf2-NTRK1, RRNAD1-NTRK1, LOC101060524-NTRK1, ARHGEF11-NTRK1). The RRNAD1-NTRK1 case was coexist with L858R mutation of EGFR, and the ARHGEF11-NTRK1 was coexist with G12A mutation of KRAS. All of these five fusions were confirmed by FISH, while only the canonical TPM3-NTRK1 was confirmed by Oncomine Focus Assay. Conclusions: In summary, NTRK1 fusion is rare in lung adenocarcinoma and does not exist in squamous cell carcinoma or adenosquamous carcinoma cases. Age and gender are not significantly correlated with NTRK1 fusion. NTRK1 fusions were more common in non-smokers. Genomic DNA capture-based NGS can detect both canonical and noncanonical NTRK1 genomic rearrangements. Noncanonical NTRK1 genomic rearrangements need confirmed by other methods such as FISH. NTRK1 fusion may coexist with other canonical driver gene mutation.