tbuckley/cabot-search huggingface dataset:
Next generation sequencing (NGS) in soft tissue / bone sarcoma (STS/BS) patients.
Authors: Ofer Merimsky, Sivan Shamai
Journal: Journal of Clinical Oncology (2018)

e23523 Background: Recent evidence has introduced targeted therapies for treating sarcoma patients. Sarcoma sensitivity to targeted therapeutics have lead us to the hypothesis that comprehensive genomic profiling of advanced STS by next generation sequencing (NGS) may identify genomic-derived drug targets. Methods: Retrospective data collection of demographics, NGS results, and therapies were assessed for sarcoma patients undergoing NGS testing by various platforms (FoundationOne, Circulogene, OncoDEEP and Oncomine + PDL-1) between November 2011 and September 2017. Our primary endpoints were the range and incidence of targeted therapy options identified and the number of patients who subsequently received genotype-directed therapy. Results: Samples from 36 patients were tested by FoundationOne platform, most frequently sarcoma NOS, leiomyosarcoma, liposarcoma, osteosarcoma and single cases of MPNST and pecoma. Mean age of the patients was 49y (range, 18-75) . Most patients harbored at least one alteration (96%), with a total of 131 genomic alterations (GA) and a mean of 3.6 GA per tumor. GA included (47%) copy number changes (45 amplifications, 16 gene deletions). 58% of patients harbored potentially actionable GA, involving cell-cycle regulation (38%), mTOR pathway (32%) cell death (TP53, MDM2, 27%), receptor tyrosine kinase (RTK's, 19%), and DNA repair (12%). Samples from 27 additional patients were tested by other platforms. Mean age was 53y (23-91y). The sarcoma types included liposarcoma, Ewing sarcoma, Leiomyosarcoma, HG STS NOS , fibrosarcoma , uterine sarcoma, osteosarcoma, pecoma. GA were found in 14 patients, and included CDK4, P53, IGFR overexpression, CD8, BRAF S605G, SMARCB1, FGF2, APC, PIK3CA, KIT, PDL-1, EGFR , BRAF G466E, RET, MET, and NRAS. Treatment decisions have been made accordingly for patients in all subtypes including TKI's, mTOR inhibitors, CDK4/6 inhibitors. Four out of 27 patients were offered related therapies, resulting in no real response. Conclusions: For STS/BS, comprehensive genomic profiling can identify a significant number of potentially clinically relevant GA. Results suggest that although there are potentially treatable targets, the benefit remains very poor.
Association of STK11/LKB1 mutations with primary resistance to PD-1/PD-L1 axis blockade in PD-L1 positive non-squamous NSCLC.
Authors: Ferdinandos Skoulidis, Brett W. Carter, Jianjun Zhang, Ignacio Ivan Wistuba, Vassiliki Papadimitrakopoulou, John Heymach
Journal: Journal of Clinical Oncology (2018)

9028 Background: The genomic determinants of response to PD-1/PD-L1 axis blockade in non-squamous NSCLC are incompletely understood. We previously identified STK11/LKB1 alterations as a major genomic driver of low tumor cell PD-L1 expression and primary resistance to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. A critical unanswered question is whether STK11/LKB1 alterations predict for lack of response to PD-1/PD-L1 blockade independently of PD-L1 expression. Here, we report the impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors in PD-L1-positive non-squamous NSCLC. Methods: 66 patients with non-squamous NSCLC treated with PD-1/PD-L1 inhibitors at MDACC (61% pembrolizumab, 24% nivolumab, 8% atezolizumab, 5% durvalumab/tremelimumab) with available STK11/LKB1 NGS-based genomic profiling and positive tumor cell PD-L1 expression (≥1%, based on the FDA-approved 22C3 pharmDx assay) were identified retrospectively. Response assessment was based on RECIST1.1. Results: In this PD-L1-positive population of non-squamous NSCLC, STK11/LKB1 alterations were associated with significantly lower ORR to PD-1/PD-L1 blockade compared to tumors with intact STK11/LKB1 status (ORR 0% versus 34.5%, P = 0.026). STK11/LKB1-mutant tumors exhibited significantly shorter progression-free survival (mPFS 1.7 months versus 19.3 months, HR 4.76, 95% CI 2.0-11.1, P = 0.00012, log-rank test) and overall survival (mOS 11.1 months versus 26.5 months, HR 14.3, 95% CI 3.4-50.0, P < 0.0001, log-rank test) with PD-1/PD-L1 blockade. Although fewer STK11/LKB1-mutant tumors expressed high (≥50%) levels of PD-L1 (45.5% versus 61.8%), the difference did not reach statistical significance (P = 0.5). Conclusions: STK11/LKB1 genomic alterations are associated with de novo resistance to PD-1/PD-L1 inhibitors even among PD-L1-positive non-squamous NSCLC patients, suggesting that their effect is at least partially independent of PD-L1 expression. Evaluation of STK11/LKB1 genomic status may enhance the predictive utility of a composite PD-1/PD-L1-inhibitor predictive biomarker panel incorporating PD-L1 expression and TMB.
Prognostic significance of the proliferation signature in mantle cell lymphoma measured using digital gene expression in formalin-fixed paraffin-embedded tissue biopsies.
Authors: David W. Scott, Pau Abrisqueta, George Wright, Pedro Jares, Graham W Slack, Anja Mottok, Cristina Royo, Guillem Clot, Magda Pinyol, Merrill Boyle, Diego Villa, Christian Steidl, Joseph M. Connors, Andreas Rosenwald, Louis M. Staudt, Lisa M Rimsza, Randy D. Gascoyne, Elias Campo
Journal: Journal of Clinical Oncology (2016)

7510 Background: Mantle cell lymphoma (MCL) is a group of aggressive B-cell lymphomas displaying heterogeneous outcomes after treatment. A number of prognostic indices have been described. A powerful biomarker, the “proliferation signature”, was developed using gene expression in fresh frozen material in 2003 (Rosenwald et al Cancer Cell). Here we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods: FFPE biopsies were used to train an assay on the NanoString platform using Affymetrix U133 microarray gene expression in matched fresh frozen biopsies as a gold standard. The locked assay (including gene coefficients and score thresholds to define high, intermediate and low risk groups) was then applied to pre-treatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with R-CHOP chemotherapy at the BC Cancer Agency. In 59 of these patients, aged 65 years or younger, there was intention-to-treat with an autologous stem cell transplant to consolidate response (the “ASCT-ITT” group). The MIPI was available for 95 patients. Results: The MCL55 assay, containing a 16-gene proliferation signature, yielded gene expression of sufficient quality to assign a score and risk group in 108/110 (98%) archival FFPE biopsies and assigned patients to high (26% of patients), intermediate (29%), and low (45%) risk groups with significantly different overall survival (OS); median OS of 1.1, 2.6 and 8.6 years, respectively (logrank for trend P<0.001). Within the ASCT-ITT group the median OS in these 3 risk groups were 1.4 years, 5.9 years, and not reached, respectively (logrank for trend P<0.001). In multivariate analysis, the risk groups assigned by the MCL55 assay and by the MIPI were independently associated with OS in the total cohort (P<0.001 for both variables). Conclusions: The newly developed and validated MCL55 assay for FFPE biopsies uses the proliferation signature to define groups of patients with MCL with significantly different OS independent of the MIPI.
Linking MAPK inhibition and the response to TNF in melanoma.
Authors: Sanjay Chandrasekaran, Maiko Sasaki, Brian P. Pollack
Journal: Journal of Clinical Oncology (2018)

e24143 Background: Antigen presentation plays a central role in anti-tumor immunity and the response to immunotherapy. Recent studies have underscored the importance of MHC class I (MHC I) and class II (MHC II) expression in obtaining a response to immune checkpoint blockade. Many cytokines can induce MHC expression, including interferon (IFN) and tumor necrosis factor (TNF). While it has been shown that MAPK inhibitors enhance the induction of MHC molecules by interferons, the impact of MAPK inhibitors on TNF-a-regulated MHC expression is not well defined. We examine the impact of MAPK inhibitors on MHC induction by TNF-a in human melanoma cells. Methods: BRAFV600E heterozygous cell line SKMEL3 and BRAFV600E homozygous cell lines A375 and SKMEL28 were treated with TNF-a alone or in combination with the MEK inhibitor trametinib or BRAFV600E inhibitor vemurafenib. Cell surface levels of MHC I and MHC II were measured by flow cytometry. Steady-state mRNA levels of MHC I and MHC II were measured using real-time RT-PCR. Results: We found that trametinib and vemurafenib could enhance the induction of MHC I by TNF-a in the BRAFV600E homozygous A375 and SKMEL28 cells but not in the BRAFV600E heterozygous SKMEL3 cells. Additionally, TNF-a repressed basal MHC II expression in A375 cells and this effect was prevented by trametinib and vemurafenib. In A375 cells, steady state mRNA levels of HLA-A2 and HLA-DR were increased by trametinib and/or vemurafenib as were those of MHC I and MHC II co-activators NLRC5 and CIITA. Conclusions: MAPK inhibitors alter the effect of TNF-a on MHC expression in BRAFV600E homozygous melanoma cells. Further research is warranted to better understand the role of MAPK inhibitors on the cellular response to TNF-a in melanoma.
A preliminary study of apatinib in Chinese patients with osteosarcoma.
Authors: Yong Zhou, Fan Tang, Li Min, Wenli Zhang, Rui Shi, Yi Luo, Hong Duan, Chongqi Tu
Journal: Journal of Clinical Oncology (2017)

e22500 Background: Osteosarcoma is the most common malignant tumor of bone that displays hyperproliferative characteristics and high vascularity, making vascular endothelial growth factor receptors (VEGFRs) become promising targets. Apatinib, a tyrosine kinase inhibitor targeting VEGFR-2, shows anti-cancer effects against a broad range of malignancies. This study reported the clinical experience of apatinib in osteosarcoma. Methods: We collected the medical data of osteosarcoma cases who received apatinib for at least one month in our hospital. The objective response rate (ORR), disease control rate (DCR), and 6-month progression-free survival (PFS) and overall survival (OS) rates were evaluated, and the safety profile was observed. The cut-off date of analysis was 01/17/2017. Results: Between May 2015 and Nov 2016, a total of 34 cases received apatinib with informed consent (4 as neoadjuvant, 1 as neoadjuvant and first line, 10 as first line, 15 as second line and 4 as third line). Among them, 18 (52.9%) cases suffered from pulmonary metastases before apatinib administration; 29 (85.3%) patients had an Eastern Cooperative Oncology Group performance status of 1–2. Initial dosages of 250, 425, and 500 mg/d were given to 5 (14.7%), 3 (8.8%), and 26 (76.5%) cases, respectively. Dosage adjustment occurred in only 8 (23.5%) patients. The median duration was 5.9 months (95%CI, 4.5–9.4 months). According to RECIST v1.1, complete response, partial response, stable disease and progressive disease were achieved in 1 (2.9%), 6 (17.6%), 25 (73.5%) and 2 (5.9%) patients, respectively. The ORR was 20.5%, and the DCR was 94.1%. Patients with pulmonary metastases showed a relatively better response to apatinib, as the ORR and DCR were 33.3% and 88.9%, respectively. As for safety analysis, the most 3 common adverse events (AEs) were hand-foot syndrome (HFS) (29, 85.3%), diarrhea (16, 47.1%), and decreased appetite (9, 26.5%). Nine grade III AEs were occurred including 3 HFS, 2 hypertension, 1 diarrhea, 1 oral mucositis, 1 proteinuria and 1 serious peeling. Conclusions: Apatinib seems to be effective in treating osteosarcoma with acceptable safety profile. Perspective clinical studies with adequate sample size are required to validate our results.
Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative
Authors: Mitchell M. Levy, Foster C. Gesten, Gary S. Phillips, Kathleen M. Terry, Christopher W. Seymour, Hallie C. Prescott, Marcus Friedrich, Theodore J. Iwashyna, Tiffany Osborn, Stanley Lemeshow
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: In 2013, the New York State Department of Health (NYSDOH) began a mandatory state-wide initiative to improve early recognition and treatment of severe sepsis and septic shock.Objectives: This study examines protocol initiation, 3-hour and 6-hour sepsis bundle completion, and risk-adjusted hospital mortality among adult patients with severe sepsis and septic shock.Methods: Cohort analysis included all patients from all 185 hospitals in New York State reported to the NYSDOH from April 1, 2014, to June 30, 2016. A total of 113,380 cases were submitted to NYSDOH, of which 91,357 hospitalizations from 183 hospitals met study inclusion criteria. NYSDOH required all hospitals to submit and follow evidence-informed protocols (including elements of 3-h and 6-h sepsis bundles: lactate measurement, early blood cultures and antibiotic administration, fluids, and vasopressors) for early identification and treatment of severe sepsis or septic shock.Measurements and Main Results: Compliance with elements of the sepsis bundles and risk-adjusted mortality were studied. Of 91,357 patients, 74,293 (81.3%) had the sepsis protocol initiated. Among these individuals, 3-hour bundle compliance increased from 53.4% to 64.7% during the study period (P < 0.001), whereas among those eligible for the 6-hour bundle (n = 35,307) compliance increased from 23.9% to 30.8% (P < 0.001). Risk-adjusted mortality decreased from 28.8% to 24.4% (P < 0.001) in patients among whom a sepsis protocol was initiated. Greater hospital compliance with 3-hour and 6-hour bundles was associated with shorter length of stay and lower risk and reliability-adjusted mortality.Conclusions: New York’s statewide initiative increased compliance with sepsis-performance measures. Risk-adjusted sepsis mortality decreased during the initiative and was associated with increased hospital-level compliance.
Efficacy and safety of lurbinectedin (PM1183) in Ewing sarcoma: Final results from a phase 2 study.
Authors: Vivek Subbiah, Kamalesh Kumar Sankhala, Ravin Ratan, Enrique Sanz Garcia, Valentina Boni, Thierry Gil, Victor Manuel Villalobos, Sant P Chawla, Pilar Lardelli, Mariano Siguero, Carmen Maria Kahatt, Arturo Soto-Matos, Stefano Ferrari
Journal: Journal of Clinical Oncology (2018)

11519 Background: Patients (pts) with relapsed Ewing sarcoma (ES) have a poor outcome. New therapeutic agents are needed. L is a new anticancer drug that blocks transcription and induces DNA double-strand breaks, leading to apoptosis. Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, L might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins. Methods: A multicenter phase 2 trial to assess efficacy and safety of L in several types of advanced solid tumors (basket trial), including ES, is ongoing. In the ES cohort, 15 adult pts who had received no more than two prior chemotherapy regimens for advanced disease were recruited. If one confirmed response was observed, recruitment was to be increased to at least 25 evaluable patients. The study treatment was lurbinectedin 3.2 mg/m2 in a 1-hour infusion every 3 weeks. Results: 28 evaluable pts were enrolled. Median age was 33 years (range, 18-74) and 16 (57%) were males. 26 (93%) had an ECOG of 0/1. ES was extraosseous in 15 pts; 7 pts had ≥3 disease sites and 27 had received ≥2 lines of prior chemotherapy. 28 pts received a median of 4 cycles of L (range, 1-12) and a median total dose of 11.9 mg/m2 (range, 3.2-38.4). Efficacy: 4 pts (14.3%) had a partial response and 12 (42.8%) had disease stabilization, 6 of them for ≥4 months. Median duration of the response was 2.9 months (range, 2.9-5.5) and median progression-free survival was 2.8 months (CI 95% 1.4-4.2). Safety: Most common adverse events were related to myelosuppression: 53.6% neutropenia grade (G) 3/4, 14.3% febrile neutropenia, and 18% thrombocytopenia G 3/4; 6 pts had dose delay due to neutropenia G 2-4 or thrombocytopenia G1, and 6 pts had dose reduced because of neutropenia G2-4. G-CSF was given to 12 pts. There were no withdrawals or deaths due to toxicity. Conclusions: L as a single agent has shown activity in pretreated pts with advanced ES, with acceptable safety profile and tolerability. Myelotoxicity was well controlled with dose adjustments and G-CSF. Further and larger studies of L alone or in combination regimens are warranted for pts with advanced ES. Clinical trial information: NCT02454972.
Application of NCCN guidelines in PD-L1 expression for patients with stage IV non-small cell lung cancer.
Authors: Ilana Schlam, Karyn M. Dyehouse, Patrick J. Ward
Journal: Journal of Clinical Oncology (2018)

e15030 Background: Immune checkpoint blockade with PD-1/PD-L1 inhibition is a promising therapeutic option for patients with advanced NSCLC. The NCCN guidelines for NSCLC recommend analysis for PD-L1 expression at the time of diagnosis; the PD1 inhibitor pembrolizumab is recommended as first line therapy in patients with PD-L1 over-expression ( > 50%) without mutations or rearrangements of EGFR, ALK or ROS1. In our institution, the test turnover time is 4 days and the cost is $560. Methods: The aim of this project was to determine the utilization of PD-L1 expression testing and immune checkpoint blockers in a single community hospital to identify limitations in utilization in order to improve patient care. Results: Thirty-nine patients were treated for stage IV NSCLC in 2016. Twenty-two were males and 17 females; age ranged from 46 to 91 years with a mean age of 67 years. Sixteen were active smokers at the time of diagnosis, 19 former smokers and, four were never smokers. Thirty-two had adenocarcinoma, three squamous cell carcinomas, and three non-differentiated NSCLC. Eighteen (46%) patients had molecular profiling at the time of diagnosis. PD-L1 expression was tested in five patients, they had 0%, 2%, 70%, 70% and 100%. There was no correlation between the smoking history and the genetic profiling testing, three patients were formers smoker, one an active smoker and one never smoked. Only the patient with 100% expression of PD-L1 was treated with pembrolizumab as first line therapy. Conclusions: New developments in immunotherapy are significantly changing the prognosis of patients with advanced malignancies and therefore changing our practice. Moving forward, our goal is to increase molecular profiling based on the NCCN recommendations, including PD-L1 expression at the time of the diagnosis of NSCLC. We will accomplish this by increasing availability of this tests and with education of our patients, medical, and non-medical staff. A significant limitation to testing is the cost of the genetic profiling as well as the cost of PD-1/PD-L1 inhibitors.
Characterization of resistance to APO010, a recombinant hexameric FAS ligand, in human myeloma cell lines.
Authors: Haatisha Jandu, Annette Nielsen, Nils Brunner, Anker Hansen, Steen Knudsen, Peter Buhl Jensen
Journal: Journal of Clinical Oncology (2018)

e20025 Background: Multiple myeloma (MM) is one of the most common hematological malignancies. It tends to be a hard-to-treat cancer since all patients eventually progress due to drug resistance. Given the current lack of lasting therapeutic benefit for MM patients, there is a need for new treatment options. We aim to address this issue by introducing a new immune-oncology drug (APO010) in MM treatment. APO010 is a hexameric FAS-ligand and acts like a cytotoxic T-lymphocyte to induce apoptosis in cancer cells and could therefore be a new effective drug for MM as these cells express CD95 (FAS-receptor). APO010 is now in a clinical trial in MM patients. However, as resistance to APO010 may develop in these patients, it is important to understand the molecular mechanism underlying this resistance as such knowledge could lead to the identification of predictive biomarkers of APO010 in MM treatment. A 160-gene predictor of APO010 sensitivity is currently used in the clinic. Methods: We developed APO010-resistant variants of four human myeloma cell lines (LP1, Raji, MOLP-8 and KMS-12-BM) by exposing the cells to gradually increasing concentrations of APO010 over a period of 6 months to 1 year. The resistant cell lines were characterized on the basis of FAS-receptor protein expression, global gene expression and pathway analysis. Results: All APO010 resistant cell lines showed significant increase in resistance to APO010 as compared to their parental controls. The protein expression of FAS-receptor was down-regulated in all resistant cell lines, completely in LP1APO and KMS-12-BMAPO and partially in RajiAPO and MOLP-8APO. Gene expression profiling of the resistant and parental lines did not show any significant alteration in FAS receptor expression between sensitive and resistant cell lines, but did reveal differences in mRNA processing. The 160-gene APO010 predictor in all cases predicted a lower sensitivity of the resistant cell line than its parental sensitive cell line. Conclusions: Based on data obtained so far points to a post-transcriptional or post-translational modification of the FAS-receptor being responsible for APO010 resistance.
The relationship between serum level of copper and ceruloplasmin and pathologic and clinical characteristics in early breast cancer patients.
Authors: Jing Fan, Yi Wan, Yidi Wang, Hongliang Wei, Ge Zhao, Songpeng Li, Mengxuan Li, Meiling Huang, Ting Wang
Journal: Journal of Clinical Oncology (2018)

e13504 Background: The increase in serum copper and ceruloplasmin has been reported to positively related with the progress of advanced breast cancers. However, the role of copper and ceruloplasmin in early breast cancer(EBC) is unknown. Methods: 209 female patients that been diagnosed as EBC and treated within Xijing Hospital from Oct 2016 to Apr 2017 were included in the present study. The level of serum copper and ceruloplasmin were assayed using atomic absorption spectroscopy and immunoturbidimetry assay. respectively. The pathologic and clinical characteristics of patients such as age, pathologic type, etc. were analyzed by X test, t test and Pearson correlation analysis. p< 0.05 is significant. Results: After transforming copper and ceruloplasmin into binary variable (elevated and normal), age was both significant (p< 0.01). The different expression level of ER, PR , Ki67and molecular type, number and percent of metastatic lymph nodes were significant (p< 0.01). After correlation analysis, negative relationship existed between age and copper or ceruloplasmin (coefficient = 0.265 or 0.233, p< 0.01). And copper was positively related to the level of Ki67(coefficient = 0.169, p= 0.018). While ceruloplasmin was negatively related to PR (coefficient = -0.273, p< 0.01) and molecular type (coefficient = -0.217, p= 0.05). Conclusions: This is the first study that tried to reveal the expression of serum copper and ceruloplasmin in Chinese early breast cancer patients. The levels of both serum copper and ceruloplasmin were significantly higher in patients of young age, high Ki67 index and Luminal type. It is inferred that copper and ceruloplasmin might also play an important role in early procedure of breast cancer, and need collect more data in the future to validate.