tbuckley/cabot-search huggingface dataset:
A phase 2 study to assess olaparib by homologous recombination deficiency status in patients with platinum-sensitive, relapsed, ovarian, fallopian tube, or primary peritoneal cancer.
Authors: Karen Anne Cadoo, Carol Aghajanian, Cindy Fraser, Alvin Milner, Geert Kolvenbag
Journal: Journal of Clinical Oncology (2017)

TPS5606 Background: The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is approved for treatment of patients (pts) with germline BRCA mutations ( BRCAm) and advanced ovarian cancer (OC). BRCA mutations are genetic alterations leading to homologous recombination deficiency (HRD) and tumor susceptibility to DNA-damaging agents, including PARP inhibitors. Loss of genetic heterozygosity, telomeric-allelic imbalance, or large-scale state transitions may identify additional pts who could benefit from PARP inhibitor therapy. Methods: LIGHT is a non-randomized, open-label, phase 2 study to assess the efficacy and safety of olaparib in patient cohorts identified by different HRD genetic tests (NCT02983799). Patients will have platinum-sensitive (progression &gt; 6 mo after the end of the last platinum-based chemotherapy), relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer; ECOG performance status 0–1; and ≥2 prior lines of platinum-based chemotherapy for OC. Key exclusion criteria include prior PARP inhibitor treatment; concomitant use of potent CYP3A4/5 inhibitors or inducers; and symptomatic uncontrolled brain metastases. Patients will be enrolled into 4 cohorts of 30 pts each based upon BRCAm or tumor HRD status determined by genetic test results: germline BRCAm; somatic BRCAm; MyChoice HRD-positive and wildtype BRCAm; MyChoice HRD-negative and wildtype BRCAm. All pts will receive 300 mg olaparib tablets twice daily until disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) according to RECIST v1.1 criteria. The maximum precision of the ORR is approximately ±18.7% for 30 pts. Secondary endpoints include duration of response, cancer antigen-125 response rate, disease control rate, progression-free survival, time to any progression, overall survival, and homologous recombination repair gene panel mutation status related to clinical outcome. Planned enrollment of 120 pts at sites in the United States was initiated in December 2016. Clinical trial information: NCT02983799.
A Quality Improvement project to decrease overuse of vancomycin in an inpatient Hematology/Oncology service.
Authors: Shebli Atrash, Katherine T Lusardi, Juan Carlos Rico, Rajesh Banderudrappagari, Angela Pennisi, Belal Firwana, Denese D Harris, Barbara T Slatton, Konstantinos Arnaoutakis, Issam Makhoul
Journal: Journal of Clinical Oncology (2016)

e18167 Background:Vancomycin (vanc) is an important but frequently misused antibiotic. In hematology/oncology (hem/onc) population, aggressive dosing, with concurrent nephrotoxic medications and chemotherapy can cause higher rates of renal failure; under dosing risks resistance and inefficacy. Pharmacist-led dosing programs minimize these risks. To further minimize these risks, a quality improvement project was implemented to reduce non-indicated vanc use. Methods: Between Oct - Dec 2015, patients (pts) admitted to inpatient hem/onc service who received vanc were assessed daily for vanc indication. Appropriate indications were defined using guidelines from the Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN). Indications were determined to be appropriate by a hem/onc fellow and infectious disease physician. Plan-Do-Study-Act (PDSA) method was applied with each intervention phase. Phase 1 IDSA and NCCN based education to rounding team. Phase 2 Targeted education and feedback for misunderstood/unapplied guidelines. Phase 3 Empowering pharmacists to alert team when a patient is on vanc for 48 hours. Results: We assessed a sample of 109 consecutive pts who received a cumulative 532 days of vanc. An average of 6 of 45 (13%) pts daily on service received vanc. Fever & pneumonia were common indications. During Phase 1 (general education), vanc was unjustified in 139/189 vanc days (73.5%). After Phase 2 (targeted education), unjustified vanc decreased to 107/181 vanc days (59.1%). Failure to stop vanc after 48 hours despite negative cultures and clear chest images were the least applied guideline recommendation. Phase 3 (pharmacy alerts) further decreased unjustified vanc use to 63/162 vanc days (38.8%), (p < 0.005). Vanc use was higher on weekends during last phase (18/48 vs 48/115 p < 0.005), when physicians may not have time to adequately revisit antibiotic indications. Conclusions: Vanc is an overused antibiotic on hem/onc services. Increasing awareness of proper antibiotic use is an essential part of fellowship training, and patient care. Further decreasing vanc use, aiming at < 20%, might require improving physician to pts ratio over weekends.
Combination of lactate dehydrogenase and tumor mutational burden to predict clinical benefit of anti-CTLA-4 therapy in melanoma.
Authors: Wenjing Xiao, Nan Du, Taoyuan Huang, Jinan Guo, Xing-kui Mo, Tao Yuan, Yong Chen, Ting Ye, Chunwei Xu, Wen xian Wang, Guoqiang Wang, Shangli Cai, Jing Chen
Journal: Journal of Clinical Oncology (2018)

e15029 Background: Tumor mutational burden (TMB) has been revealed to be associated with the clinical outcome of immune checkpoint blockade (ICB). Nevertheless, part of patients with relatively lower TMB may still benefit from ICBs, indicating that TMB alone might be insufficient to distinguish all the patients that respond to ICBs. In this study, we combined TMB with lactate dehydrogenase (LDH) to determine whether this combination performs higher efficacy in predicting the effect of ICBs. Methods: Two cohorts of advanced melanoma patients treated with anti-CTLA-4 therapy were included. The first discovery cohort consisting of 110 patients was applied to investigate the prognostic effect of TMB/LDH alone or combination. The second validation cohort containing 64 patients was employed to further confirm the result concluded from the discovery cohort. The TMB level below the median of each cohort was defined as TMB-low and the LDH level beyond the upper limit of normal was defined as LDH-abnormal. Results: In the discovery cohort, TMB alone was not significantly correlated with the overall survival (OS), while LDH alone displayed prognostic potentials. While in LDH-abnormal group, the individuals with higher TMB exhibited longer OS (median, 248 vs. 148.5 days, hazard ratio [HR], 0.45, 95% CI, 0.22-0.75, P = 0.005) and progression-free survival (PFS) (median, 81 vs. 70 days, HR, 0.54, 95% CI, 0.26-0.88, P = 0.023) in contrast to TMB-low group. Taking TMB and LDH into account concurrently, LDH-normal/TMB-high group acquired better OS (median, 360 vs. 145 days, HR, 0.34; 95% CI, 0.10-0.37, P < 0.0001) and PFS (median, 97 vs. 70 days, HR, 0.40; 95% CI, 0.14-0.50, P < 0.0001) compared to LDH-abnormal and TMB-low group. These results were reproduced in the validation cohort that the combination of TMB and LDH, not TMB/LDH alone, performed significant association with the OS (median, 1058.5 vs 255.5 days, HR, 0.38, 95% CI, 0.06-0.80, P = 0.025). Conclusions: Coupled prognostic strategy containing TMB and LDH exhibited higher efficacy in predicting the clinical benefit of anti-CTLA-4 therapy in patients with metastatic melanoma, in comparison with TMB or LDH alone. Future prospective studies are warranted.
Executive summary of the 2018 KDIGO Hepatitis C in CKD Guideline: welcoming advances in evaluation and management
Authors: Michel Jadoul, Marina C. Berenguer, Wahid Doss, Fabrizio Fabrizi, Jacques Izopet, Vivekanand Jha, Nassim Kamar, Bertram L. Kasiske, Ching-Lung Lai, José M. Morales, Priti R. Patel, Stanislas Pol, Marcelo O. Silva, Ethan M. Balk, Craig E. Gordon, Amy Earley, Mengyang Di, Paul Martin
Journal: Kidney International (2018)

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline. This Executive Summary highlights key aspects of the guideline recommendations.
Patient reported outcomes (PROs) of multiple myeloma (MM) patients treated with panobinostat (PAN) after ≥2 lines of therapy based on the international phase 3, randomized, double-blind, placebo-controlled, PANORAMA-1 trial.
Authors: Paul G. Richardson, Sagar Lonial, Robert L. Schlossman, Anuja Nidumolu Roy, Istvan Majer, Ashok Panneerselvam, Monika Sopala, Jesus San Miguel
Journal: Journal of Clinical Oncology (2016)

8054 Background: PAN, in combination with bortezomib (BTZ) and dexamethasone (DEX), is FDA-approved for the treatment of MM patients who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory drug, based on significant clinical benefit of PAN+BTZ+DEX observed in PANORAMA-1. This analysis focuses on the impact of PAN+BTZ+DEX on patient experience, including measures of symptoms, function, and health-related quality of life (HRQoL), measured by EORTC-QLQ-30, QLQ-MY20, and FACT/GOG-Ntx. Methods: In PANORAMA-1, patients who had received between 1 and 3 previous treatment regimens were randomized 1:1 to receive 21-day cycles of placebo (PBO) or PAN, in combination with BTZ+DEX. PRO measures were administered at screening, cycle 1 day 1, and every 6 wks thereafter until end of treatment. We present here the results at the end of 24 wks, when treatment benefit was assessed for evaluation of treatment continuation. Results: In the US label population, PRO baseline data was available for 94 v 92 (EORTC QLQ-C30, Global Health Status/QoL scale) and 91 v 95 (QLQMY20, Disease Symptoms (DS) subscale and FACT/GOG-Ntx Neurotoxicity subscale) PAN+BTZ+DEX vs PBO+BTZ+DEX treated patients, respectively. At wk 24, FACT-GOG-Ntx scores were similar across treatment arms, suggesting no difference in neurotoxicity symptoms (32.03 v 33.92, respectively). An initial improvement followed by stabilization in the QLQ-MY20 DS subscale was observed, with no difference between arms (Wk 24: 20.65 v 15.85, respectively). After initial decline, EORTC QLQ-C30 Global Health Status/QoL scores were also comparable in the 2 arms (Wk 24: 54.84 v 58.55, respectively). Conclusions: These findings support the addition of panobinostat to the well-established BTZ+DEX regimen as an efficacious treatment option with limited symptomatology and impact on patients’ HRQoL. With the increasing importance of patient-relevant humanistic benefits in determining the overall value of oncology products, as seen in the recent ASCO value framework, findings such as these are important for treatment decision making. Clinical trial information: NCT01023308.
TCT-320 Impact of Pre-Procedural High-Sensitivity C-Reactive Protein, LDL-C and SYNTAX Score on Outcomes Following Percutaneous Coronary Intervention
Authors: Anton Camaj, Gennaro Giustino, Usman Baber, Melissa Aquino, None Paul Guedeney, Sabato Sorrentino, Birgit Vogel, Serdar Farhan, Nitin Barman, Pooja Vijay, Jason Kovacic, None Joseph Sweeny, George Dangas, Annapoorna Kini, Samin Sharma, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Icotinib and rh-endostatin as first line therapy in advanced non small cell line cancer patients harboring activating epidermal growth factor receptor mutations.
Authors: Qiong Zhao, Ling Peng, Feng Chen, Zhihai Hong, Haibo Mou, Yina Wang, Yemin Tang, Junfang Liu
Journal: Journal of Clinical Oncology (2016)

e20074 Background: It is unclear about the clinical outcome of the combination of icotinib and rh-endostatin (Endostar) in treating advanced non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations. This single-arm pilot study aims to investigate the preliminary efficacy and safety of the combination therapy for those patients. Methods: Patients with histologically confirmed nonsquamous advanced NSCLC who had exon 19 exon del or L858R were included. All patients received icotinib (125 mg po TID) plus rh-endostatin (15 mg civ for ten days, every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) at 24 weeks, and secondary endpoint is safety profile. In addition, exploratory evaluation was performed using dynamic contrast enhanced MRI (DCE-MRI) to analyse the tumor vascular permeability parameter, Ktrans. Results: 10 patients have been enrolled. The median age was 60 years old, with 7 female and 3 male patients. There were 6 patients with exon 19 del, 3 patients with L858R mutation, and 1 patient with L858R and S768I muation. The preliminary results showed the clinical ORR at 24 weeks was 60% (1 complete resonse, 5 partial responses, and 4 stable diseases) and a mean reduction in tumor size of 32.5%. Compared with baseline, there was 52.4% and 7.5% increase in patients who obtained ORR and SD as their best response with mean Ktrans of 0.22 and 0.40, respectively. The dynamic changes of Ktrans were consistent with clinical outcome of tumor responses. In ORR group, the tumor Ktransdropped as early as seven days after the therapy, while it remained stable in SD group. The overall tolerability of the combination was good, as there were no toxicities of CTC-AE 4.0 grade 3 or greater. Conclusions: The combination of icotinib and rh-endostatin was effective and safe. Serial Ktrans derived from DCE-MRI could be used as a non-invasive imaging biomarker to prodict the tumor response after treatment, optimize the regimen and facilitate the identification of the best patient population who may potentially benefit from this combination regimen. Clinical trial information: NCT02375022.
Next-generation sequencing reveals high intra-individual molecular concordance between primary head and neck tumors and matched local or distant recurrences
Authors: N. Martin, N. Ebran-Bendahhou, J. Boyer, V. Duranton-Tanneur, A. Bozec, F. Peyrade, J. Guigay, A. Sudaka-Bahadoran, G. Milano, E. Saada-Bouzid
Journal: Annals of Oncology (2018)

Background: Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is an uncurable disease and is responsible of 4 000 deaths every year in France. Targeted therapies improve outcomes in several types of cancer and lead to development of the prescription of drugs according to the molecular features of the tumor, called "precision medicine". The need to perform recent biopsy to perform those molecular analyses is a critical restriction and limits inclusion of patients into precision medicine programs. Methods: To compare molecular profiles of primitive tumor and recurrence, we analyzed molecular alterations in primary HNSCC and paired local or distant recurrences from 31 patients using targeted next-generation sequencing (MiniSeq, Illumina), of 42 "cancer-associated" genes (Solid Tumor Solution, Sophia Genetics). Results: Primary tumors and recurrences harbored alterations common in HNSCC. The most frequent were TP53 mutations (76%), CDKN2A mutations (21%), PIK3CA mutations (16%), MET mutations (16%) and EGFR amplifications (8%). Twenty-six patients (83.9%) showed concordant molecular profiles between primary tumors and matched local or distant recurrences. Fifteen patients harbored alterations with potential therapeutic implications (mostly tyrosine kinase receptor genes or oncogenes activation) according to local Molecular Tumor Board criteria. Twenty-seven out of the 31 patients (87.1%) had concordant molecular profile between primary and recurrence when considering only these "druggable" alterations. Conclusions: HNSCC primary tumors and metastases exhibit an intra-individual high genomic concordance. As these patients had limited therapeutic options, inclusion in precision medicine programs represents an important opportunity and should be allowed regardless of the origin of the sample, the primary tumor or its recurrence. Legal entity responsible for the study: Centre Antoine Lacassagne. Funding: Centre Antoine Lacassagne. Disclosure: All authors have declared no conflicts of interest.
High neutrophil to lymphocyte ratio is associated with poor outcome during immunotherapy treatment in metastatic renal cell carcinoma.
Authors: Rohit K. Jain, Rohit Gosain, Saby George
Journal: Journal of Clinical Oncology (2018)

e15140 Background: Studies have shown that high pretreatment neutrophil-to-lymphocyte ratio (NLR) is related to host inflammation and associated with poor outcomes in variety of cancers. This study aims to determine clinical association between NLR pretreatment and on treatment levels with outcome in metastatic renal-cell carcinoma (mRCC) patients treated with immunotherapy. Methods: Retrospective chart review of patients with mRCC who received PD-1 inhibitor therapy between Jan 2012 to Dec 2016 in or outside of clinical trial was conducted. An optimal cutoff of high NLR (³5) was used based on prior studies. NLR was calculated before treatment and at 6 (±2) weeks on treatment. Survival analysis was performed using the Kaplan-Meier method and multivariate cox proportional models. Results: A total of 65 patients were treated. Median age was 60 (range 40-87) years; 25% were females. Forty percent patients received ³ 2 prior systemic therapies, 81% patients had clear-cell histology, 6 had mixed clear-cell with sarcomatoid/rhabdoid features, and 4 with mixed papillary histology. 47% patients had stage IV disease at presentation, and 63% had ECOG PS ³1. Median overall survival (OS) was 12 months. In univariate analysis, pretreatment NLR < 5 (median 29 vs 6 months; HR 0.21, 95% CI 0.10-0.45; p < 0.001), NLR < 5 at 6 (±2) weeks (median 47 vs 6 months; HR 0.13, 95% CI 0.05-0.30; p < 0.001) were associated with superior OS. In multivariate analysis adjusting for age, sex, grade, ECOG PS, and number of previous treatments; the pretreatment NLR < 5 (HR 0.21, 95% CI 0.08-0.52, p = 0.001) and NLR at 6 (±2) weeks (HR 0.17, 95% CI 0.07-0.38, p < 0.001) were independently associated with better survival. Median progression–free survival (PFS) for the cohort was 7 months. In univariate and multivariate analysis, NLR < 5 was associated with better PFS at baseline as well as at 6 weeks on treatment. Conclusions: These results highlight that high NLR at baseline or at 6 weeks on immunotherapy treatment is associated with worse OS and PFS in mRCC patients. It also may have a unique predictive value and will require further investigational studies.
EPHA2/MAPK pathway confers acquired resistance of afatinib in gastric cancer
Authors: Z. Chen, Z. Liu, J. Gao, L. Shen
Journal: Annals of Oncology (2018)

Background: We explored antitumor activity of afatinib in vitro and in vivo in gastric cancer (GC). In addition, underlying antitumor and acquired resistant mechanisms of afatinib were also investigated. Methods: Four GC cell lines were used to evaluate cell viability, cell cycle and apoptosis using cell proliferation assay and flow cytometry, respectively. Nine patient-derived xenograft (PDX) models were established to investigate the antitumor activity of afatinib in vivo. Immunohistochemistry and western blot were used to detect the expression level of ErbB family and downstream PI3K/AKT and MAPK pathway in cell lines and PDX models after afatinib treatment. In addition, one afatinib-resistant PDX model was established, and we detected the gene expression alterations between parental, sensitive and resistant PDX models via RNA sequencing and immunoblot. Furthermore, potential mechanisms of acquired resistance and corresponding reverse strategy were explored. Results: Afatinib significantly inhibited the proliferation of NCI-N87 cell line (IC50 = 2nM) and induced tumor growth regression or inhibition in EGFR-amplified/overexpressed and HER2-positive PDX models (TGI: 61.9% -116%, p < 0.05). However, in PDX models without ErbB family molecular variations, the anti-tumor activity of afatinib were weak (TGI: 25% -38%, p > 0.05). The effective treatment of afatinib induced cell cycle arrest at G1 (p < 0.05) and obvious apoptosis (p < 0.05) in NCI-N87 cells. Afatinib exerted its antitumor effect by inhibiting the phosphorylation of ErbB family and activation of PI3K/AKT and MAPK signaling pathway. We observed the overexpression and phosphorylation of EPHA2, and reactivation of MAPK pathway in the afatinib-resistant PDX model. The EPHA2 inhibitor ALW-II-41-37 could restore the sensitivity to afatinib by monotherapy (TGI: 60%, p < 0.001) or in combination with afatinib (TGI: 81%, p < 0.001). Conclusions: Afatinib exerted selective antitumor activity against GC cell lines and PDX models via inducing cell apoptosis and cell cycle arrest at G1 phase, and suppressing phosphorylation of ErbB family, PI3K/AKT and MAPK signaling pathway. EPHA2 conferred the acquired resistance of afatinib against GC and the inhibition of EPHA2 could reverse the resistance of afatinib. Legal entity responsible for the study: Zuhua Chen. Funding: The National Key Research and Development Program of China. Disclosure: All authors have declared no conflicts of interest.
MET aberrations across multiple tumor types: Results of a molecular screening program (MOSCATO 01).
Authors: Yolla El Dakdouki, Loic Verlingue, Christophe Massard, Etienne Rouleau, Ludovic Lacroix, Nathalie Auger, Jean-Yves Scoazec, Zsofia Balogh, ERIC ANGEVIN, Jean-Charles Soria, Antoine Hollebecque
Journal: Journal of Clinical Oncology (2017)

e23110 Background: MET gene, encoding the tyrosine kinase receptor for HGF, has been shown to have an oncogenic role in several tumors. We report here the frequency, distribution and clinical characteristics of the patients (pts) found to have MET alterations in a molecular screening trial. Methods: InMOSCATO clinical trial, pts with locally advanced or metastatic solid cancers had an on-purpose tumor biopsy to perform a comprehensive molecular characterization. Results: Among the 844 adult pts who had a successful molecular portrait, 29 (3.4%) had MET aberrations distributed as follows: 18 had abnormalities at the genomic analysis level while 11 had exclusively expression of phosporylated-MET by immunohistochemistry (IHC) and/or a positive fluorescence in situ hybridization (FISH). Only one of the 74 pediatric pts included had a missense mutation. According to the primary tumor, MET alterations were found in 13/170 successfully biopsied pts with lung cancer, 8/197 with digestive tumors, 3/158 with genito-urinary tumors, 2/83 with gynecologic tumors, 2/111 with head and neck cancers, 1/135 with breast cancer and 1 pt with pediatric glioblastoma. Pathogenic variants (PV) were detected in 3 pts by targeted Next Generation Sequencing (NGS), 2 of these PV were exon 14 donor splice site mutations detected also by whole-exome sequencing (WES) in 2 lung tumors. Missense mutations were identified in 3 pts by RNA-sequencing and in one patient by WES. 8 pts had MET amplification identified by comparative genomic hybridization array (CGH) in 5 cases, by FISH in one case and by both FISH and CGH in 2 cases. One patient displayed both amplification and a missense mutation. Ten pts received an anti-MET targeted therapy. One had PV on NGS and missense mutation on WES, 3 had amplification on CGH or FISH and 6 positive IHC. One patient displaying MET exon 14 donor splice site mutation was treated with crizotinib achieving a rapid and sustained partial response. The other 9 pts were treated with SAR125844, a selective MET tyrosine kinase inhibitor, in TED11449 trial (NCT01391533). Conclusions: In this analysis, we saw that MET aberrations are rare in various types of advanced cancers. In selected patients, targeting MET is of clinical interest. Clinical trial information: NCT01566019.