tbuckley/cabot-search huggingface dataset:
Intensive sequential chemoterapy with etoposide, mitoxantrone and cytarabine (EMA) as salvage in patients with AML relapsing after hematopoietic stem cell transplantation.
Authors: Ayla Gokmen, Ender Soydan, Zafer Gokgoz, Kerem ozan Ozkumur, Onder Arslan, Osman Ilhan, Muhit Ozcan
Journal: Journal of Clinical Oncology (2017)

e18537 Background: Relapse after allogeneic hematopoietic stem cell transplantation ( HSCT) for AML is the main cause of treatment failure.The optimal treatment strategy for patients with AML relapsing after HSCT remains controversial. We evaluated the efficacy of intensive sequential chemotherapy with etoposide,mitoxantrone and cytarabine as salvage therapy in patients with AML relapsing after alloHSCT. Methods: Fifteen AML patients relapsing after HSCT who were treated with EMA regimen between January 2015 and December 2016 were analysed retrospectively. EMA regimen consisted of mitoxantrone 12 mg/m² on days 1-3, etoposide 200 mg/m² on days 8-10 and cytarabine 500 mg/m² on days 1-3 and 8-10. Results: Median age was 49 ( range 22-64) years. At transplantation , 12 patients were in CR ( 10 CR1 and 2 CR2) , 3 patients had active disease. 9 donors were matched related, 3 were matched unrelated and 3 were haploidentical. Median time from transplantation to relapse was 163 ( 62-576) days. Complete response ( CR) was achieved in 7 of 15 patients ( 46.6 %). Five patients died during treatment before assessment of response to treatment with a median day of 32 due to infection. Three patients did not respond to treatment. All patients suffered grade 4 neutropenia and thrombocytopenia. Neutropenic fever was obseved in all patients. Grade 2-3 a GVHD was observed in 10 patients (66%) during EMA chemotherapy at a median day of 15. Further treatment was given in 6 patients who achieved CR with EMA : 2 patients underwent second allogeneic HSCT, 1 patient underwent second haploidentical HSCT, 2 patients were treated with DLI, 1 patient was treated with azacytidine-DLI combination. Median OS was 100 d ( range 24-402). Median duration of OS in responding patients were 248 d ( 67-402). At last folllow-up 3 patients are still alive and disease free. Conclusions: Intensive sequential chemotherapy with EMA is an efficacious option as salvage therapy in patients with AML relapsing after HSCT. However further treatment strategies such as second transplantation, DLI after chemoterapy or maintanence with targeted drugs are required to obtain long term remission.
Absence of natriuretic peptide clearance receptor attenuates TGF-β1-induced selective atrial fibrosis and atrial fibrillation
Authors: Dolkun Rahmutula, Hao Zhang, Emily E Wilson, Jeffrey E Olgin
Journal: Cardiovascular Research (2018)

TGF-β1 plays an important role in atrial fibrosis and atrial fibrillation (AF); previous studies have shown that the atria are more susceptible to TGF-β1 mediated fibrosis than the ventricles. Natriuretic peptides (NPs) play an important role in cardiac remodelling and fibrosis, but the role of natriuretic peptide clearance (NPR-C) receptor is largely unknown. We investigated the role of NPR-C in modulating TGF-β1 signalling in the atria.MHC-TGF-β1 transgenic (TGF-β1-Tx) mice, which develop isolated atrial fibrosis and AF, were cross-bred with NPR-C knock-out mice (NPR-C-KO). Transverse aortic constriction (TAC) was performed in wild type (Wt) and NPR-C knockout mice to study. Atrial fibrosis and AF inducibility in a pathophysiologic model. Electrophysiology, molecular, and histologic studies were performed in adult mice. siRNA was used to interrogate the interaction between TGF-β1 and NP signalling pathways in isolated atrial and ventricular fibroblasts/myofibroblasts. NPR-C expression level was 17 ± 5.8-fold higher in the atria compared with the ventricle in Wt mice (P = 0.009). Cross-bred mice demonstrated markedly decreased pSmad2 and collagen expression, atrial fibrosis, and AF compared with TGF-β1-Tx mice with intact NPR-C. There was a marked reduction in atrial fibrosis gene expression and AF inducibility in the NPR-C-KO-TAC mice compared with Wt-TAC. In isolated fibroblasts, knockdown of NPR-C resulted in a marked reduction of pSmad2 (56 ± 4% and 24 ± 14% reduction in atrial and ventricular fibroblasts, respectively) and collagen (76 ± 15% and 35 ± 23% reduction in atrial and ventricular fibroblasts/myofibroblasts, respectively) in response to TGF-β1 stimulation. This effect was reversed by simultaneously knocking down NPR-A but not with simultaneous knock down of PKG-1.The differential response to TGF-β1 stimulated fibrosis between the atria and ventricle are in part mediated by the abundance of NPR-C receptors in the atria.
Symptom distribution of terminally ill cancer patients in a palliative care unit of a developing country.
Authors: Shristi Tiwari
Journal: Journal of Clinical Oncology (2017)

e21500 Background: Palliative care is new concept in developing countries like Nepal, It encompasses physical, psychosocial and spiritual aspects. Methods: This is a retrospective study of symptom patterns of 668 terminal cancer patients (median age: 51 years; 58% female), admitted to the Palliative Care Unit of Nepal Cancer hospital, Kathmandu Nepal from Jan 1 st 2015 to Dec 31 st 2016 Results: The most common primary cancer sites in these patients were lung (41%), GI (28%), ovarian (20%) and liver (10%). Physical and psychological symptoms were assessed using different scales. The median number of symptoms was 13.5 (range: 9-18) on admission, among which pain, nausea, vomiting, dyspnea, fatigue and depression were the most common. There was 23% mortality during palliative care ward stay. Anorexia-cachexia and dyspnea symptoms showed highest mortality association with in ward mortality Conclusions: A very rational approach in regards to socioeconomic beliefs and symptom presentation is required for relief of these incurable symptoms at the end stage of life for these patients.
Comprehensive analysis of germline and somatic BRCA1/2 mutations in ovarian cancer population: Interim results of OVATAR prospective study.
Authors: Alexandra Tyulyandina, Tatiana Kekeeva, Vera Karaseva, Vera Gorbunova, Larisa Kolomiets, Maxim Filipenko, Irina Demidova, Liudmila Lyubchenko, Evgenii Imianitov, Nadezhda Cherdyntseva, Yuri Moliaka, Dmitriy Vodolazhky, Sergei Andreev, Galina Statsenko, Valeria Saevets, Svetlana Khokhlova, Svetlana Tkachenko, Irina Koroleva, Alla Lisyanskaya, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2017)

e23109 Background: The most promising method for the detection of BRCA 1/2 mutations is next-generation sequencing (NGS). There is no enough data about prevalence of large deletions of BRCA mutations and somatic alterations in ovarian cancer (OC). NGS technology is important approach for somatic mutations search in tissue samples. Methods: 498 pts with serous and endometrioid OC were enrolled in OVATAR study (NCT02122588). NGS testing of BRCA1/2 in blood and tumor tissue, multiplex ligation-dependent probe amplification (MLPA) for large deletions in blood were employed. Results: Interim analysis included pair tumor and blood samples from 336 pts (median age 54 (22 - 84) years; family history in 79 (23.5%). The total rate of BRCA1/2 mutations was 29.2% (98/336) pts including 80.6% (79/98) germline mutations and 19.4% (19/98) somatic mutations. Hotspot mutations were detected in 42/98 (42.8%) pts, among them 5382insC mutation was observed in 29.6% (29/98). Blood MLPA was performed in 142 (42.2%) pts; germline large deletions were found in 2 (1.4%) cases. Differences in NGS results for tumor and blood are listed in the table. Conclusions: Application of NGS revealed rare mutations in 57.2% among all detected mutations in OC pts; moreover, NGS in tumor tissue provided a significant increase in BRCA mutations of 19% due to somatic alterations. Large deletions in BRCA1/2 are rare event in OC in our study. [Table: see text]
A retrospective analysis of the impact of antithrombin III supplementation on the incidence of pegaspargase-induced venous thromboembolism.
Authors: Jason Chen, Dat Thanh Ngo, Ibrahim Aldoss, Sepideh Shayani, Vinod A. Pullarkat
Journal: Journal of Clinical Oncology (2018)

e19006 Background: Pegaspargase (PEG), a key component in the treatment of acute lymphoblastic leukemia (ALL), can cause venous thromboembolism (VTE). Limited studies have explored the benefit of antithrombin III (ATIII) supplementation in preventing PEG-induced VTE. The purpose of this single-center study was to evaluate the incidence of VTE in ALL patients who received ATIII versus those who did not following PEG administration. Methods: Between April 2014 and October 2017, 75 adult ALL patients were retrospectively identified to have received at least one dose of PEG. Patients were assigned to the ATIII group if a physician monitored ATIII levels to replace low ATIII levels (less than 60%). All other patients were assigned to the control group. The primary outcome was incidence of VTE observed on imaging studies within 30 days after PEG administration. Coagulopathies were monitored using routine laboratory studies. ATIII cost analysis was performed based on the wholesale acquisition cost ($4.66 per unit). Results: Incidence of VTE was not significantly different, with 17% (8/47) of the ATIII patients and 11% (3/28) of the control patients experiencing a VTE (p = 0.53). The majority of VTE occurred in the extremities. Two cerebral sinus venous thrombosis (CSVT) occurred in the ATIII group, and one CSVT occurred in the control group. Occurrence of bleeding and other coagulopathies was not significantly different. Cryoprecipitate use was significantly higher in the ATIII group (55%) than the control group (11%), possibly attenuating any beneficial effects from ATIII supplementation (p < 0.001). Twelve patients (26%) in the ATIII group and 2 patients (7%) in the control group received prophylactic anticoagulation (p = 0.07). Within the ATIII group, 37 patients (78%) received ATIII, and median ATIII% prior to supplementation was 49%. The median number of ATIII doses received was 2 (range 0 to 12) and the average cost of ATIII per patient was $11,847. Conclusions: ATIII supplementation did not reduce the incidence of PEG-induced VTE in adult ALL and significantly increased treatment costs. Our data does not support routine ATIII supplementation for patients receiving PEG.
<i>MET</i> gene fusions in non-small cell lung cancer (NSCLC) in the Chinese population: A multicenter study.
Authors: Wen xian Wang, Chunwei Xu, Yu Chen, You-cai Zhu, Yueping Liu, Hong Wang, Wu Zhuang, Xiaohui Chen, Yun-jian Huang, Jinhuo Lai, Meiyu Fang, Zhenghua Zhang, Ye Tao, Shuguang Xu, Xue Qian, Hongyu Zhao, Shangli Cai, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2018)

e13539 Background: Screening of c-mesenchymal-epithelialtransition (MET) gene fusions in non-small cell lung cancer (NSCLC) patients enables the identification of the patients likely to benefit from type I or type II MET inhibitors. The aim of this study was to evaluate the prevalence of MET fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2017. Capture-based comprehensive genomic profiling was performed on 2410 NSCLC FFPE samples (non-squamous/squamous =2061/349) sequenced to a mean coverage depth of > 650X for up to 381 cancer-related genes. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.2 Mb of sequenced DNA. Results: Of this entire cohort, just one (0.04%) patient was identified with a MET-ATXN7L1 fusion. The patient was a 56-year-old never smoking female, who was diagnosed with lung adenocarcinoma. Biopsies were obtained from metastatic sites, MET-ATXN7L1 fusion was found by NGS, the genes co-altered with MET fusion was no concurrent with KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases, and MET fusion driven NSCLC responding to crizotinib will be presented. The patient was considered to have a partial response (PR) to crizotinib, and she was alive up to now. Conclusions: NSCLC MET fusions are a rare molecular subtype that may be associated with primary resistance on EGFR TKI therapies. Given clinical evidence for the activity of targeted therapy approaches, molecular eligibility for clinical trials of type I or type II MET TKIs should include these fusion subtypes. The clinical evidence for responsiveness of MET fusions driven NSCLC provides an opportunity to personalize treatments and improve clinical outcomes for patients.
Evaluation of centrosome clustering protein KIFC1 as a potential prognostic biomarker in serous ovarian adenocarcinomas.
Authors: Karuna Mittal, Da Hoon Choi, Sergey Klimov, Shrikant Pawar, Ramneet Kaur, Anirban Mitra, Meenakshi Vij Gupta, Ralph Sams, Guilherme Cantuaria, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2016)

e17083 Background: Centrosome amplification (CA) is a hallmark of cancer. In order to evade spindle multipolarity and mitotic catastrophe, cancer cells cluster their extra centrosomes at the two spindle poles; this tactic allows them to survive but engenders low-grade aneuploidy. KifC1 is a centrosome clustering molecule essential for viability of cancer cells with CA. Since ovarian cancers display robust CA, we examined KIFC1 expression in human ovarian tumors. Methods: Paraffin-embedded formalin-fixed tissue microarrays of epithelial ovarian cancer (EOC) (n = 120) and normal ovarian epithelial tissue (n = 13) were immunostained for KifC1 and nuclear KifC1 weighted indices (WIs) were determined. KIFC1 expression levels in serous ovarian adenocarcinoma (SOC) (n = 154) patients were evaluated in single channel microarray data from publically available Gene Expression Omnibus (GEO) (GSE9899) database. Kaplan-Meier survival analyses, uni-and multi-variable (MV) analyses were performed to evaluate if KIFC1 expression levels have a bearing on patients’ overall survival (OS). Results: Nuclear KifC1 WI was higher in EOCs when compared to normal tissues (p < 0.01). Also, nuclear KifC1 WI increased with tumor grade (p < 0.05). In silico gene expression and survival analyses showed that irrespective of histological subtype, patients with above-threshold KIFC1 expression had shorter OS (p < 0.067). In SOC (n = 154), this association stayed significant (HR = 2.6, p = 0.006) in MV analysis after adjustment for tumor grade and stage. KIFC1 expression levels in high-grade SOC (HGSOC) correlated highly with expression of genes driving CA. GSEA revealed that genes enriched in KIFC1-high group were mainly related to microtubule-based processes or were centrosome components. Notably, in vitromodels of HGSOC (OVSAHO, KURAMOCHI, OVCAR3 and SKOV3) displayed robust CA and KifC1 levels were directly associated to levels of mitotic centrosome clustering, enabling cells to bypass mitotic catastrophe. Conclusions: KIFC1 expression level is a potential prognostic biomarker in ovarian adenocarcinomas and may help identify patients who could benefit from inclusion of KifC1 inhibitors in their therapy.
Programmed cell death (PD-1) ligands expression in gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs): relationship with angiogenesis and clinical outcome.
Authors: David James Pinato, Matthew Brown, Solomon D T White, Hua Zhang, Samin Toloue, Roberto Dina, Pritesh Trivedi, Justin Stebbing, Francesco A Mauri, Rohini Sharma
Journal: Journal of Clinical Oncology (2016)

e15658 Background: PD-1 receptor-ligand signalling underlies anti-tumour immune-elusion in a variety of malignancies. We evaluated the prognostic role of PD-1 and its ligands in association with biomarkers of hypoxia and angiogenesis in patients with GEP-NETs. Methods: Tissue microarrays sections including 66 cases diagnosed between 1988-2010 were stained for PD-1, PD-L1 & 2, Ki-67, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A), somatostatin receptor 2 (SSTR2) and CD31. Candidate immune-response biomarkers were tested in parallel in immortalised NET cell lines (BON-1 and QGP-1). Results: 66 patients with a median age of 45 years, 64% metastatic, 83% of pancreatic origin were included. Most patients had grade 1-2 tumours (94%) and median overall survival was 2.1 years range (0-12 years). Expression of PD-L1 in tumor cells was observed in 9% of cases, whilst PD-L2 was present in 50% with no association with disease stage at diagnosis or survival. PD-L1 positive tumours had lower VEGF-A (p = 0.02), Hif-1a (p = 0.003) and CaIX expression (p = 0.02). PD-L2 positive tumours had lower CaIX ( < 0.001) and lower proportion of vascular invasion (p = 0.02). Differential expression of PD ligands was confirmed in immortalized cell lines. Conclusions: We report for the first time PD-1 ligands expression in GEP-NETs, showing an inverse relationship with renowned oncogenic drivers relating to hypoxia/angiogenesis. These findings support a potential therapeutic role for PD-L1 inhibitors in a subset of GEP-NETs.
Advancing evidence-based decisions in the management of EGFR-mutated metastatic NSCLC.
Authors: Tara Herrmann, Martin Warters, Douglas Blevins, Panos Fidias
Journal: Journal of Clinical Oncology (2017)

e20663 Background: In patients diagnosed with metastatic NSCLC it is now essential to identify targetable mutations and markers of treatment resistance in order to determine the appropriate therapy. A study was conducted to determine if simulation-based educational interventions to address clinical practice gaps could improve decisions of oncologists in the management of EGFR-mutated metastatic NSCLC. Methods: A cohort of US-oncologists who participated in a virtual patient simulation (VPS)-based education was evaluated. The VPS consisted of 2 cases that allowed oncologists to assess the patient and choose from a database of diagnostic possibilities matching the scope and depth of practice. Clinical decisions were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided after each decision. Oncologists were allowed a second chance at each decision point and decisions before and after CG were compared using a 2-tailed paired T-test to determine differences from pre- to post CG. P values are shown as a measure of significance; with P &lt; .05 statistically significant. Results: 197 oncologists made clinical decisions within the simulation. As a result of CG, significant improvements were observed in: Ordering EGFR mutational testing (16%, P= 0.008) and making an accurate diagnosis (36%) Selecting an EGFR TKI in the first-line setting (24%, P&lt; 0.001) Ordering a PET scan to assess disease progression (10%) and in diagnosing patients with EGFR T790M disease that is resistant (29% , P&lt; 0.001) Evidence-based treatment selection for individuals whose disease progressed on first-line therapy (19%, P= .003) Number of oncologists who ordered adverse event education and counseling (23%, P&lt; .001) Conclusions: This study showed improvements in evidence-based practices of oncologists in the diagnosis and management of EGFR-mutated NSCLC; demonstrating that VPS-based instruction that immerses and engages oncologists for an authentic, practical and16. consequence-free learning experience can result in an increase in appropriate clinical decisions. Therefore, VPS may have a role in improving the quality of patient care.
Comprehensive analysis of potential immunotherapy genomic biomarkers by profiling paired tumor/normal exome of 1,000 Chinese cancer patients.
Authors: Qiang Xu, Guan Wang, Chun Dai, Xiaoman Xu, Jinwang Wei, Jiayue Xu, Angela Wu, Jiping Wang
Journal: Journal of Clinical Oncology (2017)

11605 Background: With the broadening landscape of immunotherapy use, it is important to identify patients who are likely to benefit from the therapy. We reported the comprehensive analyses of potential predictive biomarkers for PD1/PD-L1 inhibitors based on Chinese patients’ exome profiling data. Methods: Over 1,000 cancer patients from 70 hospitals across 20 provinces in China were recruited and the whole exome of tumor/normal samples of each patient were sequenced. Four potential genomic biomarkers: tumor mutation burden (TMB), mismatch repair deficiency (MMR), microsatellite instability (MSI), and PD-L1 (CD274) amplification (PD-L1 AMP) were analyzed in this Chinese cohort and compared with the mainly Caucasian cohort in TCGA database. Results: At least one of the four preselected genomic biomarkers was identified in 40.8% of this Chinese cancer patient cohort by clinical whole exome sequencing (CWES) analysis. Similar to TCGA cohort, the top 3 high TMB tumor types are lung, esophagus and colorectal cancer. Chinese hepatocellular carcinoma (HCC) patients showed higher TMB than the TCGA cohort (Median: 106 vs. 65 non-synonymous mutations per tumor NMT), which might be due to different etiologies. Five late stage cancer patients (3 lung, 1 melanoma and 1 gallbladder) using PD1/PD-L1 blockade with high TMB showed durable clinical benefit (SD≥6months/PR/CR). Comparing with TCGA data, Chinese colorectal cancer cohort (252 patients) had relative lower MSI-high or MMR related mutations (8.33% vs. 12.5%, and 3.97% vs. 10.0% respectively). PD-L1 AMP most frequently occurred in lung squamous (14.3% VS 9.8% TCGA), HER2-positive breast cancer (8.8% VS 6.8% TCGA with unknown HER2 status) and sarcoma (6.0% VS 9.4%TCGA). One Chinese renal cell carcinoma patient with PD-L1 AMP received anti-PD-1 treatment and on-going PFS is 7 months by far. Conclusions: Our CWES analysis and limited clinical follow-up observations suggested that about 40% Chinese cancer patients had at least one of the 4 potential immunotherapy predictive biomarker mutations. Long-term follow-up is needed to verify the validity of those markers.