tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) and safety of enzalutamide in healthy Chinese males.
Authors: Qian Chen, Yan-Mei Liu, Xiaopeng Zhang, Risa Fukushi, Seitaro Asahina
Journal: Journal of Clinical Oncology (2017)

e14073 Background: Enzalutamide (ENZ), an androgen receptor inhibitor, is approved in over 60 countries except China for use in metastatic castration-resistant prostate cancer. The PK of ENZ have been assessed in healthy Caucasian males (Gibbons 2015). This open-label, single-dose study evaluated the PK of ENZ and its major metabolites, and safety of ENZ, in healthy Chinese male volunteers. Methods: Non-elderly healthy Chinese male volunteers received a single oral dose of ENZ (160 mg) under fasting conditions on day 1 and were followed for 50 days. Full PK profiles were obtained for ENZ and its major metabolites, carboxylic acid metabolite (M1; inactive metabolite) and N-desmethyl enzalutamide (M2; active metabolite), on day 1 up to 1176 hours (49 days). Safety data were collected from screening until the end of study visit. Results: 14 healthy Chinese male volunteers were enrolled and received a single ENZ dose (mean age, 29.0 years; mean BMI, 21.7 kg/m 2 ). All volunteers receiving study drug were included in the PK and safety analyses; two subjects withdrew from the study during the study period. ENZ plasma concentration rapidly increased (median t max of 1.5 hours) followed by a slow decrease (mean t 1/2 of 90.7 hours). Plasma concentrations of M1 and M2 increased gradually with a median t max of 72.0 and 121 hours, respectively. M1 and M2 mean metabolite to parent ratio was 0.206 and 1.32, respectively. Mean AUC 0-inf of the sum of ENZ and M2 was 828 μg·h/mL compared to 368 μg·h/mL for ENZ. C max and t max of the sum of ENZ and M2 were comparable to ENZ. Mean t 1/2 of the sum of ENZ and M2 was 155 hours, which was similar to that of M2 (162 hours). Treatment-emergent adverse events (TEAEs) were reported in seven out of 14 males (50.0%). Possible/probable drug-related TEAEs were reported in four males (28.6%); one each of upper respiratory tract infection, chest discomfort, increased bilirubin, and decreased white blood cell count. No deaths, serious TEAEs, or TEAEs of grade ≥3 were observed. Conclusions: The PK profiles of ENZ, M1, M2, and the sum of ENZ and M2 in healthy Chinese males were generally consistent with Caucasian males. No clinically relevant safety concerns were reported. Safety and PK profiles indicate that ENZ 160 mg/day is appropriate in a Chinese population.
NEK2 as a prognostic marker and therapeutic target in adenocarcinoma of the lung.
Authors: Jun Zhang, Xin Zhan, Muhammad Furqan, Taher Abu Hejleh, Gerald H. Clamon, Shengxiang Ren, Fenghuang Zhan
Journal: Journal of Clinical Oncology (2016)

e23282 Background: NEK2 (Never In Mitosis A-Related Kinase 2) is a centrosome/microtubule regulator that plays a key role in cell cycle progression. Previous works including ours have shown NEK2 also contributes to oncogenesis and cancer metastasis, and its high expression correlates with poor prognosis and drug resistance in multiple myeloma (Zhou et al. Cancer Cell 2013). Here we investigate its clinical implication in adenocarcinoma of the lung. Methods: Lung adenocarcinoma cell lines H1299 and A549 were used in mechanistic studies. The lentivirus-mediated human NEK2 cDNA and a tetracycline-inducible lentiviral expression system containing shRNA to NEK2 were used to over-express and knock down NEK2 respectively. Array-CGH and FISH were used to study chromosomal instability, MTT and clonogenic soft agar assay to study proliferation, and flow cytometry and immunoblotting to investigate apoptosis and relevant signaling pathways. The TCGA database including 522 lung adenocarcinoma patients with expression data was used to address the clinical correlation of NEK2 as well as its co-expression pattern. Results: In both cell lines, NEK2 over-expression induced chromosomal instability, promoted cell proliferation, down-regulated pro-apoptotic PUMA and BAD, up-regulated anti-apoptotic BCL-2 and MCL-1, increased phosphor-AKT and phosphor-S6 levels, and enhanced nuclear accumulation of β-catenin. Opposite phenomenon was observed when NEK2 was silenced by shRNA, suggesting NEK2 promoted cancer survival by activating AKT/mTOR and Wnt/β-catenin signaling pathways. Using TCGA database, NEK2 over-expression (mRNA expression z-score > = 2) was found in 8% lung adenocarcinoma patients, and significantly correlate to both poor disease free survival (p = 0.0456) and overall survival (p = 0.00342). Interestingly, the expression of NEK2 has a positive correlation with several centrosome proteins implicated in oncogenesis such as CEP55 and CENPA, suggesting that CIN (chromosomal instability) genes play a general role in the maintenance and progression of lung adenocarcinoma. Conclusions: NEK2 is a potential prognostic marker and therapeutic target for adenocarcinoma of the lung.
Abstract 15101: Pellino1 is Required to Preserve Myocardial Function and Promote Neovascularization in the Infarcted Myocardium
Authors: Mahesh Thirunavukkarasu, Babatunde Oriowo, Vaithinathan Selvaraju, Mandip Joshi, Leonidas Tapias, Vladimir Coca-Soliz, Ibnalwalid Saad, Juan A Sanchez, J.Alexander Palestey, Siu-Pok Yee, Nilanjana Maulik
Journal: Circulation (2016)

Introduction: Acute myocardial infarction is a leading cause of death among patients with cardiovascular disease. We have recently shown that Pellino-1 (Peli1) gene therapy can induce angiogenesis and improve heart functions in the infarcted myocardium making it an attractive therapeutic target. In the present study, we aimed to explore the functional role of Peli1 in inducing neovascularization after myocardial infarction (MI) using Peli1 global knockout mice (Peli1KO). Methods: Wild-type (Peli1fl/fl) and Peli1KO ( Peli1-/-) mice were subjected to either permanent ligation of the left anterior descending coronary artery (LAD) or sham surgery (S). Left ventricular risk area post-MI at different time points were collected for gel shift analysis (NFκB), protein analysis and immunohistochemistry after echocardiographic analysis. Results: Peli1 deficiency (Peli1KO) exacerbated myocardial dysfunction 60 days after MI compared to WT with reduced ejection fraction [30±2.5 vs. 41±2.6% (n=8); p<0.0001] and fractio...
TCT-694 Outcome of High Risk Percutaneous Coronary Intervention in Octogenarians: Insight from the from the cVAD Registry
Authors: M Chadi Alraies, Amir Kaki, Nimrod Blank, Alejandro Figueroa-Navarro, Reema Hasan, James Glazier, Mahir Elder, Theodore Schreiber
Journal: Journal of the American College of Cardiology (2018)
Activity and outcomes of a cardio‐oncology service in the United Kingdom—a five‐year experience
Authors: Nilesh Pareek, Joaquim Cevallos, Pedro Moliner, Mit Shah, Li Ling Tan, Vicki Chambers, A. John Baksi, Rajdeep S. Khattar, Rakesh Sharma, Stuart D. Rosen, Alexander R. Lyon
Journal: European Journal of Heart Failure (2018)
Primary resistance to <i>ALK</i> inhibitor in <i>ALK</i>-positive non-small-cell lung cancer.
Authors: Jin Kang, Huajun Chen, Qing Zhou, Hai-Yan Tu, Xu-Chao Zhang, Su Jian, Zhen Wang, Bin-Chao Wang, Yi-Long Wu, Jin-Ji Yang
Journal: Journal of Clinical Oncology (2017)

9063 Background: Crizotinib is a standard of care in anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancers (NSCLC). Undoubtedly,the resistance to crizotinib is a current bottleneck which resists its clinical application. However, there are few reports about the primary resistance to crizotinib, especially the difference between the primary and acquired resistance. Methods: Totally,171 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China from October 2010 to July 2016. The status of an ALK gene rearrangement was assessed by Vysis ALK Break Apart fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or ALK Ventana immunohistochemistry (IHC). Among 18 patients with primary resistance, 12 had tumor tissue (n = 6) or plasma (n = 6) at the baseline and meanwhile tumor tissue (n = 2) or plasma (n = 2) specimens were collected for 4 patients after primary resistance. Next generation sequencing was used to test the tissue or plasma from 16 patients with primary resistance to crizotinib. Results: Among 171 patients treated with crizotinib, 47.9% (82/171) developed acquired resistance, and 10.5%(18/171) had primary resistance. Using the specimens at the baseline, there were 6 ( 33.0%) patients with uncommon ALK fusion partners, 4 (22.2 %) with BIM deletion polymorphism, 2 (11.1%) with PTEN/mTOR mutations, and 1 (5.5 %) with a pre-existing ALK G3709A mutation.These uncommon ALK fusion partners included ZC3H8-ALK, ALK-LOC102723854 and ALK-DTNB-ASXL2. In addition, one patient was found to coexsist with KIT mutation after primary resistance. Median PFS was significantly shorter in patients with primary resistance than those with acquired resistance (2.2 vs. 10.8 months, P &lt; 0.001). Conclusions: Uncommon ALK fusion partners, BIM deletion polymorphism, PTEN/mTOR mutation, pre-existing ALK G3709A mutation and KIT mutation might contribute to molecular mechanisms of primary resistance to crizotinib in ALK-positive NSCLC. Further investigations are warranted to overcome these primary resistances.
A phase 1/1b multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI3726 in patients with metastatic, castration-resistant prostate cancer who have received prior treatment with abiraterone or enzalutamide.
Authors: Mark T. Fleming, Richard Cathomas, Daniel Peter Petrylak, Judy Sing-Zan Wang, Neil Harrison Bander, Francesca Zammarchi, Patrick H. van Berkel, Song Hye Cho, Nairouz Elgeioushi, John Bothos, Anita Scheuber, Johann de Bono
Journal: Journal of Clinical Oncology (2017)

TPS5088 Background: Therapeutic advances have recently been achieved for patients with metastatic, castration-resistant prostate cancer (mCRPC) due to abiraterone acetate (ABI) and enzalutamide (ENZ). However, virtually all patients with mCRPC eventually progress in their disease, and further treatment options are limited. Prostate-specific membrane antigen (PSMA) is highly expressed in nearly all prostate cancers, and its expression is highest in mCRPC. MEDI3726 is an antibody-drug conjugate composed of anti-PSMA antibody derived from J591, site-specifically conjugated to the cytotoxic, DNA cross-linking, pyrrolobenzodiazepine dimer. MEDI3726 has demonstrated potent and specific in vitro and in vivo antitumor activity in human prostate cancer-derived preclinical models with different expression levels of PSMA. Methods: This is a first-in-human, phase 1/1b, multicenter, open-label, dose escalation and dose expansion study in patients who have received prior treatment with ABI or ENZ, with or without prior taxane-based chemotherapy in the mCRPC setting (NCT02991911). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or maximum administered dose of MEDI3726. The secondary objectives are to evaluate MEDI3726 for its antitumor activity (based on a composite response according to RECIST Version 1.1, a reduction in prostate-specific antigen level of 50% or more compared to baseline, or a conversion in the circulating tumor cell count [defined as a reduction from ≥5 cells/7.5 mL blood to &lt; 5 cells/7.5 mL blood]), safety and tolerability in combination with ENZ, pharmacokinetics alone and in combination with ENZ, and immunogenicity. Recruitment is ongoing for this study, which has an estimated total target enrollment of 224 patients. Clinical trial information: NCT02991911.
P01.058 Higher immune associated markers (PD-L1, PD-1, TMB, MSI) in gliosarcoma compared to glioblastoma.
Authors: S Phuphanich, N Sanai, J Xiu, S Mittal, S Michelhaugh, D S Subramaniam, M K Pandey, S Kesari, A B Heimberger, Z Gatalica, W M Korn, A L Sumrall
Journal: Neuro-Oncology (2018)

Gliosarcomas (GS) are rare histological glioblastoma (GB) variants with glial and mesenchymal components. GS has been reported to have a similar genetic profile to primary GB. In a small series of GS, tissue from both the glial and sarcomatous components revealed PTEN and TP53 mutations, and p16 deletion in both tissue components. Studies on systematic comparison of GS and GB are scarce. A total of 44 GS and 1449 GB tumors profiled by Caris Life Sciences from 2013 to 2017 were tested by NextGen sequencing (NGS, 592 or 45 gene panels) for mutations and gene amplification. Tumor mutational burden (TMB) was calculated using somatic nonsynonymous missense mutations. Microsatellite instability (MSI) was tested by NGS. PD-L1 immunohistochemistry (SP142) was done on tumor cells and PD-1 on tumor-infiltrating lymphocytes. MGMT promoter methylation was tested by pyrosequencing; EGFRvIII and gene fusions by RNA-sequencing (ArcherDx FusionPlex). Mutations in 16 genes were seen in GS: the most frequent were TP53 (41 %), NF1 (33 %), PTEN (29 %), RB1 (10%), PTPN11 (7%) and PIK3CA (5%). Amplification of CDK4 (8%), MET (8%) and MDM2 (4%) were seen and NTRK1 fusion was seen in 1 of 20 (5%) GS tumors tested with RNA-SEQ. When compared to GB, GS had significantly higher NF1 (GS: 33% vs. GB 14%, p = 0.008) and PTPN11 (7% vs. 2%, p = 0.04) mutations. Furthermore, immune-associated markers: PD-L1 (38.5% vs. 16.3%, p = 0.0003), PD-1 (75% vs. 49.2%, p = 0.01) and MSI-High (3.8 vs. 0.5%, p = 0.038) were significantly higher in GS; TMB-High (> = 17mut/MB) (7.7 vs. 2.9%, p = 0.17) showed a trend. In contrast, EGFR alterations including EGFR amplification (7.7 & 37.2%, p = 0.0021) and EGFR mutations (0 vs. 11%, p = 0.02) were less prevalent in GS than GB as also EGFRvIII (5.9 vs. 18.9%, p = 0.055), EGFR fusions (0 vs. 9%, p > 0.05), IDH1 mutation (0 vs. 7.8%, p = 0.054) and MGMT promoter methylation (34.1 & 45%, p > 0.05). In summary, based on our analysis, GS appears to be a distinct biological entity with unique genomic features and immunophenotype compared to GB. These results also provide insight into potential immune therapy, based on the association of PD-1/PD-L1 with other key genetic alterations in this population, which warrants further investigation in clinical studies.
Factors influencing <i>BRAFV600</i> mutation testing quality in melanoma: Results from a large, non-interventional, multicenter study in Germany.
Authors: Arndt Hartmann, Peter Schirmacher, William Sterlacci, Winfried Koch, Birgit Schif, Claus Garbe
Journal: Journal of Clinical Oncology (2016)

e23142 Background: BRAFV600 testing is mandatory before initiating targeted therapy in patients (pts) with advanced stage malignant melanoma, but testing quality is still an issue and comparability between testing centers is limited. As molecular pathology testing is decentralized challenges include diversity of diagnostic assays and emerging novel technologies. We assessed local routine BRAFV600 testing to evaluate factors affecting BRAF mutation frequency and diagnostic accuracy. Methods: This prospective, non-interventional study systematically collected data on clinical, histological, and mutational findings e. g. melanoma patient characteristics, sample source, sample location, melanoma subtype, routine BRAFV600 test result, and quality assurance measurements. Factors influencing BRAF mutation rate were identified via multiple logistic regression. The study population was used to develop a statistical model to predict mutation probability for pts and centers. Results: Data were collected from 642 cases in 28 pathology institutes (Apr 2013–Apr 2015). Baseline characteristics were typical of the melanoma population. Overall, BRAFV600 mutations were detected in 37.5% of pts, with BRAFV600E the most common variant (29.3%). Age (p < 0.0001), testing method (p = 0.0027), and sample location (p = 0.0028) had a significant influence on BRAFV600 mutation frequency (Likelihood ratio test). A prediction profile identified age and sample location as the most significant parameters; gender was not significant. Mutation testing site, accreditation level, and client who requested testing (clinical dermatologist) were representative of German pathology institutes. Conclusions: The rate of BRAFV600 mutations was lower than expected and various factors influenced mutation frequency. The prediction model identified age, testing method, and sample location as predictive variables, but was unable to predict a BRAF mutation within a clinically acceptable range. To ensure optimal treatment for pts with melanoma, and in the context of approved and emerging combination therapies, the validation and standardization of diagnostic testing is key.
Analysis of delayed reconstruction and tumor relapse in breast cancer.
Authors: Facundo Alberti, Cristina Morales-Estevez, Rosa Maria Rodriguez-Alonso, Alberto Moreno, Ignacio Porras, Javier López-González, Juan de la Haba-Rodriguez, Enrique Aranda
Journal: Journal of Clinical Oncology (2016)

e23003 Background: Some studies show that the surgery be associated with the increase of cell growth stimulating factors and angiogenesis of tumor dormancy. Furthermore clinical observations have found as the highest percentage of recurrence in breast cancer arise in the nearest time to primary tumor surgery, supporting the hypothesis of the stimulating effect of surgery on tumour dormancy cells. However it is unknown whether other surgery as breast reconstruction influences equally in the recurrence. Methods: 200 delayed breast reconstructions were performed in one or two surgical times using different techniques, in patients diagnosed with breast carcinoma. The clinical, histo-pathological, surgical and recurrence pattern were analyzed. Results: A 92% had T1-T2 tumors, 66% were N0, 87% had IDC, 60% were G1-G2, 65% were PgR / ER-positive and 55% underwent surgical reconstruction technique in two times vs. 44% who did so in one time. The 25% (50/200) of the patients had relapsed. They displayed significant differences with those known prognostic factors associated with relapse as tumor size, lymph node involvement, histological grade and hormone receptor status. Of patients with relapsed, 70% had been reconstructed in two times and 30% in one surgical time. Statistically significant difference between the type of reconstruction and tumor relapse were found. No significant differences were found between times since reconstruction to relapse, according to the type of reconstruction. Taking into account the time of relapse, 52% occurred in the 24 months following the reconstruction, 18% between 25-50 months post-reconstruction, 16% between 50-100 months post-reconstruction and 14% above 101 months. Conclusions: In our series, delayed breast reconstruction in two times is associated with increased tumour recurrence. There are no differences in time to recurrence according to the technique used, although there are a greater number of relapses in the two years after reconstruction. These findings support the hypothesis of reconstructive surgical stimulus, which through the modification of the homeostasis of tumour dormancy cells, could modify the pattern of tumour relapse.
Long-term followup of bi-shRNA<sup>furin</sup> and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies.
Authors: Minal A. Barve, Anton M. Melnyk, Luisa Manning, Gladice Wallraven, Martin Birkhofer, John J. Nemunaitis
Journal: Journal of Clinical Oncology (2017)

e15100 Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&amp;2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]
Effect of histological subtype on overall survival in cutaneous melanoma: A Surveillance, Epidemiology, and End Result program (SEER) database review.
Authors: Srinath Sundararajan, Utkarsh Acharya, Abhijeet Kumar, Mohammed Kanaan, Haiyan Cui, Joanne M. Jeter
Journal: Journal of Clinical Oncology (2016)

e21051 Background: The most common histological subtypes of cutaneous melanoma (CM) include superficial spreading (SSM) and nodular melanoma (NM). We aimed to compare overall survival (OS) between these two CM subtypes. Methods: We queried the Surveillance, Epidemiology, and End Result Program (SEER) databasefor adults with histologically confirmed cutaneous NM and SSM diagnosed between 2004 and 2007 with ICD codes 8721/3 and 8743/3, respectively. The primary end point assessed was 5-year OS. The 5-year OS rate was estimated using the Kaplan–Meier method. Results: A total of 23,826 cases of SSM and NM were identified. The sample included 13,652 men (57.3%) and 10,173 women (42.7%). SSM accounted for 19,475 cases (81.7%), and 4,351 cases (18.3%) were of NM subtype. The mean ages at diagnosis for SSM and NM were 56.1 and 64.8 years, respectively. The percentage of NM was higher in men compared to women (20.6% vs. 15.2%, p<0.0001) and African Americans (AA) compared to Caucasians (37.14% vs. 18.69%, p<0.0001). The proportion of metastatic CM cases was significantly higher within the NM group compared to the SSM subgroup (74.3% vs. 25.8%, p<0.0001). OS favored SSM compared to the NM subgroup [HR 0.243 (95% CI 0.230 - 0.25, p <0.0001)]. When adjusted for age, gender, race, stage, and anatomical site, OS reliably favored SSM compared to NM [HR 0.615 (95% CI 0. 574 - 0.658, p <0.0001)](Table 1). Conclusions: Superficial spreading melanoma showed better OS compared to nodular melanoma based on available examinable variables in our study, including stage at diagnosis. Our analysis provides a quantification of the effect of disease subtype on survival, independent of stage at diagnosis. Based on these results, NM may represent a higher risk disease profile and may warrant more aggressive treatment strategies. Association between CM histology and OS in patient sub-groups. n 5-years OS (%) NM SSM p-value Gender M 13204 52.77 84.57 <0.0001 F 10622 60.94 91.84 <0.0001 Race AA 70 56.83 86.48 0.002 Caucasian 22610 55.90 87.61 <0.0001 Stage I 17410 74.47 90.98 <0.0001 II 2992 56.73 65.67 <0.0001 III 1646 43.78 63.86 <0.0001 IV 259 13.52 29.85 0.001 Unknown 1519 44.88 86.76 <0.0001