tbuckley/cabot-search huggingface dataset:
A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Thomas Powles, Karim Fizazi, Silke Gillessen, Charles G. Drake, Dana E. Rathkopf, Sujata Narayanan, Marjorie C. Green, Almut Mecke, Christina Schiff, Christopher Sweeney
Journal: Journal of Clinical Oncology (2017)

TPS5090 Background: In the past decade, several therapies have been approved for patients (pts) with mCRPC, including the androgen receptor (AR) antagonist enzalutamide (enza) and the androgen synthesis inhibitor abiraterone acetate (abi). Despite these advances, most pts experience disease progression and there are inadequate data to guide the sequencing of agents to optimize outcomes. Pts with mCRPC who progress on enza have increased circulating PD-L1/PD-L2–positive dendritic cells compared with enza-naive pts or pts who are still responding to treatment (Bishop et al. Oncotarget. 2014). In two recent studies, PSA and radiographic responses were observed in mCRPC pts treated with a PD-L1/PD-1 pathway inhibitor with or without enza (Graff et al. Oncotarget. 2016; Hansen et al. Ann Oncol. 2016). Atezolizumab (atezo) is an anti–PD-L1 monoclonal antibody that inhibits the interaction between PD-L1 and its receptors, PD-1 and B7.1, enhancing T-cell responses and improving anti-tumor activity. Taken together, this suggests that the combination of atezo and enza may provide an effective treatment option for mCRPC pts. Methods: A Phase III randomized, multicenter, clinical trial (NCT03016312) is being conducted to evaluate the efficacy and safety of atezo with enza compared with enza alone in mCRPC pts who have received prior abi treatment and have progressed on, are ineligible for, or have refused a taxane regimen. Eligibility criteria include mCRPC or locally advanced, incurable CRPC and ECOG PS 0-1. Exclusion criteria include CNS metastasis, autoimmune disease, history of seizures, prior immunotherapy and prior treatment with enza or any other newer AR antagonists. Pts will be randomized 1:1 to receive atezo 1200 mg q3w and enza 160 mg qd or enza alone. The primary endpoint is OS, and secondary endpoints include PSA response rate, rPFS, ORR and safety. Exploratory biomarkers associated with responses to atezo and enza will be evaluated in tumor tissue collected at baseline and progression. Approximately 550 pts will be enrolled at 150 sites globally. Clinical trial information: NCT03016312.
Novel oral nano-amorphous sirolimus formulation to exhibit comparable exposure to intravenously administered temsirolimus: An oral alternative to the treatment of mTOR-responsive malignancies.
Authors: Hristos Glavinas, Orsolya Basa-Dénes, Réka Angi, Balázs Kárpáti, Tamás Jordán, Tamás Solymosi, John McDermott, Chris Roe, Litza McKenzie, Gabor Heltovics
Journal: Journal of Clinical Oncology (2018)

e16555 Background: Rapamune (Sirolimus) exhibits low bioavailability and high variability following oral administration. Reaching the therapeutic blood concentrations in renal cancer patients was found to be challenging when the marketed drug was administered alone (Cohen et al., 2012). Therefore intravenous delivery of a prodrug of sirolumus, temsirolimus is required to achieve suitable exposures. The PK properties of a novel nano-amorphous oral formulation were investigated in a dose escalation study. The effect of food at the highest dose was also assessed. The objective of the work was to achieve comparable sirolimus exposures to the currently used temsirolimus therapy. Methods: 32 healthy volunteers divided into 4 cohorts received one of the escalating doses (0.5 – 2 – 10 – 40 mg) the novel formulation in the fasted state. To avoid degradation of sirolimus in the acidic environment in the stomach, 40 mg famotidine was administered three hours pre-dose in all regimens. The 40 mg cohort received a second dose in the fed state. PK parameters were compared with data reported for Rapamune. Results: Dose increments resulted in roughly dose proportional increases of Cmax and AUC0-48h up to 10 mg, while sub-proportional increases were observed between the 10 mg and 40 mg doses. Mean AUCinf at the 40 mg dose in the fasted state was 4300±1083 ng*h/ml, 28% higher than AUC reported for 2x45 mg Rapamune and 11% higher than exposure reported for 25 mg intravenous temsirolimus (3810 ng*h/ml). Food had no statistically significant effect on AUC. Inter-individual variability was moderate with CV values in the 20-30% range. Conclusions: The unfavorable PK performance of Rapamune was overcome making the novel formulation a better alternative for oral sirolimus administration. Increased exposure could allow the treatment of mTOR-responsive malignancies by oral sirolimus instead of intravenous temsirolimus. In addition, since adverse events of sirolimus therapies have been linked to high exposures, improved variability could result in lower incidences of the adverse events observed when oral sirolimus is used in any therapeutic areas. Clinical trial information: 2016-005018-23.
BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference
Authors: Elior Rahmani, Regev Schweiger, Liat Shenhav, Theodora Wingert, Ira Hofer, Eilon Gabel, Eleazar Eskin, Eran Halperin
Journal: Genome biology (2018)

We introduce a Bayesian semi-supervised method for estimating cell counts from DNA methylation by leveraging an easily obtainable prior knowledge on the cell-type composition distribution of the studied tissue. We show mathematically and empirically that alternative methods which attempt to infer cell counts without methylation reference only capture linear combinations of cell counts rather than provide one component per cell type. Our approach allows the construction of components such that each component corresponds to a single cell type, and provides a new opportunity to investigate cell compositions in genomic studies of tissues for which it was not possible before.
Abstract 18645: Rare SCN10A Variants Associated With Lone Atrial Fibrillation Modulate Peak and Late Sodium Currents
Authors: Eleonora Savio Galimberti, Peter Weeke, Carlos G Vanoye, Tao Yang, Kaylen C Kor, Thomas Atack, Alfred L George, Dan M Roden, Dawood Darbar
Journal: Circulation (2013)

Introduction: SCN10A encodes the sodium channel isoform Nav1.8, which is variably expressed in atria and has been linked to altered cardiac conduction and atrial fibrillation (AF). We resequenced SCN10A in 274 lone AF probands and identified 18 heterozygous rare variants (6.6% prevalence). Based on evidence of AF co-segregation, initial assessment of functional importance, and presence in ≥1 lone AF proband, four single variants (Y158D, 417delK, R814H, A1886V) and a compound one (Y158D-R814H) were selected for functional studies. We tested the hypothesis that rare SCN10A variants modulate biophysical properties of Nav1.8 channel, providing a mechanism for enhanced AF susceptibility. Methods: SCN10A variants generated by site-directed mutagenesis were transiently expressed in ND7/23 cells. Macroscopic currents obtained using voltage-clamp protocols were measured after 48 hr incubation at 37°C. Results: Variant 417delK showed near-total loss of current, and the remaining ones exhibited enhanced peak I Na and late sodium current (I Na-L ) measured at 100 ms post-depolarization (gain-of-function). The magnitude of peak I Na density of variants A1886V (103.3±16.6 pA/pF, n=10) and Y158D (-81.9±7.2 pA/pF, n = 7) was ~2-fold larger than WT (-42.8±4.9 pA/pF, n=9, P&lt;0.01), while R814H variant generated peak I Na density ~4 times larger than WT (-187±22.6 pA/pF, n=17, P&lt;0.01). The effect of the compound variant was close to the average effect of both variants expressed independently (table). Conclusion: Rare SCN10A variants associated with lone AF displayed strikingly altered functional properties. There was both enhanced peak I Na and I Na-L (Y158D, R814H, and A1886V) as well as near-absent SCN10A -mediated Nav1.8 current (417delK). By demonstrating that rare SCN10A variants identified in subjects with lone AF markedly perturb Nav1.8 function in vitro , these studies provide further support for the hypothesis that these variants contribute to AF susceptibility.
Cost-effectiveness of adjuvant chemotherapy in early stage breast cancer.
Authors: Preethi John, Raveendhara R Bannuru, Joshua T. Cohen, Rachel J. Buchsbaum, John Kalil Erban
Journal: Journal of Clinical Oncology (2018)

e18887 Background: The NCCN recommends several adjuvant chemotherapies for Her2-negative early stage breast cancer (ESBC) that have shown similar efficacy but lack direct comparisons in randomized clinical trials (RCTs), making the optimal regimen unclear. Regimens of interest include dose dense doxorubicin/cyclophosphamide followed by dose dense paclitaxel (DDACT), q. 3 week doxorubicin/cyclophosphamide followed by weekly paclitaxel (ACWKT), docetaxel/doxorubicin/cyclophosphamide (TAC), docetaxel/cyclophosphamide (TC), and dose dense doxorubicin/cyclophosphamide followed by weekly paclitaxel (DDACWKT). To aid in clinical decision making, we compared the cost-effectiveness of the above regimens to DDACT. Methods: We used a Markov health state transition model to simulate 4 regimens for a cohort with node positive, HER2-negative ESBC over a lifetime. Health states included chemotherapy, disease-free, 1st and 2nd local relapse, distant metastasis and dead. Adverse events (AEs) included febrile neutropenia, congestive heart failure, and leukemia/MDS whose outcomes were derived from RCTs. Efficacy outcomes were taken from a network meta-analysis of 7 RCTs of the above regimens, except DDACWKT, for which efficacy was assumed equivalent to ACWKT and AEs equivalent to DDACT, given the lack of trial data. Health outcomes were measured in terms of quality-adjusted life years (QALYs) and cost-effectiveness (Δcosts/ΔQALYs) compared to DDACT. Quality of life adjustments were based on published health utility weights. Payer perspective costs came from literature. Results: Compared to DDACT, anthracycline-based regimens slightly reduced QALYs and increased costs. By contrast, TC slightly increased QALYs and reduced costs relative to DDACT. Conclusions: This is the first US-based cost-effectiveness analysis of NCCN recommended adjuvant chemotherapy regimens in Her2-negative ESBC. In the proper clinical context, TC is a reasonable choice when comparing QALYs, toxicity, efficacy, and costs compared to the other regimens. Regimen QALYs Cost ($US 2017) ΔQALY ΔCost ($US 2017) DDACT 10.63 305,351 N/A N/A ACWKT 10.55 305,461 -0.08 110 DDACWKT 10.47 307,691 -0.16 2340 TAC 10.34 326,175 -0.29 20824 TC 10.67 297,882 0.04 -7469
Ranolazine and TDM1 treatment: Cardioprotective effects in vitro and in vivo.
Authors: Nicola Maurea, Carmela Coppola, Giovanna Piscopo, Gennaro Riccio, Domenica Rea, Renato De Vecchis, Carlo Maurea, Giorgia Sorrentino, Claudia De Lorenzo, Michele De Laurentiis
Journal: Journal of Clinical Oncology (2017)

e23102 Background: Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate consisting of trastuzumab (TRAS) covalently linked to the highly potent microtubule inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2 positive breast cancer patients. Although, the potential cardiotoxic effects of TDM1 have not yet been fully elucidated, they can include changes in Ca 2+ regulation related to blockade of ErbB2, PI3K-Akt and MAPK pathways. Here, we aim to elucidate whether Ranolazine (R), administered after TDM1 treatment, blunts or not cardiotoxicity in vivo and in vitro. Methods: In vitro, human fetal cardiomyocytes (HFC) were treated with TDM1 for 3 days and then treated in the absence or presence of R for 3 days. Cell viability was assessed by cell counting and MTT assay. To evaluate cardiac function in vivo, C57/BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured, by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using 2D speckle-stracking. These measurements were repeated after 5 days of R treatment (305 mg/Kg/day), started at the end of TDM1 treatment. Results: R reduces TDM1 toxicity in HFC, as evidenced by the higher percentage of viable cells treated with TDM1+ R with respect to the cells treated with TDM1 alone (p &lt; 0.01). In in vivo studies: after 7 days with TDM1 administration, FS decreased to 53.6±0.9%, versus 61.0±0.8 % (sham), (p &lt; 0.01), and EF decreased to 85.5±3.5 % versus 91.0±0.8% (sham), (p &lt; 0.01). Moreover, RS decreased to 20.92±3.2 % versus 42.2±10.1% (sham) (p &lt; 0.01), and LS decreased to -15.5±2.8 % versus -23.6±6.7% (sham), (p &lt; 0.01).In mice treated with TDM1 and, successively treated with R for 5 days, the indices of cardiac function partially recovered: FS 58±2.4 % (p &lt; 0.05), EF 88.8±1.7 %, (p &lt; 0.05), RS (35.7±8.2 %, p &gt; 0.05), whereas the alteration of LS persists even after treatment with R (-17.3±3.7 %, p &gt; 0.05) Conclusions: Here we show that in vivo R post-treatment reduces cardiotoxic effects due to TDM1, as demonstrated by the recovery of FS, EF and RS values. As expected, R increases cell viability of HFC treated with TDM1.
Efficacy of weekly vinorelbine monotherapy in patients with lung adenocarcinoma.
Authors: Da Hyun Kang, Dong Il Park, Chaeuk Chung, Jae Young Moon, Hee Sun Park, Sung Soo Jung, Ju Ock Kim, Jeong Eun Lee
Journal: Journal of Clinical Oncology (2018)

e21157 Background: Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. More than two thirds of patients with NSCLC have inoperable locally advanced tumors or metastatic disease at time of diagnosis, with a 5-year survival rate of less than 10%. The response to first-line chemotherapy is usually short-lived, and the efficacy of third-line or further-line treatment for advanced NSCLC remains controversial. Vinorelbine, a semi-synthetic vinca alkaloid, is currently used alone or in combination with a platinum derivative in advanced NSCLC. We aimed to investigate the efficacy and tolerability of weekly vinorelbine monotherapy in advanced NSCLC patients who had previously treated several times. Methods: Two hundred fourteen patients who received vinorelbine monotherapy with advanced NSCLC between January 2008 and July 2017 were included in this study. Patients received vinorelbine intravenously at a dose of 30 mg/m2 on days 1, 8, and 15 of 28-day cycle. Results: The mean age was 62.67 years, and male was 74.3% (159/214). Current or former smokers were 57.0% (122/214). The histologic types of tumor were adenocarcinoma (47.7%), squamous cell carcinoma (45.8%), and other types (6.5%). Most patients (91.6%) had received at least second line of previous chemotherapy. The overall response rate was 15.4% (33/214). Of the patients, 26.6% (57/214) had stable disease and 36.4% (78/214) had progressive disease. The median time to progression was 3.1 months (range 0.1-23.0). The average total number of vinorelbine administrations per patients was 9.3 (range 1-87). Grade 3/4 neutropenia occurred in 22.9% (49/214) of patients. Non-hematologic toxicity was mild. We analyzed the various epidemiologic and clinical factors in relation to the efficacy of vinorelbine monotherapy. There was statistically significant difference according to histologic type. Patients with adenocarcinoma had significantly higher response rate (28.9% vs. 10.6%, p = 0.003) and longer time to progression (3.9 months vs. 2.4 months, p = 0.002) than other cell types. Conclusions: Weekly vinorelbine monotherapy may be a new therapeutic option in patients with heavily treated advanced NSCLC, particularly lung adenocarcinoma.
The efficacy and safety of apatinib in patients with advanced synovial sarcoma: A single-institutional experience.
Authors: Yong Zhou, Li Min, Wenli Zhang, Yi Luo, Kai Yao, Chongqi Tu
Journal: Journal of Clinical Oncology (2018)

e23526 Background: Synovial sarcoma is an aggressive neoplasm which accounts for 10-20% of soft tissue sarcomas in the adolescent and young adult population. For advanced synovial sarcoma, conventional chemotherapy is somewhat effective, but few patients achieve an objective response, which is up to 26-40% reported for doxorubicin plus ifosfamide. Apatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, has been shown to be effective in the treatment of soft tissue sarcomas. This retrospective study aims to assess the efficacy of apatinib in patients with synovial sarcoma. Methods: This analysis enrolled patients with local advanced, recurrent or metastatic synovial sarcoma after surgery from May 2016 to Aug 2017. The tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and the safety profiles were also recorded. Results: Total 13 patients were enrolled, 2 (15.4%), 10 (76.9%) and 1 (7.7%) patients were treated with apatinib in adjuvant, first-line and second-line settings, respectively. Initial dosages of 500 and 250 mg/d were given to 12 (92.3%) and 1 (7.7%) cases, respectively. The median age was 27 years old (range 8-71), and the ratio of male to female was 7:6. Nine patients (69.2%) were lung metastasis. As of 2017/11/28, the median medication time was 5.7 months (range 2.1-10.8). Among 12 assessable patients, 8 achieved partial response, 2 achieved stable disease and 2 got progressive diseases. The objective response rate (ORR) was 66.7% and the disease control rate (DCR) was 83.3%. The most common adverse events were hand-foot syndrome (HFS) (6, 46.2%), mucositis (4, 30.8%), vomit (3, 23.1%), anorexia (3, 23.1%), and wound healing delay (3, 23.1%). Conclusions: We found an obvious improvement in objective response from the administration of apatinib, which could be an effective option for first- or later-line treatment in patients with synovial sarcoma. The finding should help individualize the care of patients with this disease.
A prognostic index to stratify survival benefit in patients of solid tumor metastases treated with stereotactic body radiotherapy.
Authors: Yi Lu, Chad Tang
Journal: Journal of Clinical Oncology (2017)

e21578 Background: To investigate the clinical factors related to the prognosis of solid tumor metastases treated with SBRT and to create a scoring system that stratifies survival benefit. Methods: The clinical factors and follow-up data of 404 patients with metastases from solid primary (127 liver metastases, 205 lung metastases and 72 adrenal gland metastases), treated with SBRT from 2005 to 2016, were analyzed retrospectively. The prognostic index (PI) of patients was calculated based on the results of multivariate cox regression model from liver metastases cohort and pretreatment variables included were race, gender, age, KPS, primary tumor and histology, number of metastases, status of disease outside, previous treatment at SBRT site, and interval time from diagnosis to metastases. This model then was used in lung and adrenal gland metastases cohorts. Results: Median follow-upwas 24 months for liver metastases cohort. The median survival time of liver metastases was 21.8 months. Three variables were selected from liver cohort-database training as independent prognostic index for survival benefit: age (HR =1.81, p =0.03), KPS (HR =0.72, p =0.03), number of organs with active disease outside (HR =1.68, p&lt;0.01). Patients were classified into three hazard groups with significant difference. The median survival of group 1(poor) was 8.1 months, group 2 (intermediate) reached 25 months, and group 3 (excellent) reached 39.1 months (p&lt; 0.001). This prognostic index model was also been approved effectively in lung and adrenal gland metastases cohorts, which identified patient subgroups into poor and excellent prognosis. Conclusions: The prognostic index model allows solid tumor metastases patient to stratify survival benefit based on the three predictive factors. Table 1 Survival score and groupings [Table: see text]
TCT-109 Intra-Coronary Administration of Tacrolimus Improves Reperfusion of Microvasculature and Left Ventricular Function in Patients with ST-Segment Elevation Myocardial Infarction (COAT-STEMI) Undergoing Primary Percutaneous Coronary Intervention
Authors: Pei-Hsun Sung, Wei-Chun Huang, Ting-Hsing Chao, Teng-Yao Yang, Rei-Yeuh Chang, Jun-Ted Chong, None chiung jen wu, Hon-Kan Yip
Journal: Journal of the American College of Cardiology (2018)
A phase 1b study of napabucasin plus weekly paclitaxel in patients with advanced thymoma and thymic carcinoma.
Authors: Matthew Hitron, Aaron John Spittler, Gregory Michael Cote, Rebecca Suk Heist, Kimiko Kossler, Wei Li, Youzhi Li, Chiang Li, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2017)

e20001 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity of napabucasin plus paclitaxel was observed in pre-clinical and early clinical testing. The STAT3 pathway is considered important in thymic carcinoma and thymoma, rare cancers with few treatment options. In 1st line, the objective response rate (ORR, partial response [PR] + complete response [CR] per RECIST) with carboplatin-paclitaxel was 22% in thymic carcinoma and 43% in thymoma (Gemma, 2011). A phase 1b cohort was established to evaluate safety and preliminary signs of activity of napabucasin plus paclitaxel in these patients (pts). Methods: Pts with previously-treated advanced thymoma or thymic carcinoma were enrolled with napabucasin (240 - 480 mg orally twice daily) plus paclitaxel (80 mg/m2 IV weekly for 3 of every 4 weeks). Adverse events were evaluated using CTCAE v4.03 and tumor assessments were obtained every 8 wks per RECIST 1.1. Results: A total of 9 pts (thymic carcinoma = 5, thymoma = 4) with a median 3 prior lines of systemic therapy were enrolled. In thymic carcinoma, the starting napabucasin dose was 480 mg BID (n = 2), and 240 mg BID (n = 3). Treatment was well tolerated and 1 pt required dose-reduction. There were no grade 3 AEs reported. As of data cut-off, 3 pts are off-study with progression and 2 remain on treatment. PRs were observed in 4 of 5 pts (ORR = 80%) and the median time on treatment is &gt; 7.0 mo. In thymoma, 4 pts received napabucasin 240 mg BID. AEs included grade 3 diarrhea and dehydration in 1 pt. As of data cut-off, 1 pt was off-study with progression, 2 died (perforated bowel; autoimmune myocarditis secondary to Issac’s syndrome), and 1 pt remains on treatment. PR was observed in 1 pt (ORR 25%). Conclusions: Napabucasin plus weekly paclitaxel has demonstrated clinical safety and encouraging signs of anti-tumor activity in patients with advanced thymic carcinoma and thymoma. Further clinical evaluation of the combination regimen is warranted in this population. Clinical trial information: NCT01325441.