tbuckley/cabot-search huggingface dataset:
Hypomethylating agent (HMA) therapy use and survival in older patients with higher risk myelodysplastic syndromes (HR-MDS) in the United States (USA): A large population-based study.
Authors: Amer M Zeidan, Xin Hu, Jessica B. Long, Rong Wang, Scott F. Huntington, Nikolai Alexandrovich Podoltsev, Smith Giri, Maximilian Stahl, Steven Gore, Xiaomei Ma, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2017)

7057 Background: The HMA azacitidine improved overall survival (OS) compared to conventional care in patients with HR-MDS in the landmark randomized clinical trial AZA-001 by a median of 9.5 months compared to conventional care regimens. However recent registry data from USA (Zeidan et al, 2016) and Spain (Bernal et al, 2015) did not show substantial population-level gains in OS. We used HMA market entry in the US (2004-06) as a natural experiment to assess the effect of HMA on OS. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare data.Individuals were included if they were 66 years or older in age, had refractory anemia with excess blasts (RAEB, considered to have HR-MDS), and were diagnosed in 2001-11.We performed 2-stage residual inclusion instrumental variable (IV) analysis, using diagnosis year as the IV. Residuals from the first stage model were added to the second stage regression to control for effects of unobserved factors between HMA treatment and OS. We also adjusted for demographic characteristics, comorbidity, disability status and transfusion receipt. Results: Among 2,581 patients with RAEB, the median OS from diagnosis was 9 months, and 35.8% received HMAs. In the first stage model, diagnosis year was a strong predictor of HMA (2001-06 vs. 2011, Odds Ratio = 0.004-0.56, P-value &lt; .01). In IV analysis, patients who received HMAs showed no gain in OS (Hazard Ratio (HR) = 0.93, 95% Confidence Interval (CI) = 0.76-1.14), while there was a strongly protective effect of unobservable characteristics on OS (HR = 0.58, 95% CI = 0.47-0.73). Conclusions: In our US population-based analysis,HMA use was not associated with survival prolongation in older adults with HR-MDS. It is unclear if this is related to suboptimal use of HMAs (alternate schedules, doses, number of cycles), use of decitabine (which did not show survival benefit in randomized studies), or the unselected nature (compared to strict eligibility in clinical trials) of patients receiving HMAs at the community level. Better understanding of these issues is vital for optimal HMA patient selection and administration.
Association of adverse events (AEs) with outcomes in early stage colon cancer (CC): An analysis of 10,695 CC patients from the ACCENT database.
Authors: Winson Y. Cheung, Thierry Andre, Axel Grothey, Rachel Kerr, Jesse Dixon, Daniel G. Haller, Aimery De Gramont, Steven R. Alberts, Christopher Twelves, Michael J. O'Connell, Leonard B. Saltz, Sara Lonardi, Takayuki Yoshino, Greg Yothers, Richard M. Goldberg, Qian Shi
Journal: Journal of Clinical Oncology (2018)

3601 Background: Initial dosing of adjuvant chemotherapy (ACT) is largely based on body surface area, but studies show that drug metabolism can vary significantly across patients. ACT-related toxicities may serve as proxies for these pharmacodynamics and pharmacokinetic variations. Thus, AEs may predict for treatment efficacy and survival. In some tumors, dose titration until toxicity has been proposed. We aimed to explore the relationship between AEs and outcomes in early stage CC. Methods: A retrospective analysis of individual CC patient data from 12 randomized trials of ACT was conducted. Severity of selected AEs was categorized as per NCI criteria. Using stratified Cox models with a landmark approach, we examined overall survival (OS), disease-free survival (DFS), time to recurrence (TTR), and time from recurrence to death (TRD) in relation to AEs, adjusting for treatment duration as well as clinical and pathological factors. Analyses were performed based on the type of ACT that patients received, including fluoropyrimidine (FP) alone, FP + irinotecan (Iri), or FP + oxaliplatin (Ox). Due to multiple comparisons, the significance level was set at 0.001. Results: We included 10,695 patients of whom 79.5%, 5.8%, and 14.7% received FP, FP + Iri, and FP + Ox, respectively. Women were more likely to experience worse toxicities than men, independent of ACT regimen (all p < 0.001). Diarrhea and neutropenia were the most common grade 3+ AEs across all ACT while neuropathy was a frequent grade 3+ AE in the FP + Ox group. Other AEs, such as grade 3+ thrombocytopenia and transaminitis, were rare. Grade 3+ transaminitis was associated with worse OS (3-year OS 68.9 vs. 87.3%; adjusted hazard ratio 2.46, 95% CI 1.49 – 4.06, p < 0.001), but not DFS, TTR and TRD, in patients who received FP + Ox. There were no consistent correlations between additional AEs and outcomes in all other ACT regimens. No differences were observed when the analyses were stratified by disease stage. Conclusions: In this large cohort of clinical trial patients, most clinically observable AEs do not appear to be reliable biological correlates of optimal dose intensity or survival outcomes.
5-fluorouracil plus bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): An investigator-initiated, open-label, single-arm, multicentre, phase 2 study.
Authors: Nicolas Isambert, Alice Hervieu, Audrey Hennequin, Christophe Borg, Cedric Rebe, Valentin Derangere, Corentin Richard, Julie Blanc, Aurelie Bertaut, Francois Ghiringhelli
Journal: Journal of Clinical Oncology (2018)

e15540 Background: In patients with metastatic colorectal cancer resistant to chemotherapy few therapeutic option are available. In preclinical models, we show that IL-1b inhibition enhance efficacy of 5-fluorouracil by inhibiting IL-17A dependent tumor neoangiogenesis. In this phase 2 study, we assessed the activity and safety of 5-fluorouracil plus bevacizumab plus anakinra (an IL-1 inhibitor) in patients refractory to classical chemotherapies. Methods: We did this investigator-initiated, open-label, single-arm, multicenter, phase 2 trial of 5-fluorouracil plus bevacizumab plus anakinra in two French centers. Eligible patients were aged 20 years or older; had histologically confirmed unresectable, metastatic colorectal adenocarcinoma; were refractory to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy. Patients were treated with simplified LV5FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100mg) was administrated by subcutaneous injection daily. The primary endpoint was 2 months response rate determined upon CHOI criteria. Results: Between October 06, 2014, and May 15, 2017, we enrolled 32 patients with metastatic colorectal cancer. Five patients have response rate upon Choi criteria and 22 patients had stable disease as the best overall response. Median progression-free survival and overall survival were 5.4 and 14.5 months, respectively. Twenty patients experiment grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia (8 [25%] patients), digestive (7 [21.88%] patients) and hypertension (6 [18.75%] patients). Biological study underline that the treatment limits tumor neoangiogenesis and impact Th1/Th17 ratio. Conclusions: 5-fluororuracil plus bevacizumab and anakinra has promising activity with few and manageable safety profile, suggesting that this combination might become a potential treatment option for patients with metastatic colorectal cancer in a refractory setting. Clinical trial information: NCT02090101.
Cabazitaxel in metastatic castrate resistant prostate cancer (mCRPC) in the era of enzalutamide (ENZA) and abiraterone acetate (AA).
Authors: Amy Body, Gane Pranavan, Laeeq Malik
Journal: Journal of Clinical Oncology (2017)

e16517 Background: The concurrent development of cabazitaxel, AA, ENZA, and radium-223 has recently increased the number of therapeutic options for mCRPC. Cabazitaxel is currently approved for mCRPC patients who have previously received docetaxel. There are no data on the activity of cabazitaxel in patients who had previously progressed on docetaxel and either ENZA or AA. We examined the efficacy and tolerability of cabazitaxel in patients who progressed on docetaxel and either AA or ENZA. Methods: We searched our databases for all mCRPC patients who had received cabazitaxel up to July 2016. We reviewed medical records to collect information on tolerability, treatment sequencing and treatment outcomes. These data were analysed descriptively using Excel 2010. Results: Of 30 patients screened, only 20 patients received cabazitaxel after progressing on docetaxel and either ENZA or AA. The median age at the time of treatment was 70.8 years. All except one patient had Zubrod performance status (PS) ≥1. All patients had ≥4 sites of metastatic disease, 20% had liver or lung metastases. About 11/20 (55%) individuals had previously received ENZA (median duration 5.8 months) and 12/20 (60%) received AA (median duration 10 months). The median number of cabazitaxel administered was 6 cycles. Only 3/20 (15%) completed 10 cycles. The most common reasons for treatment discontinuation were progressive disease (35.3%) and toxicity (23.5%). The dose of cabazitaxel was reduced at baseline in most patients due to poor PS. PSA response occurred in one-third of patients while stable disease (clinical+radiological) was seen in 40% patients. The median progression free survival (PFS) was 4 months and overall survival measured 4.6 months. About 20% had ≥6 months PFS. After progression, only one-fourth went on to receive further systemic therapy. The most common toxicities were anaemia (100%), neutropenia (65%), fatigue (65%), peripheral neuropathy (35%) and diarrhoea (25%). Conclusions: Within limitations of a small retrospective study, cabazitaxel showed very modest antitumour activity in this cohort of mCRPC patients with significant tumour burden and prior exposure to docetaxel and biological agents.
The meaning of determination of some immunophenotypical parameters of bone marrow in patients with multiple myeloma in the disease monitoring.
Authors: Irina B. Lysenko, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Nadezhda V. Nikolaeva, Elena A. Kapuza, Olga N. Shatokhina, Tatiana F. Pushkareva, Margarita Pugacheva, Natalia Zuderman
Journal: Journal of Clinical Oncology (2016)

e19501 Background: Current protocols of therapy for multiple myeloma (MM) can lead to the complete elimination of tumor cells, allowing ascertaining the presence of MRD-negative remission in the patient. Current possibilities of laboratory diagnostics allow assessment of the therapy effectiveness according to clinical, morphological and serological parameters, as well as determination of the individual parameters of antigen expression of tumor cells. The purpose of the study was to analyze the necessity of determination of some parameters by immunophenotyping of bone marrow in patients with MM for the disease monitoring. Methods: The study included 16 stage II-III MM patients aged 55-68 years, including 11 (69%) women and 5 (31%) men. Chronic renal failure, grade 2 was observed in 3 patients. 0.5-1 ml of bone marrow was taken to Vasutainer tubes (BD, USA) with dry EDTA for immunophenotyping (IPT). Samples were prepared by staining-lysing-washing method using Lyse Wash Assistant. Analysis of anigen expression (CD38, CD138, CD56, CD117, CD45) was performed using flow cytometer FACSCantoII (Becton Dickinson, USA). Results: All patients received chemotherapy in regimens: bortezomib, lenalidomide, M2, VBAP. Bone marrow IPT was performed before the treatment and after 4-6 chemotherapy courses. The treatment resulted in remission in 9 (56%) patients (very good partial remission and partial remission), primary resistant course – 4 (25%), stabilization - 3 (19%). Patients with remission in dynamics of treatment showed decrease in the number of cells with immunophenotype (CD38, CD138, CD56, CD117, CD45) to 0.23-0%, while in patients with primary resistant disease course cells with immunophenotype (CD38, CD138, CD56, CD117, CD45) amounted to 34-42%. Conclusions: Determination of minimal residual disease by immunophenotyping of bone marrow cells allows effective monitoring of tumor response to therapy, as well as determination of expediency and the need to continue chemotherapy.
Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease
Authors: Xianjun Dong, Zhixiang Liao, David Gritsch, Yavor Hadzhiev, Yunfei Bai, Joseph J. Locascio, Boris Guennewig, Ganqiang Liu, Cornelis Blauwendraat, Tao Wang, Charles H. Adler, John C. Hedreen, Richard L. M. Faull, Matthew P. Frosch, Peter T. Nelson, Patrizia Rizzu, Antony A. Cooper, Peter Heutink, Thomas G. Beach, John S. Mattick, Ferenc Müller, Clemens R. Scherzer
Journal: Nature Neuroscience (2018)
Investigation of the combined action of cisplatin and 6-phosphogluconate dehydrogenase inhibitor on pancreatic and lung cancer cell lines
Authors: D.V. Savenkova, L.F. Minigulova, K.V. Havrysh, V.S. Skripova, R.G. Kiyamova
Journal: Annals of Oncology (2018)

Background: One of the possible mechanisms of cisplatin resistance of tumors is a 6-phosphogluconate dehydrogenase (6-PGD) activation [R. Lin, 2015]. Investigation of the 6-PGD inhibition by selective small-molecule compound named Physcion is likely to be studied. However, there is a problem with selection of a less toxic solvent due to hydrophobicity of Physcion. This study was designed to optimize conditions and to study features of a combined action of cisplatin and Physcion on cell lines of pancreatic cancer AsPC-1 and lung carcinoma H1299. Methods: For resazurin viability assay cells were cultured in 96-well plates (2000 cells/well) with 0-150 uM of Physcion in different solvents or in combination with cisplatin (0-128 uM). To detect a level of reactive oxygen species (ROS) by DCFDA (2',7'–dichlorofluorescin diacetate) cells were cultured in 96-well plates (25000/well) with 0-150 uM of Physcion alone as well as in combination with cisplatin (1-16 uM). Results: There were no differences in cell viability between an action of solvents (DMSO and ethanol) and inhibitor in the range of 0-1000 uM of Physcion and 1-5% of solvents accordingly. Decreased cell viability in AsPC-1 by 35% and in H1299 by 40% was detected at 150 uM of Physcion dissolved in 3% ethyl acetate. Since ethyl acetate was not toxic for cells at this concentration it was used for further experiments. Combination of Physcion with cisplatin led to an increased cisplatin sensitivity of AsPC-1 cells in 1.4-1.6 times, H1299 cells in 1.9-2.2 times, as well as to an increase of ROS level in both cell lines in 1.3-1.7 times and 1.3-2.5 times, respectively. It was found that the level of ROS increased under Physcion treatment starting from 10 uM Physicion, while the decrease in viability began at 100 uM of Physcion. Conclusions: As a result of the work it was shown that ethyl acetate was less toxic for cells. Combination of Physcion and cisplatin led to an increased cisplatin sensitivity of AsPC-1 and H1299 cells, as well as to an increased level of ROS. The obtained data is important for designing new schemes of chemotherapy and for further study of molecular mechanisms of resistance to chemotherapy. Legal entity responsible for the study: Kazan Federal University. Funding: The work was performed according to the Russian Government Program of Competitive Growth of Kazan Federal University. Disclosure: All authors have declared no conflicts of interest.
A new diagnostic method based on RT-PCR and CLART technology for non-small cell lung cancer (NSCLC) to detect major EML4-ALK and ROS.1 translocations: CLART CMA ALK and ROS.1.
Authors: Nuria Manjon, Jaime Martinez, Gonzalo Garcia, Ana Aragon, Jaime Carrillo, Jose Luis Rodriguez-Peralto, Jose Ramón Antunez Lopez, Javier Hernandez-Losa, Rosario Cospedal, Maria Luisa Villahermosa
Journal: Journal of Clinical Oncology (2017)

e20045 Background: EML4-ALK and ROS1 translocations represent 3-6% and 1-2% of NSCLC patients, respectively. These patients would benefit for a tyrosine kinase inhibitor therapies. Currently, the gold standard for ALK and ROS.1 detection are break-apart fluorescence in situ hybridization (FISH) or inmunodetection (IHC) of the chimeric fusion proteins. FISH has both high sensitivity and specificity, although often present technical interpretation problems due to signal instability and scoring. IHC is a rapid and low cost technique; however it presents several challenges regarding sensitivity and reproducibility. CLART CMA ALK &amp; ROS.1 kit is based RT-PCR and detection of the amplified product was carried out by a low-density microarray platform: CLART (Clinical Arrays Technology) of major fusion transcripts of EML4-ALK and ROS.1 translocations ( V1: E13;A20 , V6: E13; ins69;A20 , V2: E20;A20 , V3a: E6:A20 , V3b: E6;ins33 A20 ,V5a: E2;A20 and V5b: E2;ins117A20 for EML4-ALK and SDC4-ROS1 S2;R32/ S2;R34, CD74-ROS1 C6;R34 and SLC34A2-ROS1 S4;R32/S4;R34). Methods: The translocations analysis was performed with CLART CMA ALK &amp; ROS.1 kit. Clinical testing was performed using the RNA extracted from 115 samples of NSCLC patients being 34 patients with translocations detected in ALK or ROS.1 genes and 81 patients without any translocations. The results were cross-checked by comparison to Next GenerationS methodology performed on the PGM platform with the Ion Ampliseq Panel Oncomide Solid Tumor Fusion and the concordance was 95.6%. Results: Analytical sensitivity was assessed using fusion transcripts cloned in recombinant plasmids. Results ranged from 10 to 100 copies/5µl of recombinant plasmids. The analysis of 115 clinical samples allowed establishing the diagnostic sensitivity and specificity in 90.9-100% and 99-100% respectively. Conclusions: CLART CMA ALK &amp; ROS.1 emerges as a suitable alternative of FISH/IHQ for diagnosis of the most common translocations in EML4-ALK and ROS.1 genes in NSCLC samples and therefore selecting patients that would best benefit from a target therapy.
Galeterone in treatment-naïve patients with castration-resistant prostate cancer with C-terminal androgen receptor loss: Results from ARMOR2.
Authors: Mary-Ellen Taplin, Franklin Chu, James S. Cochran, Karen J. Ferrante, David Uri Lipsitz, Jennifer Roberts, Oliver Sartor, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2016)

5064 Background: Galeterone is an oral small molecule that disrupts androgen receptor (AR) signaling via multiple pathways: AR degradation, CYP17 inhibition, and AR antagonism. Immunofluorescent staining of circulating tumor cells (CTCs) is used to measure N-terminal and C-terminal (C-term) AR immunoreactivity. Reduced C-term immunoreactivity is indicative of CTCs that express AR splice variants with C-term loss, of which AR-V7 is the most common form. C-term loss is associated with abiraterone and enzalutamide resistance in patients with castration-resistant prostate cancer (CRPC) (Scher 2015). Methods: ARMOR 2 is a phase II study in 121 total patients; 107 patients with CRPC received the recommended phase II dose of 2550 mg in 4 cohorts: treatment-naïve (never treated with abiraterone/enzalutamide) non-metastatic (M0), treatment-naïve metastatic (M1), abiraterone-refractory, and enzalutamide-refractory. Endpoints included prostate-specific antigen (PSA) response and changes in CTC enumeration and AR expression. C-term AR expression was evaluated in patients with >4 N-terminal AR+ CTCs/mL. C-term loss status, PSA response, and percent change from baseline were evaluated for 61 treatment-naïve patients. Results: Seven patients (M0=1; M1=6) were identified as C-term loss positive; 54 patients (M0=22; M1=32) had C-term loss status of negative/unknown. PSA decline of ≥50% was achieved across groups, including 6 C-term loss patients. Conclusions: Patients with CRPC with C-term loss experienced meaningful benefit with galeterone, as assessed by decline in PSA. PSA response was similar between patients with C-term loss and those without. These data support the rationale for further development of galeterone for mCRPC, both with and without AR splice variant expression. Clinical trial information: NCT01709734.Cohort M1 Imputed M0 + M1 Imputed M1 Measured C-term loss + N=6 C-term loss - N=32 C-term loss + N=7 C-term loss - N=54 C-term loss + N=6 C-term loss - N=4 PSA50 83.3% 75.0% 85.7% 57.3% 83.3% 50.0% 95% CI on difference 41.2 to 27.6 30.3 to 31.1 33.7 to 73.0 % Change from baseline -60.7 -55.9 -60.8 -57.3 -60.7 -32.2 95% CI on difference 38.1 to 28.5 32.2 to 25.1 107.2 to 48.1 CI = confidence interval
Bioanalysis of samples from advanced ovarian cancer subjects treated with a combination of DPX-Survivac, metronomic cyclophosphamide, and epacadostat: Preliminary data from the phase Ib DeCidE<sup>1</sup> Trial.
Authors: Olga Hrytsenko, Genevieve Weir, Cynthia Tram, Heather Torrey, Robert Charles Newton, Marianne Stanford
Journal: Journal of Clinical Oncology (2018)

e17550 Background: DPX-Survivac is a novel T cell activating therapy containing a mix of HLA class I peptides designed to evoke a T cell response against survivin, optimized for cytotoxic activity when delivered with intermittent metronomic cyclophosphamide (CPA). Epacadostat is a potent and selective inhibitor of indoleamine 2,3-dioxygenase 1 that may reverse tumor-associated immune suppression. Analysis of blood and tumor samples was conducted to correlate clinical responses to immune response and changes within the tumor microenvironment Methods: Subjects with advanced ovarian cancer (stage IIc-IV with evidence of disease progression) were treated with DPX-Survivac (2 priming doses q3w and up to 6 boosting doses), CPA (50 mg BID), and epacadostat (up to 300 mg BID). Primary endpoints include safety and immunogenicity. Antigen-specific T cell immunity was assessed in PBMC by IFN-γ ELISPOT, tetramer analysis, and bioanalysis of pre- and post-treatment tumor biopsy conducted using RNA sequencing and multiplex IHC in subjects with available biopsy (N = 8). Secondary endpoints include objective response by modified RECIST v1.1 Results: Evaluable subjects demonstrated increases in survivin-specific T cells, with these responses being sustained throughout treatment. RNA sequencing and/or mIHC analysis of T cell markers showed increases in T cells within the tumors of subjects who achieved a partial response, correlating with Ki-67 decreases within the tumor. Pretreatment survivin mRNA levels were not significantly different. A subject with evidence of T cell infiltration without clinical benefit demonstrated upregulation of checkpoint markers and low MHC class I expression within the tumor, indicating a potential mechanism of resistance. Conclusions: DPX-Survivac induces systemic survivin-specific T cell responses. T cells were demonstrated to migrate into tumors and correlated with objective clinical responses to combination therapy. The data indicates de novo T cell activation in response to combination immunotherapy in this patient population, which has low response rates to other immunotherapies Clinical trial information: NCT02785250.