bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of effect of bendamustine on Fridericia corrected QT interval (QTcF) in a phase III study of bendamustine-rituximab in advanced indolent non-Hodgkin’s lymphoma (NHL) or mantle cell lymphoma (MCL).
Authors: Burke John M. , Flinn Ian , Craig Michael , Van Der Jagt Richard H. C. , MacDonald David , Hallman Doreen M. , Munteanu Mihaela C. 
Published: March 2020

e19518 Background: Clinical data on the arrhythmogenic potential of bendamustine are limited. Bendamustine and rituximab (BR) are commonly combined, and rituximab concentrations are essentially constant ≥1.5 hours due to its long half-life. This BR single-arm study assessed the effects of bendamustine on QTcF over 1.5 hours in previously untreated adults with advanced indolent NHL or MCL. Methods: Patients in this open-label study were aged ≥18 years with QTc on screening electrocardiogram (ECG) ≤450 ms. Exclusion criteria included low serum potassium or magnesium and history of cardiac conditions with QT prolongation risk. Bendamustine 90 mg/m2 was given on days 1 and 2 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. On day 2 of cycle 1, ECGs and blood sampling were performed ~15 min prior to bendamustine infusion (baseline), at the end of infusion (EOI)/Cmax, and 1 h post-EOI. The primary measure was change in QTcF at EOI. Secondary measures included outlier analyses of QTcF intervals, pharmacokinetic/pharmacodynamic (PK/PD) analysis, and changes in ECG morphology. The ECG analysis included patients with ≥1 ECG at baseline and on treatment. Results: There were 53 enrolled patients (92% white; 60% male; mean age 63.0 y, range 37-84 y; mean body surface area 2.0 m2, range 1.4-2.6 m2). No clinically relevant signal of any bendamustine effect on cardiac repolarization was detected based on the mean change in QTcF from baseline and outlier analyses (Table). In the PK/PD analyses, predicted change in QTcF for bendamustine and its metabolites, M3 and M4, were not significant: 5.4 ms (upper CI 7.6 ms), 6.0 ms (8.8 ms), and 7.1 ms (10.1 ms), respectively, but there were few data. No new ECG morphologic changes were seen. Conclusions: In this small population with previously untreated advanced NHL or MCL, bendamustine was associated with a small increase in mean QTcF that was not clinically meaningful. Support: Teva BPP R&D, Inc. Clinical trial information: NCT01073163. [Table: see text]
Phase II study of low-dose methotrexate to reduce the incidence of human anti-mouse antibodies in patients receiving I-131 tositumomab as first-line treatment for follicular lymphoma.
Authors: Lebovic Daniel , Avram Anca M , Dewaraja Yuni , Estes Judith , Jacobi Kathryn , Goeman Sara , Kyle Sarah , Chapman Erica , Griffith Kent A. , Kaminski Mark Stefan 
Published: March 2020

e19519 Background: I-131 tositumomab is a radiolabeled murine anti-CD20 antibody. In a frontline phase II follicular lymphoma (FL) trial, treatment with I-131 tositumomab produced a 95% ORR with 75% CR (NEJM 352:441, 2005). Median PFS was 6.1 yrs. However, 30% of patients (pts) developed high levels of human anti-mouse antibodies (HAMA) and a serum sickness syndrome within 7 weeks of treatment (early onset HAMA). The 5-yr PFS for this group was 35% compared to 70% for the others (p = 0.003). Low-dose oral methotrexate (mtx) reduces the incidence of human anti-chimeric antibody (HACA) formation in rheumatoid arthritis pts receiving infliximab. We hypothesized that low-dose mtx would likewise reduce the incidence of early onset HAMA when given in combination with I-131 tositumomab. Methods: This is a single arm, phase II study in pts with FL, grade 1-2, stage III or IV disease without limits on marrow involvement, and ≥ 1 of the GELF criteria. Prior therapy, other than focal radiotherapy, is not allowed. Pts must have adequate hematologic, hepatic and renal function, and serum HAMA levels ≤ ULN. I-131 tositumomab is given as a dosimetric dose followed within 1-2 weeks by a therapeutic dose of 75cGy of total body radiation. Pts take mtx 7.5 mg orally once weekly for 3 weeks prior to their dosimetric dose, followed by 7 additional weekly doses. The primary endpoint is the rate of HAMA formation within 7 wks of I-131 tositumomab treatment. Secondary endpoints are overall HAMA incidence, ORR, CR, PFS OS, and safety. Results: Between 8/2011 and 10/2012, 15 pts were enrolled. Median age was 56 (39-83); 11 were male. Three pts had serum HAMA levels >ULN at baseline. One pt had a spontaneous remission prior to starting treatment, leaving 11 evaluable pts. One pt developed early onset HAMA (9%). ORR = 82%, CR = 64%. Two pts progressed with DLBCL. Grade 3 or 4 toxicities included thrombocytopenia n = 3, neutropenia n = 2 and pain n = 3. Conclusions: These preliminary results show that concurrent low-dose oral mtx appears to reduce the incidence of early onset HAMA in FL patients receiving first- line I-131 tositumomab (9% vs. 30% in historical controls) while preserving efficacy. Clinical trial information: NCT01389076.
Sphingolipids as a novel target for the treatment of multiple myeloma.
Authors: Kang Yubin , Kummetha Venketa Jagadish 
Published: March 2020

e19534 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States and accounts for ~10,600 deaths annually. MM remains an incurable disease and almost all patients will eventually relapse and become refractory to currently available therapeutic agents. There is an unmet need for better understanding the disease’s molecular pathways and for identifying novel therapeutic targets. Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor cell proliferation and in tumor sensitivity to anticancer drugs. We hypothesize that altered sphingolipid metabolism plays an important role in the pathogenesis of MM, thus providing a novel target in the treatment of MM. Methods: We first assayed sphingolipid metabolism including sphingolipid metabolites and sphingolipid metabolizing genes in myeloma cell lines, in freshly isolated human primary CD138+myeloma cells, and in publically available dataset. We then tested the efficacy of the selective SK2 inhibitor (ABC294640) and the SK2 shRNA in killing myeloma cells in vitro. Results: 1) Compared to immortalized B cells, the levels of pro-apoptotic ceramides were decreased whereas the proliferative sphingosine 1-phosphate (S1P) was increased in myeloma cell lines. 2) The expression of several key sphingolipid-metabolizing genes including sphingosine kinase (SK) 1 and 2 was altered in freshly isolated human primary bone marrow myeloma cells and in publically available microarray dataset. 3) The selective SK2 inhibitor (ABC294640) induces apoptotic cell death and inhibits myeloma cell growth with an IC50of ~20 μM in 9 myeloma cell lines. 4) Interestingly, OPM-1 myeloma cell line was extremely sensitive to ABC294640 with an IC50of <5 µM whereas U266 myeloma cell line was resistant to ABC294640. SK2 shRNA induced apoptotic cell death in OPM-1, but not in U266 cells. We are currently investigating the molecular mechanisms underlying the resistance of U266 myeloma cells to ABC294640. Conclusions: Our data demonstrated that sphingolipid metabolism provides an attractive target in the treatment of refractory/relapased multiple myeloma.
Pazopanib in soft tissue sarcoma: Experience from a U.K. expanded-access program.
Authors: Frezza Anna Maria , Benson Charlotte , Miah Aisha , Linch Mark David , Alvarado Rolyn , Mitchell Scott , Esler Claire , Hatcher Helen , Judson Ian Robert 
Published: March 2020

e21516 Background: Pazopanib has been recently proven to be a valuable treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma (STS). We present our expanded-access experience to assess the safety and efficacy in routine clinical practice. Methods: Twenty-two patients were treated at 3 UK Sarcoma Centres between December 2011 and September 2012. Response was assessed according to RECIST 1.1 criteria and treatment toxicity graded. Results: Patients had a median age of 50 years (range-21-83), female (54%), 19 (86%) were metastatic. Primary sites were limb (27%), abdominal cavity (46%) and trunk (27%). Median number of previous chemotherapy lines was 2 and all patients were angiogenesis inhibitor naïve. Eighteen patients (82%) started pazopanib at 800 mg daily, 4 (18%) at 600 mg due to borderline PS. The most common side effects included fatigue (G1/2: 59%; G3/4: 9%), hypertension (G1/2: 5%, G3/4: 23%), liver function abnormalities (G1/2: 14%, G3/4: 9%) and diarrhoea (G1/2: 18%). Nine patients (41%) required a dose reduction and four (18%) discontinued the drug due to toxicity. One patient with metastatic pleomorphic sarcoma underwent RFA of the largest lung lesions and was started on pazopanib two weeks later. Despite achieving a partial response, pazopanib was discontinued due to the development of lung cavitation at the site of a previous RFA. Twenty-one patients were available for response evaluation. There were 7 (33%) partial responses (2 synovial sarcoma, 2 undifferentiated sarcoma, 1 fibromyxoid sarcoma, 1 fibromatosis and a 1 retroperitoneal leiomyosarcoma), 5 (24%) stable disease and 9 (43%) progressive disease. Clinical benefit rate (PR+SD) was 56%. Follow-up data were available for 18 patients. At a median follow-up of 25 weeks (range: 9-49), 8 patients (44%) were still alive and 5 (28%) were progression free. Median TTP was 11 weeks (95% CI 5.6-16.3). Conclusions: Pazopanib is effective in the treatment of STS progressing despite standard chemotherapy and has a manageable toxicity profile. However, due to its anti-angiogenic effect, it can interfere with the healing process and its use should be carefully considered in patients undergoing invasive procedures.
Tumor response assessment in locally unresectable or metastatic soft tissue sarcoma (aSTS) patients (pts): A three-year Regina Elena Cancer Institute (IRE) experience with trabectedin therapy.
Authors: Nuzzo Carmen , Anelli Vincenzo , Carpano Silvia , Torsello Angela , Sergi Domenico , Covello Renato , Zoccali Carmine , Vaccaro Vanja , Di Filippo Franco , Giannarelli Diana , Ferraresi Virginia , Cognetti Francesco 
Published: March 2020

e21517 Background: Trabectedin has emerged as an effective agent for aSTS pts pretreated with anthracyclines and ifosfamide. Recent data suggest that RECIST criteria could underestimate tumor response. Methods: ASTS pts who received trabectedin as 2nd or further line of treatment were retrospectively reviewed. Tumor response was assessed using RECIST, mChoi and MASS criteria. A good response according to mChoi Criteria was defined as ≥ 10% mean decrease in tumor size or a ≥ 15% decrease in tumor attenuation on contrast-enhanced CT images. Predominantly solid enhancing target lesions were evaluated for marked central necrosis or marked decreased attenuation on axial contrast-enhanced CT images by MASS Criteria. Results: From May 2009 to December 2012, 30 pts with aSTS received trabectedin; pts characteristics are summarized in the table. Median number of previous treatment lines was 2 (range 1-5); median number of cycles administered was 4 (range 1–22 cycles). Treatment was well tolerated; main causes of dose-reduction were hematological and liver toxicities. Median progression free survival (PFS) was 8 wks (95% CI: 2-14); median overall survival (OS) was 44 wks (95% CI: 18-94). According to RECIST, 4 pts (15.4%)obtained a partial response (PR)), 9 pts (34.6%) achieved a stable disease (SD); tumor control rate was 50%. 13 pts (43%) obtained a progression of disease (PD). CT Scans of 13 pts were available for comparison of different response assessment methods (2 RP, 5 SD, and 6 PD). In our small series of pts concordance between the three radiologic methods tested was 90%. Conclusions: In aSTS patients treated with trabectedin, there is substantial concordance between mChoi, MASS and RECIST criteria. Prospective validation of the potential role of mChoi and MASS criteria in this setting is warranted. [Table: see text]
Relationship of the oncogene Notch and CXCR4/SDF1 signaling in human epithelial ovarian cancer.
Authors: Konala Venu , Platonova Natalia , Colombo Michela , Mirandola Leonardo , Lazzari Elisa , De Simone Daria , Radhi Saba , Aulakh Amardeep , Zepeda Kristopher , Wade Raymond , Mer Jesse , Saadeh Charles , Yu Yuefei , Jenkins Marjorie , Figueroa Jose A. , Cobos Everardo , Chiriva-Internati Maurizio , Chiaramonte Raffaella 
Published: March 2020

e22003 Background: Ovarian cancer (OC) is the most aggressive gynecologic cancer. Understanding OC molecular pathogenesis is critical to provide novel therapeutic strategies. We aim to elucidate Notch oncogenic role in OC by focusing on its extensive crosstalk with other important pathways as CXCR4/SDF1alpha chemokine system whose involvement in OC development and metastasis is well recognized. Methods: We used flow-cytometry, cell cycle analysis, real-time PCR, and Transwell chemotaxis assay to investigate the outcome of Notch signaling withdrawal on tumor cell response to CXCR4 and SDF1alpha. Results: The analyzed OC cell lines expressed high levels of CXCR4 and its ligand SDF1alpha. Treatment with DAPT, an inhibitor of Notch activity, reduced OC cell proliferation and blocked cell cycle in G0/G1 phase without affecting apoptosis. In addition, Notch withdrawal diminished CXCR4 and SDF1alpha expression levels and hampered SDF1-driven migration and proliferation. Conclusions: Notch deregulation might affect important features of OC such as cell growth and migration through the modulation of CXCR4/SDF1a pathway. This indicates that these intertwined pathways are promising therapeutic targets in OC.
Effect of pharmacologic inhibition of c-Jun N-terminal kinase (JNK) signaling pathway on cell proliferation and cell cycle progression in human granulosa cell tumor.
Authors: Oktem Ozgur , Muftuoglu Meltem , Senbabaoglu Filiz , Urman Bulent 
Published: March 2020

e22004 Background: No data are available regarding the signaling pathways that controls the proliferation of granulosa cell tumors (GCT). Preliminary findings showing the activation of c-Jun N-terminal kinase (JNK) signaling pathway in the proliferating granulosa cells has led us to investigate the role of this pathway in human GCT. Methods: Human GCT line COV 434 was used. Cell proliferation was monitored real-time quantitatively for 120h using an impedance-based system. Two different pharmacologic JNK inhibitors SP600125 and AS601245 were used. Their inhibitory concentrations were determined in western blot. Cell cycle was analyzed with flow cytometry and apoptosis with yo-pro-1 staining. Results: First, the growth characteristics of this cell line was delineated (Table 1A). Then the cells were treated with the inhibitors at the indicated doses during the log phase. Their proliferation was significantly halted in a dose-dependent manner by both inhibitors (Table 1B). Furthermore, the cells failed to complete mitosis, and began to accumulate at G2 in a dose dependent manner when JNK pathway was interrupted with AS601245 (59%) and SP600125 (39%) during G2/M transition compared to control cells (7%) proceeding through G2/M phase regularly (p<0.001). Compared to 3.5% of control cells, 14% and 30% of the cells underwent apoptosis when treated with 50 µM SP600125 and AS601245, respectively. At 100 µM, the apoptotic fraction increased to 68% and 76%, respectively (p<0.01). Conclusions: These results suggest that pharmacologic manipulation of JNK pathway may provide a therapeutic benefit in the treatment of GCT for which currently, no curative therapy exists beyond surgery. Funded by a Grant to Ozgur Oktem (TUBITAK109S164). [Table: see text]
Malignancy testing by AmpliSeq cancer panel sequencing-based assessment in NSCLC.
Authors: Lai Rensheng , Wu Xiaobin , Sun Yi , Chen Jie , Xie Ling , Yu Bo , Sun Lele 
Published: March 2020

e22026 Background: Bringing PGM sequencing into clinical laboratories needs the same confidence and consistency with Sanger sequencing. We have developed a approach to assess the known EGFR mutation of NSCLC using AmpliSeq Cancer Panel and demonstrated high specificity and sensitivity. Methods: Fifteen standard cell line samples with known EGFR mutation frequency (1%, 5%, 20%, 50%) were issued by CPC of National Health Ministry. These were first examined by sanger sequencing, then by AmpliSeq cancer panel on PGM. Results were compared each other. Next, we applied the AmpliSeq cancer panel sequencing to test the mutation status of 8 clinical malignancy FFPE samples including 4 NSCLC, 1 Esophagus Cancer, 1 Breast Cancer, 1 Gastric Cancer and 1 stroma tumor. gDNA was extracted from FFPE section then subject to library construction. Emulsion PCR was performed and beads were enriched, Sequencing was performed with 200 bp readlength by pooling 2-4 samples on one 314 chip. Data yield ranges from 13,311 to 203,061 eligible reads (2 Mb to 44M) per sample. Results: Validation of AmpliSeq Cancer Panel Sequencing: Among all 15 samples, 14 cases (14/15, 93%) were confirmed by Sanger sequencing. AmpliSeq FFPE malignancy: For all 8 FFPE samples, the sequencing depth of EGFR site ranges from 20x to 2000x with 100% on-target coverage. Each patient can be identified with more than 3 target drugs based on mutant frequency (>5%) with 99% confidence (CI 0.99-0.995). All patients were shown with the presence of rare subpopulations of interrogating 739 mutations in 46 genes (0.1% to 94% allele frequency). Conclusions: AmpliSeq cancer panel sequencing shows equal or higher sensitivity to sanger sequencing . Call analysis shows that a minimum of 100x coverage is required to detect mutations ≥ 5%. [Table: see text]
CARD8/BCL-2 cascade in early adaptive drug resistant tumor escape against targeted inhibitors in NSCLC.
Authors: Bagai Rakesh K. , Zhang Wei , Leahy Patrick , Yin Lihong , Ma Patrick C. 
Published: March 2020

e22032 Background: Lung cancer targeted therapy is largely limited by inevitable recurrent resistant disease after initial response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), typically accompanied with divergent late acquired resistance mechanisms. We now focused on studying the emergence of early adaptive resistance to uncover attractive therapeutic targets to overcome drug resistance. Methods: HCC827 cells were treated with EGFR-TKI (0-9 days) with apoptosis pathway-specific QPCR array and TLVM analysis performed. MTS and crystal violet assays were performed. Western blot analysis was performed to examine prosurvival signaling developed against erlotinib, alone or in combination with MET inhibitor SU11274. IHC was performed on lung cancer tumor microarray (TMA) using BCL-2 and caspase-recruitment domain-containing protein 8 (CARD8) antibodies and graded (4 tier scoring system). NSCLC cell lines and murine xenograft models (HCC827, H1975) were developed for resistance biomarkers expression analysis in pre-/post-TKI treatment using anti-human CARD8, p-STAT3 and BCL-2 antibodies. Results: We characterized the emergence of early resistant lung cancer cells in escape against targeted TKIs with 100-fold higher IC50 in adaptive drug resistance. The resistant cells that evaded EGFR-TKI based targeted inhibition exhibited MET-independent induction of CARD8 and STAT3/BCL-2 mitochondrial prosurvival signaling in cellular quiescence, and inhibited cytoskeletal functions. Expression analysis studies demonstrated common tumor-associated expression of CARD8 but relatively low BCL-2 level in NSCLC. In vitro cell line studies suggest that CARD8 induction was preceded by a resurgence of STAT3 activation. In vivo xenograft model (HCC827/erlotinib; H1975/erlotinib+ SU11274) also verified upregulated CARD8/BCL-2 activation within early resistant cells. Conclusions: Resistant tumor cells that evaded EGFR inhibitors, alone or in combination with MET inhibitors, exhibited increased expression of CARD8-STAT3/BCL-2 prosurvival signaling cascade. Further studies to define the mechanism of CARD8 in promoting adaptive tumor drug resistance would be warranted.
Oncogenic mutations in colorectal cancer, indications for anatomical sites, and targeted intervention.
Authors: Corso Giovanni , Pascale Valeria , Flauti Giuseppe , Marrelli Daniele , Roviello Franco 
Published: March 2020

e22037 Background: Oncogenic mutations, such as KRAS, in colorectal cancer patients are considered standard molecular biomarkers that predict the clinical benefit for the targeted intervention with EGFR inhibitors. In addition, these mutations are associated with specific anatomical area in the colon tumor development, as BRAF mutations with the microsatellite instability. Methods: In this translational study we aim to assess the mutation frequencies of the EGFR [hotspot area and polyadenine deletions (A13_del)], KRAS, BRAFV600E, and PIK3CA oncogenes in a series of 280 colorectal cancer patients. Microsatellite instability phenotype is considered in this series. All patients' clinicopathological data were considered for statistical analysis and associations. Results: In this study, we verified multiple associations between oncogenic mutations and specified clinicopathological tumor features. Respectively, we identified the following significant results: 1) EGFR A13_deletions are associated with right colon carcinoma (22.2% vs. 3.3%; p<0.005), mucinous histotype (16% vs. 7.8%; p=0.042), G3 grading (19% vs. 7.3%; p=0.024) and microsatellite instability status (p<0.005); 2) PIK3CA mutations are related mucinous histotype (12% vs. 4.4%; p=0.021) 3) KRASG12 and KRASG13mutations are correlated respectively with the left (91.4% vs. 59.3%) and right (40.7% vs. 8.6%) colon cancer development (p<0.005), and finally 4) microsatellite instability is associated with right colon tumors (28.4% vs. 5.5%; p<0.005). Conclusions: Mostly, we verified a high frequency rate of the KRASG13 and EGFR A13_del oncogene mutations in right colon cancer; whereas KRASG12 codon mutation occurs more frequently in left colon cancers. In particular, we assessed that right colon cancer is associated with specific molecular characteristics, in comparison to left colon tumors. These evidences, in association with specific clinicopathological data, can delineate novel approaches for the colorectal cancer classification and targeted intervention.