bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical and safety data of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer (MBC).
Authors: Mundhenke Christoph , Schem Christian , Bauerschlag Dirk Olaf , Weigel Marion T. , Wenners Antonia Sophie , Schaefer Fritz Werner , Tiemann Katharina , Hanson Sven , Muth Mathias , May Christoph , Jonat Walter , Maass Nicolai 
Published: March 2020

e13503 Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated > 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study >28 days (“ITT>28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication >6 months, 15.2% > 12 months (mean 133 days, 15-617 days). Within “ITT>28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.
A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.
Authors: Lim Joline Sijing , Dimitrov Todor , Yong Kol Jia , Gao Chong , Tenen Daniel G , Chai Li 
Published: March 2020

e13505 Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.
Glycosylation and cancer: A potential target for therapeutic intervention.
Authors: Baldwin Gouri , O'Sullivan Brendan , Desai Anant , Gourevitch David , Woodman Ciaran , Taniere Philippe , Johnson Philip James 
Published: March 2020

e13507 Background: Aberrant glycosylation is a hallmark of cancer progression. Altered expression of glycosyltransferases and molecular facilitators within the ER and Golgi apparatus contributes to these changes. The tetraspanin are a family of molecular facilitators, expression of which have been shown to either promote or suppress cancer progression. CD151, a member of this family, modulates the glycosylation of its partner, the α3β1 integrin, affecting the integrin’s affinity towards its laminin ligand. Methods: We have characterised the glycosylation characteristics of CD151 and CD63 using glycosylation inhibitors and glycosidases to explore their patho-physiological role. Results: Inhibition of glucosidaseI/II resulted in the downregulation of CD151 and its partners, α3β1 and α6β1 integrins. 3D cell culture of the glioblastoma cell line (U87MG) in the presence of the inhibitor restrained its dendrite-like invasive growth. Similarly, the migration potential of the breast cancer cell line, MDA-MB-231, towards Lm332 decreased by 90% upon glycosylation inhibitor treatment. Since brain tumours have been shown to have elevated expression of α3β1 and Laminin332 our results suggest that glycosylation inhibitors might have a potential for investigation of therapeutic agents. Glyco-analysis of CD63 in MDA-231 cells indicated the presence of phosphomannosylated(PM) group, which might contribute to its role in lysosomal targeting. Compared to MDA-231, U87MG cells showed markedly reduced PM of CD63. Increased sialylation has previously been identified as a signature for brain metastasis in MDA-231 cells. Accordingly, comparison of CD63 in high and low sialylated populations of MDA-231 showed, upon sorting, showed similarity between the highly sialylated population of MDA-231 and U87MG. Conclusions: Using glycosylation inhibitors, we have identified a novel use for these compounds in down-regulating two major cancer associated integrins, α3β1 and α6β1. We have also uncovered a previously unknown glycomodification of CD63, phosphomannosylation which may affect the metastatic potential of cancer cells. Both findings suggest a potential for glycosylation inhibitors as part of cancer therapy.
Pilot study on antitumor efficacy of intravenously applied synergistic combinations of salicylic acids in patients with advanced solid tumors.
Authors: Drevs Joachim , Spangenberger Holger , Jenny Matthias , Mueller-Huebenthal Jonas , Kamijo Izumi , Kreutz Werner 
Published: March 2020

e13508 Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Using this differentiation a new therapy method has been developed for targeted chemotherapy. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of diflunisal, paraaminosalicylic acid (PAS) and aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance. Methods: A total of 30 patients (n=30) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of diflunisal and aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response. Results: Out of 30 patients treated 4 patients suffered from colorectal cancer, 11 from breast cancer, 2 from ovarian cancer, 2 from lung cancer, 2 from gastric cancer, 2 from glioblastoma, 1 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 1 from pancreatic cancer, 1 from choledochus cancer, 1 from prostate cancer, respectively. Side effects related to the therapy have been fatigue (6,7%), nausea (13,3%), tinnitus (10%), hypertension (6,7%), dyspnea (3,3%) and burning sensation in tumor areas (3,3%). Out of 30 patients treated, until today 14 were evaluable for metric response, 12 for metabolic and 13 for tumor marker response assessment. For tumor marker follow up 2 patientis (6,7 %) had a CR, 6 (20 %) a PR, 4 (13,3 %) a SD of > 3 month and 1 (3,3 %) a PD. For metric follow up 0 patients (0 %) had a CR, 6 (20 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. For metabolic follow up 1 patients (3,3 %) had a CR, 3 (10 %) a PR, 5 (16,7 %) a SD of > 3 month and 3 (10 %) a PD. Conclusions: This pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous salicylic acids in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study will be performed.
Serum VEGF in patients (PTS) receiving bevacizimab (BEV) for early-stage breast cancer (ESBC): ICORG 08-10.
Authors: O'Donovan Norma , Canonici Alexandra , Parker Imelda , O'Shea Tanya , Moulton Brian , Gullo Giuseppe , Kennedy John , Tryfonopoulos Dimitrios , Walsh Naomi , Crown John 
Published: March 2020

e13520 Background: Approximately 30% of pts with ESBC develop metastasis despite apparently curative loco-regional therapy. Angiogenesis, partly mediated by vascular endothelial growth factor (VEGF), may promote metastases. BEV, an anti-VEGF monoclonal antibody which has some efficacy in metastatic BC is being studied as an adjuvant in ESBC, but there are no validated biomarkers, and the effect on VEGF levels in pts with ESBC is unknown. We studied VEGF serum concentration in ESBC receiving BEV. Methods: 106 pts with HER-2 negative ESBC were included in this study. Patients received 4 cycles of docetaxel (75 mg/m2) + cyclophosphamide (600 mg/m2) with BEV (15 mg/kg) once every three weeks for one year. Serum samples were collected prior to commencement of treatment, at 6 months and 12 months. The VEGF levels in serum samples were determined, at each time point, using a VEGF enzyme-linked immunosorbent assay (ELISA). Results: VEGF concentration was determined in serum samples from 65 patients. Three pts (5%) had no detectable VEGF at 0, 6 and 12 months. The median level of serum VEGF in the remaining 62 patients was 325.4 ± 244 pg/ml. These 62 patients showed a significant decrease in VEGF concentration after 6 and 12 months of treatment (median 9 ± 42.1 pg/ml, p<0.001 and 9 ± 43.9 pg/ml, p<0.001 respectively). However, no significant change in VEGF levels were observed at 12 months compared to 6 months (median 0 ± 60.3 pg/ml, p=0.704). Conclusions: Adjuvant therapy with chemotherapy and BEV is associated with a significant reduction in VEGF levels at 6 months.
Recombinant adenoviral human p53 gene intracavity infusion in treatment of malignant pleural effusions and peritoneal effusions.
Authors: Hu Yi 
Published: March 2020

e13521 Background: Malignant pleural or peritoneal effusion adversely affects patients' quality of life. Once the effusions formed it is difficult to control. This report showed intra-cavity infusion of recombinant adenoviral human p53 gene (rAd-p53) was very effective for controlling malignant pleural or peritoneal effusion. Methods: Twenty-seven patients, 15 males and 12 females with a median age of 59 years old , were included this study. The malignant pleural effusions, consisting of 13 patients, were caused by primary lung cancers (12 cases) and breast cancer (1 case), and 14 cases of peritoneal effusions were caused by gastric cancer (5 cases), ovarian cancers (3 cases), primary live cancer (2 cases), pancreatic cancer (2 cases), esophageal cancer (1 case) and bile duct cancer (1 case). The rAd-p53 intra-cavity infusion was given after removing most of fluids. For intra-chest cavity infusion 2×1012 viral particles (VP) of rAd-p53 diluted into 200 ml of saline solution, and for intra-abdominal cavity infusion 4×1012 VP of rAd-p53 diluted into 500 ml of saline solution, were given weekly for 3 weeks. Results: A total of 3 cases, 2 with pleural effusion and 1 with peritoneal effusion achieved a complete response (CR), and 10 cases (7 pleural effusions and 3 peritoneal effusions) had a partial response (PR). The overall response rate is 48.1%. The CR was defined as the complete disappearance of pleural or peritoneal fluid and negative cytologic findings for >4 weeks, and the PR is defined as a decrease over 50% of the fluid without the need of drainage and negative cytologic findings for >4 weeks. The fluids in 8 cases with peritoneal effusions decreased by over 30% but less than 50%. The associated symptoms relieved in 23 patients (85.2%). There were no serious side effects observed except for self-limited fever found in all the cases. Conclusions: For some patients with malignant pleural or peritoneal effusions, Intra-cavity infusion of rAd-p53 is effective and safe controlling treatment.
Analysis of GTV artifacts in all phases of four dimensional CT for peripheral lung cancer based on three-dimensional CT assisted with active breathing control.
Authors: Qi Huanpeng , Li Jianbin , Zhang Yingjie , Shao Qian 
Published: March 2020

e13524 Background: To analysis artifacts of the gross tumor volume (GTV) and correlated affecting factors in all phases of four dimensional CT (4DCT) for peripheral lung cancer based on three dimensional CT (3DCT) assisted with active breathing control. Methods: After respiratory trainning sufficiently, nineteen patients with peripheral lung cancer underwent 3DCT (CTFB) and 4DCT simulation scans during free breathing and underwent 3DCT simulation scans in end inspiration hold (CTEIH) and end expiration hold (CTEEH) assisted with active breathing control. By comparing GTVEIH and GTVEEH, to choose the reference GTV (GTVref) used to calculate artifacts of GTV in all phases of 4DCT. To calculate delineation error based on re-delineating GTV in one phase of 4DCT , to calculate the relative deviations (Devref) between the size of GTV delineated based on CTFB (GTVFB) and GTVref and between the size of GTV delineated based on all phases of 4DCT , and GTVref respectively, and to determine the cutoff of GTV size according to the relevance of the maximum relative deviation (Devmax) and the delineation error when artifacts occurred. Results: GTVEIH was chosen as the GTVref, the delineation error was 10.2%, for 15 of 19 patients Devmax was larger than delineation error (Z=-2.938, p=0.003). Devmax was larger than delineation error when the mean GTV size was not larger than 6.355 cm3. A significant negative correlation was found between GTVEIH and CVGTV (r=-0.68, p=0.002) and between GTVEIH and Devmax (r=-0.691, p=0.001). The maximum median Devref of GTV size was GTVFB with 17.83% (-16.10~105.88%); The maximum one throughout the 4DCT was GTV30 with 17.20% (-6.64~102.05%) and the minimum one was GTV80 with 4.14% (-18.18~132.53%). The Devref of the size of GTVFB (r=0.520, p=0.022), GTV20 (r=0.545, p=0.016), GTV30 (r=0.617, p=0.005), GTV70 (r=0.542, p=0.017), GTV80 (r=0.576, p=0.01) and GTV90 (r=0.478, p=0.039). Conclusions: The GTVs in each phase of 4DCT for the peripheral lung cancer all had artifacts,the sizes of the artifacts in 30% and 60% phases were larger, the other were relatively smaller. The size of artifacts correlated significantly with the tumor motion in the CC direction.
A pilot study of temsirolimus and body composition.
Authors: Rodrigues Heloisa Veasey , Parsons Henrique Afonseca , Janku Filip , Naing Aung , Wheler Jennifer J. , Tsimberidou Apostolia Maria , Kurzrock Razelle 
Published: March 2020

e13534 Background: Body weight and composition play a role in cancer etiology, prognosis and treatment response. Temsirolimus is an mTor inhibitor that can cause weight loss. Therefore, we analyzed weight, body composition changes and outcome in patients treated with temsirolimus. Methods: Sixteen patients with advanced solid tumors who participated in a trial with temsirolimus were studied; body composition was evaluated utilizing computerized tomography (CT) images. Sarcopenia was defined (CT-based criteria) as skeletal muscle index lower than 38.5cm2/m2 for women and 52.4cm2/m2 for men. Results: Five of 16 patients (31%) were men; median age, 60 years. There were no overall significant changes in weight, body mass index and body composition parameters after two months. Baseline sarcopenia was present in 44% (7/16) of patients. Fatigue, anemia, hyperglycemia and hyperlipidemia were common. Baseline sarcopenia and body composition did not correlate with worse toxicity or treatment outcome. However, there was significantly greater loss in the composite body fat content for patients with grade 3 or 4 toxicities versus those with grade 1 and 2 toxicities (p=0.007). There was a trend towards loss of body fat content for progressors versus those with stable disease/partial response (SD/PR)(p=0.08), and loss of body muscle content for the SD/PR group versus progressors (p=0.07). Conclusions: Patients with higher grade toxicities had a greater loss of body fat content, and patients with SD/PR showed a trend to loss of body muscle content as compared to those with progression, suggesting an end-organ metabolic effect of temsirolimus.
Phase II trial of bevacizumab (B) and ixabepilone (Ix) for advanced non-squamous NSCLC progressive after first-line therapy.
Authors: Sanborn Rachel E. , Mack Philip C , Beckett Laurel 
Published: March 2020

e13550 Background: Ix is a semisynthetic epiothilone analog which inhibits mitosis through microtubule stabilization, with activity in multiple tumor types. Weekly dosing may have less toxicity. B improves survival in combination with carboplatin and paclitaxel for previously untreated non-squamous NSCLC. The use of B in the salvage setting has not been extensively studied. Methods: Non-randomized, open-label, single arm phase II trial of B, 10 mg/kg iv every 2 weeks and Ix, 20 mg/m2 iv weekly for 3 out of 4 weeks. An initial lead-in phase of 6 patients (pts) treated with B and Ix (16 mg/m2 iv weekly for 3 out of 4 weeks) was planned. Pts with advanced non-squamous NSCLC progressive after 1 or 2 lines of therapy are eligible, prior erlotinib is allowed, ECOG 0-1. Prior B is allowed. Pts are treated for a maximum of 6 28-day cycles, with staging every 2 cycles. Pts with response or stable disease may continue on maintenance B for up to 1 year. Primary endpoint is progression free survival, with secondary endpoints ORR, OS, toxicity, and correlative studies to assess potential predictors of response. Correlative studies include evaluations of tumor and plasma levels of VEGF, PDGF, sICAM, bFGF, and IL-8, with hypothesis that lower levels of tumor or plasma levels will correlate with improved outcomes. VEGF and IL-8 polymorphisms will be measured, as will tumor expression of Aurora B, survivin, Ki-67, hyperphosphorylation of BCL2, and overexpression of Tau. Total accrual goal is 46 pts. Results: To date, the first 6 pts for the run-in phase have been accrued. 2 pts required dose reduction in the first 2 cycles (Gr 2 thrombocytopenia, Gr 3 ALT elevation; 1 each). Max treatment cycles: 9 (Range, 2-9). 2 pts had disease progression after 2 cycles and were discontinued from study. Toxicity in the first 2 cycles is primarily hematologic, with related Gr 2 toxicity of thrombocytopenia, anemia, lymphopenia (1 each). Gr 3 lymphopenia occurred in 2 pts. Gr 3 hyperglycemia occurred in 2 pts, attributed to steroid premeds. Conclusions: With 2 pts requiring dose reduction with the run-in dose, Ix will not be increased as previously planned and the ongoing dose for the phase II study will be 16 mg/m2. Accrual to the phase II portion will continue.
MK-0646 (MK), insulin growth factor 1 receptor (IGF-1R) antibody combined with pemetrexed (P) and cisplatin (C) in stage IIIb or IV metastatic nonsquamous lung cancer (NSQL).
Authors: Huang Chao Hui , Kelly Karen , Williamson Stephen K. , Neupane Prakash , Taylor Sarah A. , Allen Ace , Wick Jo , Van Veldhuizen Peter J. 
Published: March 2020

e13551 Background: IGF-1R regulates cell growth, proliferation and apoptosis. Adenocarcinoma and never smokers have higher expression of IGF-1R and it is associated with worse survival. MK is a humanized monoclonal antibody that targets IGF-1R. P has higher activity in NSQL. We initiated a randomized phase II trial to evaluate the combination of P and C +/- MK in NSQL. Methods: Eligibility criteria: untreated NSQL stage IIIB or IV, ECOG 0 or 1, measurable disease, adequate organ function and no other intercurrent illness. Standard B12 and folic acid were given. P at 500mg/m2 and C at 75mg/m2 IV were given every 3 weeks. MK was given at the dose of 10mg/kg IV weekly on days 1, 8 and 15 of every 3 week cycle in the experimental group. The patients had radiographic assessment after every 2 cycles and treated for a maximum of 6 cycles if there was either response or stable disease. The primary objective of the study was to estimate the individual response rate of standard and experimental arm. IRB reviewed and approved the study at participating institutions. Results: From 1/2009 to 2/2011, the study accrued 26 patients, 16 male, 10 female, median age 59 yo. 14 patients were treated with PC and 12 patients were treated with PC +MK. In the PC arm we observed 2 partial responses (PR), 7 stable disease (SD), 3 had progression (PD) and 2 were not evaluable (NE). In the MK arm there were 3 PRs, 4 SD, 4 PD and 1 NE. In both arms, hematologic adverse events(AE) observed were: grade 3 neutropenia(5), hemoglobin (3), febrile neutropenia (2), platelet (2) leukopenia (1), lymphopenia (1); grade 4 platelet (2), hemoglobin (1); Grade 3 non-hematological AE were: hyperglycemia (4) and 1 occurrence each of hearing deficit, pain in extremity, hyponatremia, urinary tract infection, fatigue, dyspnea, laboratory, hypokalemia, esophageal stenosis, hypoxia, dysphagia and muscle weakness; Grade 4 hypoxia and hyperglycemia. The study was closed due to termination of funding. Conclusions: PC with MK had a similar response rate to PC. There was a higher rate of hyperglycemia in the MK group. Identification of a response predictive marker would be critical in order to continue the study of this agent.