bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting of tumor cells and tumor stem cells by antibodies specific for the cell-bound alpha/beta junction of MUC1.
Authors: Pichinuk Edward , Benhar Itai , Jacobi Oded , Ziv Ravit , Smorodinsky Nechama , Rubinstein Daniel B. , Wreschner Daniel H. 
Published: March 2020

e13018 Background: MUC1 is a glycoprotein over-expressed on the cell surface of a variety of malignancies and has long been a subject of interest in targeted therapy.Cleavage of MUC1 yields two unequal chains, a large extracellular a subunit non-covalently bound to a smaller b subunit in an on-and-off mechanism. Because it is released into the peripheral circulation, the MUC1 a subunit readily sequesters antibodies directed against it. In order to avoid such peripheral sequestration, Abs directed against MUC1 must be engineered as to target cell bound moieties of MUC1. Methods: Seven anti-MUC1 monoclonal antibodies were generated, five Ig-gamma1 and two IgA, all directed against the MUC1 a/b junction, a structure which remains cell bound at all times. Results: In addition to their binding differentiated breast cancer cells at pico Molar concentrations, the anti-MUC1 mAbs strongly bind breast cancer stem cells. With a view for clinical application, the DMB5F3 anti-MUC1 mAb was partially humanized with resultant production of chimeric IgG1. In order to demonstrate that chimeric anti-MUC1 antibodies can be used in tumor cell killing, mAb DMB5F3 was linked to the pseudomonas bacterial exotoxin ZZ-PE38. The resultant anti-MUC1 immunotoxin not only efficiently internalized the toxin, it resulted in strong cytotoxicity of MUC1+ breast cancer. In fact, DMB5F3:PE38 immunotoxin bound MUC1+ cancer cells with an affinity (Ab concentrations as low as 20pM) exceeding that seen with cetuximab (anti-EGFR1)-PE38 and tratuzumab (anti-erbB2)-PE38 immunotoxins. Conclusions: Taken together, these findings indicate [1] the therapeutic use of targeting cell-bound MUC1 [2] high affinity activity against both tumor and tumor stem cells suggests that the anti-MUC1 mAbs target not only 'mature' differentiated malignancy but self-reproducing cells giving rise to new malignant growth as well [3]tumor can be targeted directly by anti-MUC1 antibodies or by linking anti-MUC1 to toxin, resulting in efficient immunotoxin cytotoxicity [4] as it was shown to be a targetable entity, the SEA domain represents a promising immunogen for MUC1 tumor vaccines.
Dextromethorphan phenotyping as a test for prediction of tamoxifen (TAM) activation in breast cancer patients receiving adjuvant hormone therapy.
Authors: Gusella Milena , Bertolaso Laura , Pasini Felice , Modena Yasmina , Bononi Antonio , Fraccon Anna Paola , Da Corte Donatella , Cretella Elisabetta , Modonesi Caterina , Vastola Francesca , Nicolardi Linda , Pegoraro Cristina , Rosti Giovanni , Brunello Antonella , Segati Romana , Durante Emilia , Falci Cristina , Raiti Concetta , Rampello Elvira , Padrini Robeto ,   Northern Italy TAM Group
Published: March 2020

e13019 Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.
Administration of contrast media just before the cisplatin-based chemotherapy increases the cisplatin-induced nephrotoxicity.
Authors: Sendur Mehmet Ali Nahit , Aksoy Sercan , Yaman Sebnem , Kos Fahriye Tugba , Arik Zafer , Civelek Burak , Özdemir Nuriye , Uncu Dogan , Zengin Nurullah 
Published: March 2020

e13031 Background: The most important dose-limiting manifestation of cisplatin is renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the glomerular filtration rate (GFR). There is a clinical need to predict the probability of cisplatin-induced nephrotoxicity (CIN), in order to support decisions about patient management and preventive measures. The aim of the present study was to develop risk prediction of CIN. Methods: Consecutive 197 patients with documented serum creatinine before at least 48 hours every cycle cisplatin-based chemotherapy were included the study. Demographic and medical data including age, performance status, tumor characteristics and comorbid diseases were collected from the medical charts. Renal function was evaluated for each cycle before treatment (day 0) and before next cycle (day 21) based on the Modification of Diet in Renal Disease (MDRD) formula. Cisplatin-induced nephrotoxicity (CIN) was defined as decrease of ≥ 25% in GFR compared to baseline GFR values. Results: The mean age of the study population was 54.5±9.6 years. Baseline MDRD levels had decreased of ≥ 25% in 58 (29.4%) patients accepted as CIN group, the rest of 139 patients of the study population accepted as a non-CIN group. There was no difference of age, gender, body mass index and smoking history between groups. In both group, the hypertension (p=0.81), diabetes mellitus (p=0.72), and cardiovascular disease (p=0.58) were seen equally. Types of concomitant therapy with cisplatin-based chemotherapy were similar between CIN and non-CIN groups. The applied radiologic examinations with contrast media was observed higher in CIN group than non-CIN group (P=0.01). In patients exposure the contrast media within one week before cisplatin administration, the risk of CIN was observed 2.56 (95%CI: 1.28-5.11) times higher than in patients not exposure to the contrast (p=0.009). Conclusions: In patients exposure the contrast media within one week before cisplatin administration, the risk of CIN was observed higher than in patients not exposure to the contrast. No additional risk factor of CIN was found in this retrospective observational study.
New clinical trial of DNA-based vaccines for patients with non-small cell lung cancer.
Authors: Cohen Edward P. , Cohen Jonathan M. 
Published: March 2020

e13034 Background: We report a new immunotherapeutic trial for patients with non-small cell lung cancer (NSCLC). The trial to be conducted at the University of Pittsburgh Cancer Institute is a two-stage uncontrolled non-randomized Phase IB study designed to evaluate the safety, immunogenicity and feasibility of a new vaccine, consisting of human allogeneic fibroblasts transfected with DNA derived from the patient’s own tumor. The vaccine is prepared by transfer of genomic DNA-fragments (25 kb) from the patient’s tumor into MRC-5 cells, a human embryonic fibroblast cell line. The rationale is that numerous mutant and dysregulated genes in the tumor specifying an array of patient-specific tumor antigens are expressed in a highly immunogenic form by the DNA-transfected cells. A large body of preclinical studies in tumor-bearing mice supports this approach. An IND has been issued. Cohort 1 is underway without DLT. Methods: We plan to use a two-stage trial design. Initially, 15 early-stage patients with NSCLC will be enrolled. If there is no evidence of toxicity, and >3 of the initial patients show an immunologic response, the second stage of the study will be opened for the accrual of 22 additional patients. A portion of the primary tumor removed at surgery will be obtained to serve as a source of tumor-DNA. Each vaccine will contain 1 X 10E7 DNA-transfected fibroblasts. The vaccine will be lethally irradiated before it is administered. It will be injected intradermally in the Outpatient Clinic. Immunologic responses to the vaccine and to the autologous tumor will be evaluated by IFN-g secretion in ELISPOT assays prior to and after vaccination for the frequency of T-cells responsive to the autologous tumor. Additional assays will include lymphocyte proliferation determinations in response anti CD3 and anti CD28 monoclonal antibodies and the effect of the immunizations on the proportion of myeloid-derived suppressor T cells in the patient’s peripheral blood. The patients will also be evaluated before and after immunization for the capacity of their T cells to respond to activating signals delivered via the T cell receptor (TcR). Results: Vaccines have been prepared. First patient has been enrolled. Conclusions: No data to report in this early trial.
Serum lipocalin-2 as a potential biomarker of liver irradiation.
Authors: Sultan Sadaf , Ramadori Giuliano , Ahmad Shakil , Rave-Fraenk Margret , Christiansen Hans , Cameron Silke 
Published: March 2020

e13039 Background: Lipocalin-2 is a pleiotropic protein synthesized under acute phase conditions. The source of increased serum levels and the major organ responsible for its production are still unknown. The aim of our study was to prospectively evaluate the Lipocalin-2 (LCN-2) expression in rat liver exposed to single dose x-irradiation. Methods: A single dose of 25 Gy was administered percutaneously to the liver of randomly paired rats after a planning CT scan. Male Wistar rats were sacrificed 1, 3, 6, 12, 24 and 48 hours after irradiation along with sham irradiated control. Blood was taken for ELISA of LCN-2, and organs were removed and deep-frozen for RT-PCR and Western Blot or prepared for immunostaining. Furthermore, hepatocytes, myofibroblasts and Kupffer cells were isolated from the liver of healthy rats and irradiated with 2 Gy ex-vivo. Results: LCN-2 serum levels increased significantly (2.5 mg/ml) within 24 hours after direct liver irradiation. In the liver, LCN-2 specific transcripts increased significantly up to 552 ±109-fold at 24 hours which was further confirmed by Western blot analysis. Immunohistology of liver sections detected positivity in recruited granulocytes within 1 hour after irradiation around the central and portal areas. Ex-vivo irradiated hepatocytes showed a significantly higher LCN-2 expression as compared to myofibroblasts and Kupffer cells. Treatment of isolated, irradiated hepatocytes with acute phase cytokines (IL-6, IL-1b, TNFa, IL-6+TNFa) showed that the main inducer of LCN-2 was IL-1β. Conclusions: Single dose liver irradiation, induces a fast and significant increase of LCN-2 serum level. Hepatocytes are the major producers of LCN-2 in oxidative stress conditions. LCN-2 may represent a new serum-biomarker when the liver is hit by irradiation.
Phase II study of personalized peptide vaccine for refractory breast cancer patients.
Authors: Toh Uhi , Iwakuma Nobutaka , Takahashi Ryuji , Otsuka Hiroko , Matsueda Satoko , Shichijo Shigeki , Sasada Tetsuro , Itoh Kyogo , Shirouzu Kazuo 
Published: March 2020

e13050 Background: To develop therapeutic cancer vaccine, we conducted a phase II study of personalized peptide vaccine (PPV) for refractory breast cancer patients. Methods: Thirty-four refractory breast cancer patients, including 8 triple negative (TN) cases, were enrolled to this study. A maximum of four HLA-class IA (A2, A3s, A24, A26)-matched peptides showing higher antigen-specific IgG responses were administered. Inflammatory markers, cytokines, and peptide-specific CTL and IgG responses were examined before and after vaccination to identify prognostic factors for overall survival (OS). Results: No vaccine-related severe adverse events were observed. Median numbers of preceding chemo- and/or hormone therapy regimens and median treatment duration from the recurrence to the vaccination were 2 regimens and 37 months, respectively. Three patients did not complete the 6th vaccination because of rapid disease progression. CTL or IgG boosting by PPV was observed in 16 or 18 of 31 patients at the time of 6th vaccination. IgG boosting was observed in all 24 patients tested at 12th vaccination. Median survival time of 31 patients receiving > 6th vaccination after the vaccination was 474 days with 2 complete responses and 1 partial response. There were no significant differences between 8 TN cases and the other cases from points of immunological and clinical responses. Lymphocyte frequency (Hazard ratio of 0.906, p=0.019) well associated with OS by multivariate Cox proportional hazard regression analysis for pre-vaccination samples. Conclusions: Next steps of PPV for the refractory breast cancer patients were warranted because of the lower toxicity and favorite immune responses along with possible clinical benefits.
Comparing the outcomes of noninferiority (NI) and superiority phase III trials.
Authors: Saad Everardo D. , Buyse Marc E. 
Published: March 2020

e13055 Background: We compared the outcomes of NI and superiority trials on advanced breast cancer (BC), non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). Methods: We searched PubMed for phase III trials on systemic antineoplastic treatments for advanced BC, NSCLC and CRC published between 1/1998 and 12/2009 in 11 leading journals. We categorized primary endpoints (PEP) as time-to-event (overall survival or any variant of progression-free survival), response rate, or other (quality of life or toxicity). We used the PEP (defined as the one stated explicitly, used for N calculation, or cited first) to ascertain trial positivity. Results: We retrieved a total of 262 trials (93 on BC, 102 on NSCLC, and 67 on CRC), 36 of which (13.7%) used a NI design (12 in each tumor type). There was no significant trend in the proportion of NI trials in the two 6-year periods compared (1998-2003 vs 2004-9). The median number of patients/arm for NI and superiority trials were 284 and 164, respectively (p<0.001). There was no significant difference in the distribution of the PEP categories between NI and superiority trials. We could ascertain trial positivity in all but six trials: 24 (66.7%, 95% confidence interval [CI], 49.1% to 81.2%) NI trials were positive, compared with 89 (39.4%, 95% CI, 33.0% to 46.1%) superiority trials (p<0.001). NI trial positivity could be determined by finding a CI for the estimated treatment effect that excluded the NI margin in 15 of 27 trials (otherwise, positivity was based on authors’ conclusions, or the experimental therapy was superior to control for the PEP). The overall rates of trial positivity varied across tumor types: 48.4% for BC, 31.4% for NSCLC, and 53.7% for CRC (p=0.002). When adjusted for trial size, NI design (vs. superiority; odds ratio [OR]=4.2; 95% CI, 1.7 to 10.3) and tumor type (BC [OR=2.2; 95% CI, 1.2 to 4.0] and CRC [OR=2.8; 95% CI, 1.4 to 5.5] vs. NSCLC as reference) remained significantly associated with trial positivity. Conclusions: NI trials are more likely than superiority trials to yield positive results. The influence of NI margin width on trial results should be investigated.
Results of a comprehensive pharmacogenetic analysis of dihydropyrimidine dehydrogenase in patients treated with fluoropyrimidines and patterns of polymorphisms partially related to treatment tolerability.
Authors: Del Re Marzia , Schirripa Marta , Michelucci Angela , Cubelli Marta , Magagna Silvia , Minichillo Santino , Loupakis Fotios , Simi Paolo , Zamagni Claudio , Falcone Alfredo , Danesi Romano 
Published: March 2020

e13057 Background: Metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, except the G>A mutation in the splicing consensus sequence of intron 14 (IVS14+1G>A), which is responsible of severe enzyme impairment, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens. Methods: Patients affected by colorectal, breast and head/neck cancers requiring standard treatment with 5-FU or capecitabine in combination with other cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled: 224 suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 61 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (IVS14+1G>A, 496A>G, 1601G>A, 1627A>G, 1896T>C, 2194G>A and 2846T>C) by automatic sequencing. The study was approved by local Ethics Committee. Results: A complex pattern of DPYD variants was identified in both cohorts; the following genotypes were detected in patients with severe toxicities vs controls: 496AG+GG: 24.1 vs 21.3%; 1601GA: 12.5 vs 1.6%; 1627AG+GG: 37.1 vs 32.8%; 1896TC+TT: 6.25 vs 8.2%; IVS14+1GA: 4.9 vs 0%; 2194GA: 25.9 vs 9.8; 2846AT: 1.3 vs 0%. Conclusions: Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated, with the exception of IVS14+1GA and 2846AT which were found only in patients with poor tolerability. This study was supported in part by a grant from AIRC to R. Danesi.
A phase I study of NK012 in combination with 5-fluorouracil with or without leucovorin in patients (pts) with advanced solid tumors.
Authors: Jones Suzanne Fields , Burris Howard A. , Infante Jeffrey R. , Greco Frank A. , Spigel David R. , Kawamura Shigeyuki , Ishioka Tatsunari , Yamazaki Hiroko , Bendell Johanna C. 
Published: March 2020

e13076 Background: NK012 is a micelle-forming macromolecular prodrug of EHC (7-ethyl-10-hydroxycamptothecin), also known as SN-38, the active metabolite of irinotecan. Irinotecan-based regimens (including FOLFIRI) are commonly used in the treatment of gastrointestinal malignancies. The development of an improved irinotecan-based regimen either by improved efficacy, schedule, or toxicity profile, has the potential for a major role in the treatment of GI malignancies. Methods: Dose escalation study to determine the maximum tolerated dose and recommended phase II dose (RD) of NK012 (day 1) in combination with bolus 5FU/LV (400 /400 mg/m2) followed by continuous infusion 5FU (2400mg/m2 over 46 hrs) on days 1 and 15 every 28 days. Results: Twenty-three pts have been enrolled. NK012 was dosed at 16, 20, and 24 mg/m2 in combination with 5FU/LV bolus + CI 5FU. Two of 3 pts at 24 mg/m2 required a delay in the day 15 treatment due to myelosuppression. As a result, 20 mg/m2 was determined to be the recommended NK012 dose in combination with 5FU/LV bolus + CI 5FU. The protocol was amended to eliminate the bolus 5FU/LV due to the potential for added myelosuppression, and NK012 was re-escalated with CI 5FU only. NK012 was dosed at 24 and 28 mg/m2. One DLT (nausea/vomiting requiring hospitalization) was reported among 6 pts treated at 28 mg/m2. The RD of NK012 in combination with CI 5FU is 28 mg/m2. Treatment-related toxicities included nausea (61%, 13% gr 3), fatigue (48%), neutropenia (44% gr 3-4), vomiting (35%, 4% gr 3), diarrhea (30%), anorexia (30%), stomatitis (26%), and alopecia (26%). Six pts (including 3 pancreatic) remained on study for > 4 cycles, and two continued treatment for ≥ 1 year (colon, pancreatic). Conclusions: The combination of NK012 and CI 5FU is well tolerated, with NK012 administered at the recommended single-agent dose of 28 mg/m2. Further exploration of the regimen is warranted, particularly in patients with GI malignancies.
Clinical experience of a targeted TCR-IL2 fusion protein in combination with cisplatin (CDDP) in patients (pts) with metastatic melanoma.
Authors: Milhem Mohammed M. , Weber Jeffrey S. , Amin Asim , Agarwala Sanjiv S , Lawson David H. , Thompson John A. , O'Day Steven , Pennock Gregory K. , Richards Jon M. , Kuzel Timothy , Hernandez Liza , Huang Bee-Yau , Rhode Peter , Wong Hing C. 
Published: March 2020

e13088 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In melanoma xenograft mouse models, this fusion protein alone demonstrated potent, targeted antitumor activity and synergistic efficacy was observed in combination with CDDP. A prior phase I study in pts with metastatic malignancies, including metastatic melanoma, showed that ALT-801 monotherapy could be safely administered and was associated with immunologic changes of potential antitumor relevance (Fishman 2011 CCR 17:7765). Here we report the results of a phase Ib study of ALT-801+ CDDP in pts with metastatic melanoma. Methods: The primary objectives of this multicenter study are to: 1) define an MTD and evaluate the safety of ALT-801+CDDP and 2) assess the objective response rate according to RECIST criteria in treated patients. Eligible pts (histologically confirmed advanced/metastatic melanoma, p53 peptide/HLA-A2+ tumor, chemotherapy naive, PS (ECOG) 0-1, adequate renal and cardiac functions) received 2 consecutive 4-wk courses of CDDP (70 mg/m2 iv, Day 1) and ALT-801 (iv, Days 3, 5, 15, 17 & 19). Pts with SD or better after 2 courses received 2 additional courses of treatment. Up to 5 cohorts (3+3 dose escalation) of ALT-801 (0.04 - 0.12 mg/kg) were planned with a 2-stage design of expanded pt enrollment at the MTD. Results: 22 patients (11M, 11F, 30-74 yrs) were evaluable at ALT-801 dose levels from 0.04 to 0.10 mg/kg. The MTD has not been reached at 0.10 mg/kg ALT-801. Toxicity was manageable and transient. RECIST-confirmed tumor response and disease stabilization was reported for some patients. Overall survival rates (6 mon, 87%; 12 mon, 58%) observed to date suggest durable clinical benefit. Conclusions: ALT-801+CDDP can be safely administered in an out-patient setting to pts with metastatic melanoma. Preliminary evaluation suggests durable clinical activity of the ALT-801+CDDP regimen in melanoma patients. A trial using ALT-801 at the 0.1 mg/kg dose level in combination with a BRAF kinase inhibitor is being planned for patients with metastatic melanoma (CA097550).