bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of multidrug resistance in acute leukemia with three methods (Pgp expression, dnr accumulation & rho accumulation)
Authors: Alimoghaddam K. , Alamsamimi M. , Tootoonchian M. , Nadeali F. , Ashori A. , Ghavamzadeh A. 
Published: March 2020

12001 Background: Multidrug resistance (MDR) is one of the most important causes of treatment failure in chemotherapy specially in acute leukemias. One of the MDR resistance mechanisms is mdr1 gene expression that causes P-glycoprotein (Pgp) expression on cell surface. Its expression and function is detected by flowcytometry. we decided to measure its expression by three method in our leukemias patients. Then we studied correlation of each of these tests with relapse, resistance, survival and some other parameters. Methods: before chemotherapy bone marrow. Pgp expression was detected with MRK16 Ab. For interpreting of Pgp we use D-value. D-value >0.15 was considered positive for Pgp. For dnr accumulation & rho accumulation D-value >0.2 was considered positive. Informations was colleced from patient chart. Correlation of OS, DFS, resistance to therapy with Pgp expression by each method was studied. Results: there were 84 patients (52 male & 32 female). 18 cases of ALL & 66 cases of AML were included. Mean age was 30 ± 13 and mean of follow up was 168 ± 106 days. Mean of dPgp was 0.35 ± 0.05, mean of ddnr was 0. 5 ± 0.28 and mean of drho was 0. 5 ± 0.28 too. There was significant correlation between patients presented with first relapse and dPgp (p-value < 0.009).But there was not true for ddnr or drho.Sensitivity and specifity of Pgp for resistance to therapy was 35% & 75% respectively. Sensitivity and specifity of dnr accumulation for resistance to therapy was 11% & 76% respectively. Sensitivity and specifity of Pgp for resistance to therapy was 11% & 76% respectively. There is on significant correlation between Pgp and OS. It was true for dnr accumulation & rho accumulation. RFS was longer for patients with negative Pgp, but there was not significant correlation. In patients with positive Pgp probability of relapse was 9 times more than negative Pgp. Conclusions: among these three tests Pgp expression is more useful for predicting resistance to therapy. There is no difference between dnr accumulation and rho accumulation in detecting resistance to therapy. But sensitivity of Pgp expression in detecting resistance to therapy is more than the two other tests. We can use Pgp expression as a helpful test for recognizing more resistant disease. No significant financial relationships to disclose.
Pharmacokinetic (PK) and pharmacodynamic (PD) study of the effect of imatinib (Ima) on tumor (T) vascularity (V) and on gemcitabine (Ge) uptake (U) using non-invasive dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) and spectroscopy (MRS)—Study BUS228
Authors: Wolf W. , Presant C. A. , Waluch V. , Chen E. J. 
Published: March 2020

12006 Background: Ima has been reported to increase T U of other chemotherapy drugs and to reduce interstitial fluid pressure (IFP) in experimental animals. Poplin et al performed a phase 1 analysis of Ima plus Ge in solid tumors (AACR 95:405, 2004). We tested ImaGe to determine the T PK and PD effects of Ima, Ge, and the ImaGe combination using DCE-MRI and MRS. Methods: Patients (pt) with measurable and MRI-imagible refractory solid T possibly responsive to Ge were randomized to receive either: one course of Ima with PK/PD, followed by one course of Ge with PK/PD, followed by the combination ImaGe; or one course of Ge with PK/PD followed by one course of Ima with PK/PD, followed by ImaGe. Ge was given at 900 mg/m2 IV over 30 min. for PK/PD and at 10 mg/m2/min. for continued therapy. Ima was given at 400 mg daily for 5 d. with Ge given on day 3. Doses were adjusted for toxicity. T V was measured by the use of DCE-MRI, as described previously (AACR 95:490,2004), where the initial contrast accumulation rate (ICAR) was calculated as the slope of the influx curve, and the delayed contrast accumulation rate (DCAR), measured between 2–20 min post contrast administration, as an approximation of IFP. Ge U was measured by serial 19F-MRS for ∼ 1hr post Ge administration. Results: To date 7 pts have been evaluated for the trial. Two pts have entered the trial and completed one cycle of therapy for PK/PD evaluation. Ima produced moderate nausea in both pts. Other toxicity was negligible. In the first pt Ima produced an 18% increase in the ICAR and a 72% increase in the DCAR but there was no significant change observed in the Ge uptake. In the second pt, Ima produced a 60% increase in the ICAR and a 21% increase in the DCAR. Neither of the 2 pts responded to treatment. Further pts are under study and their PK/PD results will be presented. Conclusions: PK and PD can be measured using DCE MRI together with MRS to determine the clinical affects of Ima, Ge, and the Ima-Ge combination. Current results indicate that Ima has a measurable effect on T V, but its relation to drug U and pt response require further pt evaluations to be definitive. [Table: see text]
Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose
Authors: Kosloff R. A. , Wright J. , Ivy P. , Escalon J. , Norwood B. , Levinson B. , Pavlick A. C. , Beric A. , Muggia F. M. , Hochster H. 
Published: March 2020

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]
A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation
Authors: Hwang J. J. , Marshall J. L. , Malik S. , Chun H. , Ahmed T. , Pilia P. A. 
Published: March 2020

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]
Phase I study of gemcitabine (GEM) and premetrexed (ptx) in the treatment of advanced solid tumors
Authors: Kalykaki A. , Agelaki S. , Kalbakis K. , Kotsakis A. , Kentepozidis N. , Christophyllakis C. , Giassas S. , Vamvakas L. , Vardakis N. , Mavroudis D. 
Published: March 2020

12025 Background: GEM has activity against a wide range of tumors and ptx is a multitargeted antifolate agent with activity in mesothelioma and non small lung cancer (NSCLC). A phase I study of a combination of GEM plus ptx for advanced malignancies was conducted. Methods: Patients with advanced malignancies were enrolled in this accelerated dose escalation trial. Both patients with or without prior chemotherapy were also eligible. They were treated with Gem followed by ptx on days 1 and 15 every 4 weeks. The starting dose was GEM 1250 mg/m2 and ptx 300 mg/m2. The dose of each drug was escalated alternately by 250 mg for GEM and 50 mg for ptx at each dose level. Results: A total of 41 patients (9 female/32 males) with median age of 60 years were enrolled at 6 dose levels. A total of 93 cycles were conducted with a median number of 2 cycles/pt. 35 patients were assessable for efficacy and all courses were assessable for toxicity. Grade 3/4 neutropenia was observed in 8 cycles whereas grade 3 /4 anemia and grade 3/4 thrombocytopenia in 3 and 2 cycles respectively. Grade 3 febrile neutropenia occurred in 1 cycle. Other ≥ grade 3 non-hematological toxicities were observed in only 3 cycles [grade 3/4 asthenia: in 2 cy; grade 3 edema: in 1 cy). The MTD was 1750 mg/m2 for GEM and 450 mg/m2 for ptx. Dose limiting toxicities were grade IV neutropenia, grade III thrombocytopenia and febrile neutropenia. Two partial responses (1 patient with ovarian cancer and 1 with NSCLC) were observed and stable disease in 4. Conclusions: The recommended doses for further phase II studies are GEM (1750 mg/m2) followed by ptx (450 mg/m2) biweekly. No significant financial relationships to disclose.
Lung deposition of aerosolized anticancer drugs with a novel inhalation system: AKITA
Authors: Hofstetter E. , Ehlich H. , Muellinger B. , Scheuch G. 
Published: March 2020

12037 Background: Inhalation of anticancer drugs might be a helpful route of delivery in cancer therapy, particularly for lung tumors and metastasis in the lungs. In this experimental setup 12 different drugs (including antineoplastic drugs and immunotherapeutics) were nebulized with two different jet nebulizer systems. Aerosol particle size (MMD) and mass output were characterized. Methods: MMD was measured using a laser diffraction system (Sympatec, Clausthal-Zellerfeld, Germany). Mass output measurements were performed after CEN Standard using a Flow/volume simulator with radiolabelled (99m Tc) solution/suspension. The amount of radioactivity on the filters was detected with a scintillation counter. For aerosolization two nebulizer systems were used: Pari LC Plus with Pari compressor (PARI) and Pari LC Star with AKITA compressor (AKITA). To determine lung deposition a lung deposition model (International Commission of Radiological Protection, ICRP66, 1994) was used, taking into account: mass output, particle size and breathing pattern of patients. The AKITA guides the patient with a positive pressure through the inhalation maneuver, it is breath activated and delivers the medication only during inspiration. The PARI nebulizes continuously and the patient inhales with different individual breathing pattern. Results: MMD with PARI was found to be 4.2 ± 0.4 μm compared to 3.40 ± 0.3 μm for AKITA. After filling 2.5 ml into the nebulizers we found 1.4 ml residual volume with PARI and 1.0 ml for AKITA. The output rate was 0.15 ± 0.02 ml/min for PARI and 0.29 ± 0.03 ml/min for AKITA. Lung deposition relative to the emitted dose was determined to be 28 ± 10% for PARI and 85 ± 4% for AKITA. This is because the AKITA nebulizes only during inspiration and guides the patient through the inhalation maneuver, where as the PARI is running continuously and patients inhale with different breathing pattern. The result is that from 2.5 ml filled into the nebulizer, on average 0.3 ml will be deposited in the lungs with the PARI and 1.3 ml with the AKITA. To deposit 1 ml in the lungs with AKITA it will take 7 min, with PARI about 24 min. Conclusions: By use of modern inhalation devices with controlled inhalation lung deposition for cancer therapy can be optimized. [Table: see text]
Plasma kinetics, uptake by neoplastic breast tissue and preliminary toxicity data of a cholesterol-rich microemulsion (LDE) associated to a paclitaxel (PCT) derivative
Authors: Pires L. A. , Hegg R. , Graziani S. R. , Rodrigues D. G. , Maranhão R. C. , Deus D. F. 
Published: March 2020

12038 Background: Previously we described the association of PCT to a cholesterol-rich microemulsion (LDE) that binds to low-density lipoprotein (LDL) receptors and concentrates in neoplastic tissues. The association is stable, preserves the anti-proliferative activity and reduces the toxicity to animals. The present study was designed to provide preliminary toxicity data on the LDE-PCT oleate formulation, to determine its plasma kinetics compared to that of commercial PCT and to verify the complex ability to concentrate in malignant breast tissue. Methods: To determine the plasma kinetics [3H]-PCT oleate associated to LDE labeled with [14C]-Cholesteryl oleate was intravenously injected into 3 pts and [3H]-commercial PCT into 2 pts 24 h before surgery. Blood samples were collected over the 24 h to quantified radioactivity and the pharmacokinetic parameters. Tumoral and normal breast tissue were excised during the surgery. Other 3 heavily pretreated pts with breast cancer were included in this study to assess toxicity. LDE-PCT (175 mg/m2) was administered as a 1-hour infusion at 3 week interval, without pre medication. Results: Fractional clearance rate (FCR) of LDE and of the drug were similar (0.030 ± 0.026 e 0.018 ± 0.018, respectively, P = 0.5742). The uptake of both [14C]-LDE and [3H]-paclitaxel oleate by breast malignant tissue was 2 and 3 fold greater than that of the normal breast tissue. The PCT oleate T1/2 (h) was greater than the commercial PCT (T½ = 18.97 ± 7.7 and 7.34 ± 0.40) and the clearence (L/h) of PCT oleate was lesser than the commercial (CL = 1.51 ± 0.18 and 7.95 ± 4.32). No hematological or neurotoxicity was found. Nausea and anorexia grade 1 was found only in one patient. Conclusion: Most of the drug is retained in the microemulsion until its removal from the circulation. The complex is stable and has greater plasma half life and lesser clearance than those for commercial one and can be concentrated in malignant breast tissue. Furthermore, LDE-PCT showed no considerable toxicity events in the 3 patients. Although data regarding response rates were not assessed, our preliminary results suggest that LDE-PCT may be a suitable and powerful weapon to treat breast cancer patients. No significant financial relationships to disclose.
A phase I study of antitumor vaccination using tumor cells genetically modified to express alpha(1,3)galactosyltransferase (αGT) in patients with refractory or recurrent non-small cell lung cancer (NSCLC)
Authors: Morris J. C. , Janik J. E. , Vahanian N. , Mertes S. , O’Hagan D. , Tennant L. , Pittaluga S. , Albert P. , Seregina T. , Link C. 
Published: March 2020

12503 Background: Despite new treatments, lung cancer remains the leading cause of cancer death. We examined the safety and activity of antitumor vaccination using genetically altered human non-small cell lung cancer cells (HAL; HyperAcute Lung Cancer Vaccine) engineered to express xenotransplantation antigens through retroviral transfer of the murine αGT gene in patients (Pts.) with NSCLC. Methods: A single institution Phase I trial. Eligibility: Stage IV, recurrent or progressive NSCLC, Age ≥18, ECOG PS ≤2, prior chemotherapies ≤2, AGC ≥1,500/μL, Plts. ≥100,000/μL, adequate hepatic/renal function and informed consent. Cohorts of Pts. received intrademal injections of 3 × 106, 10 × 106, 30 × 106, or 100 × 106 HAL vaccine cells every 4-weeks × 4, or 500 × 106 HAL cells followed by 300 × 106 HAL cells every 2-weeks × 7. Toxicity was assessed using CTCv3.0 and response by RECIST criteria. Immunological responses included anti-αGal antibody titers, interferon-γ ELISPOT and vaccine site skin biopsies. Results: Seventeen Pts., 9 men and 8 women, median age 57 years (range, 34–85), median number of prior chemotherapies 1 (range, 1–2) were vaccinated. There were no Grade 3/4 adverse events attributable to the study vaccine. Adverse events (≤grade 2) attributable to vaccination include injection site urticaria, pain/discomfort, local skin reaction, fatigue, herpes zoster, arthralgias/myalgias and hypertension. Six Pts. had stable disease ≥16 weeks duration (range, 16–85+ weeks), 9 Pts. progressed and 2 Pts. were not evaluable for response. Skin biopsies 48-hrs after vaccination demonstrated vaccine cells in the dermis with acute infiltration of lymphocytes, granulocytes and eosinophils. Serum anti-αGal titers increased 10–14 fold with vaccination. Conclusions: Xenogeneic antitumor vaccination with genetically altered allogeneic human lung cancer cells expressing αGT is safe and feasible. A phase II trial is planned. No significant financial relationships to disclose.
Pretherapy predictive immunomodulation of NK cell activity and expression of activating and inhibitory receptors in stage IV melanoma patients
Authors: Konjevic G. , Mirjacic K. , Radovanovic A. , Jovic V. , Babovic N. , Spuzic I. 
Published: March 2020

12514 Background: As melanoma (MM) is an immunogenic tumor with poor response to chemotherapy immunomodulating agents are applied in order to potentiate cytotoxic effect of chemotherapy and enhance antitumor immune response. Beside therapeutic benefit of IFN-α and IL-2, 13-cis retinoic acid (RA), as an antiproliferative, differentiating and immunomodulating agent is also investigated. The effect of these agents on NK cells, as main innate immune system effectors, is being investigated. Methods: 35 patients with MM in stage IV prior to therapy and 20 controls were investigated. We evaluated NK activity and the expression of activating (NKG2D and CD161) and inhibitory (CD158a and CD158b) receptors on freshly isolated PBL. Predicitive immunomodulation was performed in 18 h in vitro treated PBL with rh IL-2 (200U/ml), IFN (250U/ml), RA (10−6M), and their combination. Results: Native NK cell cytotoxic activity and expression of NKG2D and CD161 activating receptors on fresh NK cells in MM patients is significantly decreased compared to controls. Predictive treatments with IL-2, IFN, IFN and RA, unlike RA alone, gave a significant increase in NK cell activity of MM patients. Singly, IFN also induced a significant increase in CD161 expression on NK cells in patients. The treatments gave no change in the expression of CD158b, while RA, alone, induced significant decrease in the expression of the inhibitory CD158a antigen. Evaluation of mRNA of transcription molecule IRF-1 shows that it is promptly up-regulated by IFNα, more by IFNα and RA, while single RA has no effect on mRNA induction. Conclusions: Considering that the mechanism of applied immunomodulating agents is continually investigated in order to optimize the dose and schedule of their administration and, also, considering controversial clinical results of RA application, alone, or with IFN, in this study we give novel results that show no significant effect of RA, whereas, IFN-induced increase in NK cell activity of MM patients is for the first time associated with the increase in the expression of NKG2D and CD161 receptors on CD16+NK cells, and not with the decrease in some inhibitory receptors, as the activity of NK cells is regulated by the balance of these two types of signals. No significant financial relationships to disclose.
Phase I experience with an anti-glycotope monoclonal antibody, RAV12, in recurrent adenocarcinoma
Authors: Burris H. A. , Rosen L. S. , Lewis N. , Jones S. F. , Van Vugt A. , Cohen R. B. , Kunkel L. A. , Stewart S. J. 
Published: March 2020

13002 Background: RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody (MAb) that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell-surface proteins. RAAG12 is variably expressed on normal non-keratinizing epithelia and is not expressed on human tissues from the cardiovascular, endocrine, hematolymphatic, neuromuscular, and central nervous systems. The majority of RAAG12 expression is in the cytoplasm. In some cases, e.g. polarized epithelia such as colon and stomach, RAAG12 is located in both the cytoplasm and the apical membrane. IHC studies demonstrated that > 90% of human colon, gastric, and pancreatic adenocarcinoma samples bound RAV12, indicating expression of RAAG12. RAAG12 is distinct from previously reported mucin or Lewis blood group carcinoma-associated carbohydrates. Methods: In December 2004, a phase I dose-escalation safety and pharmacokinetics (PK) trial was begun in patients with recurrent (1 to 3 prior treatments) adenocarcinoma. RAV12 was administered weekly × 4. Fourteen patients have received treatment, 6 in a first cohort at 0.3 mg/kg, and 8 in a second cohort at 1.0 mg/kg. Nine patients had colorectal, 2 gastroesophageal, 2 pancreatic, and 1 lung cancer. Responses were evaluated on day 42. Results: All patients, except one who experienced an HSR during his fourth dose, completed the planned weekly treatments. Three clinical syndromes have been observed to date: 1) abdominal cramping pain and diarrhea (11 patients) particularly at the higher dose, 2) asymptomatic, self-limited, rapidly reversible excursions of liver function tests (3 patients), and 3) asymptomatic, self-limited, rapidly reversible excursions of pancreatic enzymes (2 patients). Three patients had stable disease as a best response at day 43. One patient, with pancreatic cancer, had a > 50% reduction in CA19–9, continued treatment for a total of 9 doses, and had a period of disease stability of 5 months. Preliminary analysis demonstrated dose-dependent PK. Dose escalation continues at 1.5 mg/kg. Conclusions: RAV12 may have activity in recurrent adenocarcinoma. Side-effects, though present, have been manageable. Further experience with the MAb will be required to evaluate safety and activity. [Table: see text]