bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of P-glycoprotein and proinflammatory cytokines with HMG-CoA reductase inhibitor simvastatin (SV) in chronic myelogenous leukemia (CML) patients with imatinib mesylate (IM) resistance
Authors: McPherson E. , Hazel E. , Tassy P. , Kleinfeld J. 
Published: March 2020

17528 Background: Primarily monocyte-derived cytokines and soluble interleukin-2 receptor (sIL-2R) form a group of proinflammatory cytokines and mononuclear cell activaton respectively which are significantly elevated in patients with CML-chronic phase (CML-CP) or CML-blastic crisis (CML-BC).C-reactive protein (CRP) correlates with IL-6. IM is a tyrosine kinase inhibitor that specifically acts intracellularly by blocking the ATP-binding site of the kinase domain of Bcr/abl in CML. Acquired drug resistance in CML-CP patients treated with IM may occur by upregulation of P-glycoprotein (P-gp) drug efflux with P-gp+ leukemic cells and P-gp dependent decline of intracellular IM levels with retained phosphorylation Bcr/abl pattern and loss of IM effect on apoptosis and cellular proliferation. Modulation of P-gp with HMG-CoA reductase inhibitor (SV), a potent inhibitor of P-gp transport, readily overcame IM resistance. Methods: We present two cases of CML: CML-CP and CML-BC with evidence of IM resistance. After one year of IM therapy an 86 yo female with CML-CP stage II, developed reactivation of Bcr/abl signaling due to excretion of IM from the cell transmembrane transporters consistent with increased proinflammatory cytokines, sIL-2R, CRP, acute coronary syndrome but normal neopterin.Results: Modulation of proinflammatory cytokines with SV, IM dose adjustments, serial measurements of Bcr-abl/abl ratio didnot exceed 0.02% on three occasions or 0.05% on two occasions after changing from 0.001% to 0.003% and now after two years of IM plus SV, real-time Bcr-abl/abl ratio is 0.000 (a 5 log reduction).sIL-2R levels normalized from 31,709.55 pg/ml to 5,345.4 pg/ml (Normal 1770–9753 pg/ml). CRP decreased to 6.23 mg/dl from 16 mg/dl. Conclusions: IM an intracellular drug demonstrating high activity against Bcr/abl gene positive CML-CP or CML-BC patients may develop resistance and loss of cellular proliferation via upregulated P-gp-mediated drug efflux mechanism. Modulation of P-gp by HMG-CoA reductase (statins) inhibitor simvastatin, a potent inhibitor of P-gp, may allow intracellular levels of IM to restore its cytotoxicity and overcome resistance mechanism. No significant financial relationships to disclose.
Autologous transplant of hematopoietic cells: Results from cryopreservation in Sanatorio Allende from Cordoba
Authors: Salvano M. L. , Molina Barrios G. , Bonini Colmano C. , Molnar S. , Arévalo M. , Dubersarsky C. , Minoldo D. , Rizzi M. L. , Lavarda M. , Jarchum G. D. 
Published: March 2020

17530 Background: Preservation of hematopoietic cells (HC) is usually achieved by storing cells in liquid nitrogen at - 1960C (Cryopreservation) (CP). We aim to: observe how many leukapheresis (LK) were necessary in order to obtain the minimal number (n°) of HC (CD34+/kg) for a proper engraftment (EG); correlate the n° of cryopreservated and infused cells with the time of EG; determine if the time of CP at -800C influences the time of EG; determine if the pre-transplant (PT) condition (partial or complete remission) plays a role in the time of EG and/or the time of hospitalization of the patients (pts). Methods: This was a retrospective study. We included all pts that received autologous transplant which HC after CP in our institution between September 2004 and August 2006. Qualitative results were analyzed by Fischer exact test and relation between qualitative and quantitative results by Mann-Whitney/Wilcoxon two- sample test (Kruskal-Wallis test for two groups). Results: 27 pts were included (N=27); the average age was 48.3± 16.6 years with a range of 64 (4–68) years. Diagnosis included: Multiple Myeloma 40%, NHL 22%, Hodgkin disease 15%, AML 15%, Amyloidosis 4%, and Ependymoma 4%. In 66.7% of the pts only one round of LK was needed for recollection. The CP time at -800C had a range of 113 (8–122) days. The median time for EG was 11 days for neutrophils (nt) and 17 days for platelets (pl). There was not significant correlation between PT condition and: n° of nt before or after day 11 (p=0.515); n° of pl before or after day 17 (p=0.972); hospitalization time (p=0.55); time for EG of nt (p-0.553) and pl (p=0.936). There was a significant difference between receiving =5x106 CD34+/Kg and pl EG time before day 17 (p=0.01) but not for nt EG time (p=3.83). CP time had no significant difference in relation to the pl EG before or after day 17 (p=0.08) or nt EG before or after day 11 (p=0.49). Conclusions: The majority of pts had a proper CD34+/Kg count with one LK round. Doses =5x106 CD34+/Kg were associated with less time for pl EG. The storage of HC at -800C showed to be safe for periods between one week and 4 months. The time of storage at -800C did not seem to affect the time of EG but showed a trend towards slowing pl recovery. The PT condition did not correlate with the time for EG or the hospitalization time. No significant financial relationships to disclose.
The expression and prognostic value of ZAP-70 and CD38 in chronic lymphocytic leukemia in a Chinese population
Authors: Wu Y. , Li J. , Zhang S. 
Published: March 2020

17538 Background: Advances in the biology of CLL have led to the identification of new prognostic markers,which may improve the accuracy of classic parameters in predicting the clinical course.For this purpose,we evaluated the prognostic value of 70-kD zata-associated protein (ZAP-70) and CD38 in B-chronic lymphocytic leukaemia(B-CLL) combined with clinical state, β2-MG and LDH. Methods: Mult-parameter flow cytometry were used to detect the expression of ZAP-70 and CD38 in 71 B-CLL patients. Results: ZAP-70 and CD38 were concordantly expressed in 70.4% of B-CLL. (P<0.05) There was significant difference between ZAP-70+ and β2-MG(P<0.05).But no significant difference between ZAP-70 and LDH(P>0.05).In a subgroup of 15 consecutive patients analysis of CD38 and ZAP-70 expression were repeated in 2 years follow-up.The expression of CD38 was changed in 7 patients and ZAP-70 was not changed over time. Conclusions: Early prognostic parameters defected disease specificity. Using FCM to detect the expression of ZAP-70 and CD38 could be performed in clinical laboratory. The expression of ZAP-70 could be a novel prognostic indicators in B-CLL because it was not changed in whole course of disease. CD38 expression was an independent prognostic indicator and it could predict time to disease progression, as judged by treatment requirement. No significant financial relationships to disclose.
A phase II trial of motexafin gadolinium (MGd) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum-based chemotherapy: Preliminary results of stage 1
Authors: Nicholas G. , Natale R. B. , Greco F. , Govindan R. , Chabot P. , Pandya K. , Eubank L. , Renschler M. F. 
Published: March 2020

18001 Background: Motexafin gadolinium (MGd) is a tumor-selective antineoplastic agent that disrupts redox dependent pathways by targeting oxidative stress-related proteins such as thioredoxin reductase (TRX). TRX often is overexpressed in NSCLC and is associated with a poor prognosis. Inhibition of TRX reverses tumor phenotype in lung carcinoma cells in vitro and in vivo. This randomized 2-stage phase II trial investigated tumor response and survival with 2 regimens of single agent MGd for the 2nd line treatment of advanced NSCLC. Methods: Patients with locally advanced or metastatic NSCLC ± brain metastases, ECOG PS 0–1, who had received one prior platinum-based chemotherapy regimen ± kinase inhibitor were randomized to intravenous MGd (10 mg/kg/week - Group A) or MGd (15 mg/kg/q 3 weeks - Group B) given in 21 day cycles. The sample size was 30 per arm in stage 1, and 24 per arm in stage 2. Response was evaluated by RECIST every 6 weeks. Results: 51 evaluable patients, median age of 62 years (range 41–85), with locally advanced (14%) or metastatic (86%) adenocarcinoma (47%), squamous cell carcinoma (14%), large cell carcinoma (10%), bronchoalveolar carcinoma (2%) or other NSCLC (27%) were randomized to group A (N=22) or group B (N=29). 37% had not responded to first line chemotherapy. MGd treatment was well tolerated, with 1–12 cycles (median 2, mean 3) administered. The most common grade 3+ adverse events were hypophosphatemia (15.7%), fatigue (13.7%), dyspnea (9.8%), hypoxia (7.8%), and finger blisters (5.9%). 48 patients were evaluable for response, with a confirmed response rate of 4.2% (2 PR). Median time to progression was 7 weeks in each group, with 26% and 15% free from progression at 4 and 6 months, respectively. Median survival of 51 evaluable patients was 10.2 months (95% CI: 6.7 months - not reached), 9.2 months for group A and not reached at > 1 year for group B. Conclusions: MGd appears active as a single agent for second line treatment of NSCLC patients with advanced or metastatic NSCLC who have failed prior platinum-based chemotherapy, with a modest response rate and promising survival. The trial has met the criteria for continuation into stage 2 for each treatment group. No significant financial relationships to disclose.
Phase II trial of carboplatin plus cetuximab for the treatment of stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Bradford D. S. , Socinski M. A. , LaRocca R. V. , Hensing T. A. , Bordoni R. E. 
Published: March 2020

18005 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. At the time of study design, triplet therapy had not demonstrated activity greater than doublets. This ongoing phase II open-label trial evaluates the doublet of cetuximab in combination with carboplatin (Cb) in patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts receive cetuximab 400 mg/m2 IV on day 1. Starting on day 8, pts receive cetuximab 250 mg/m2 IV weekly plus Cb AUC=6 IV q3w for 4 cycles (12 weeks). Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objective is to evaluate the response rate. Secondary objectives are to determine median progression-free survival (PFS) at 6 months and median overall survival (OS) at 1 year. Results: The study has completed accrual, enrolling and treating 57 pts, all evaluable for response. None had received prior adjuvant chemotherapy for NSCLC. All pts received cetuximab; 49 received Cb. Of the 57 pts, 55 have discontinued: 30 (52.6%) for disease progression or relapse. Drug-related adverse events occurred in 53 pts (93%). Conclusions: These preliminary data of cetuximab in combination with Cb demonstrated modest response rates with an acceptable toxicity profile in pts with advanced NSCLC. Final PFS and OS data are pending. [Table: see text] No significant financial relationships to disclose.
Safety of erlotinib in TRUST, a phase IV trial in patients with advanced non-small cell lung cancer (NSCLC): Initial results from the East/South East (E/SE) Asian subgroup
Authors: Wu Y. , Zhang L. , Siu-Kie Au J. , Cheng A. , Park K. , Kim H. , Srimuninnimit V. , Sriuranpong V. , Lin M. , Kuo H. 
Published: March 2020

18018 Background: Erlotinib significantly improved survival versus placebo and was well tolerated in patients (pts) with previously treated advanced NSCLC in the phase III BR.21 study (Shepherd et al. N Engl J Med 2005;353;123–32). TRUST, an open-label, multicenter study was initiated to provide erlotinib access to pts with advanced NSCLC. Here we report data for E/SE Asian pts. Methods: Eligible pts had failed 1–2 prior standard chemotherapy (CT) regimens, or were unsuitable for CT. Erlotinib 150 mg/day p.o. was given until disease progression/unacceptable toxicity. NCI CTC v3.0 was used to grade toxicities. Results: At data cut-off of 20/11/06, 885 pts were included in the analysis: n= Taiwan 297, mainland China 248, Hong Kong 160, South Korea 146, Thailand 30, Indonesia 2, Malaysia 2. Median age was 61yrs (range 22–95). Pt characteristics (%): male/female 55/45, ECOG PS 0/1/2/3 15/67/14/4, stage IIIb/IV 20/79, adenocarcinoma/other 68/32, erlotinib as 1st/2nd/3rd/other line therapy 11/55/33/<1, never/ever smoker 52/47 (no data <1). 83% pts experienced rash, of which 9% was grade (gr)3/4. Safety data forms were available for 598 pts; 54% had at least one adverse event (AE).104 pts (17%) had a treatment (tx)-related unexpected adverse event (AE) but no single AE occurred in >3% pts and only 3% were ≥gr3. Serious tx-related AEs were experienced by 19 pts (3%); 17 were gr3/4, most commonly gastrointestinal (n=6). One pt had suspected tx-related interstitial lung disease (gr2); the patient continued tx. 18 pts (3%) withdrew due to a tx-related event; 11 were gr3/4, most commonly gastrointestinal (n=4) and respiratory (idiopathic pulmonary fibrosis n=1, pneumonitis n=2). 76 pts (13%) required dose reduction due to a tx-related event (13%), mainly due to rash (n=57). 83% pts received erlotinib for >4 weeks. Efficacy will be presented. Conclusions: The results reported here for E/SE Asian pts in the TRUST study confirm in a community setting the good tolerability observed with erlotinib in clinical trials. Importantly, erlotinib was generally well tolerated and so could be administered at full tx dose to most pts. [Table: see text]
Prognostic factors for response and survival of second-line chemotherapy in patients with relapsed small cell lung cancer (SCLC)
Authors: Kim Y. , Goto K. , Yoh K. , Niho S. , Ohmatsu H. , Kubota K. , Saijo N. , Nishiwaki Y. 
Published: March 2020

18023 Background: Despite high response rates to initial chemotherapy, the majority of patients with SCLC experience tumor progression. Previous studies showed that both the response to initial chemotherapy and the response duration are important for predicting the efficacy of second-line chemotherapy. Therefore, relapsed SCLC is commonly classified into two groups: sensitive relapse (respond to initial chemotherapy and relapse more than 3 months after the completion of initial chemotherapy) and refractory relapse (not respond to initial chemotherapy or respond but relapse within 3 months). However, prognostic factors of the second-line chemotherapy have not been fully understood. Methods: From July 1992 to December 2003, four hundred and seventy-four patients with SCLC received chemotherapy as initial treatment, subsequently 229 patients received second-line chemotherapy (144 sensitive relapse and 85 refractory relapse) in our hospital. We analyzed the association of patients’ clinical factors with response and survival of second-line chemotherapy in sensitive relapsed patients and refractory relapsed patients, separately. For sensitive relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (CR/PR), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). For refractory relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (responder/non-responder), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). Results: Response to second-line chemotherapy was significantly correlated with PS in sensitive relapsed patients, however, no significant factor was detected in refractory relapsed patients. For survival, PS was the only significant prognostic factor in both sensitive and refractory relapsed patients. The median survival time was 328 days (PS<2) and 128 days (PS=2) in sensitive relapsed patients (p<0.0001), while 195 days (PS<2) and 113 days (PS=2) in refractory relapsed patients (p=0.0001), respectively. Conclusions: PS was the only significant prognostic factor for survival both in sensitive and refractory relapsed SCLC. No significant financial relationships to disclose.
Beneficial effects of elective brain irradiation (BI) in limited disease inoperable non-small cell lung cancer patients treated with combined chemo-radiotherapy (CCRT)
Authors: Umsawasdi T. 
Published: March 2020

18033 Background: BI significantly decrease brain metastases (BM) and prolonged CNS relapse free (CRF) duration (J Neurooncol 2: 253, 1984). Studies of 5 CCRT protocols using chest irradiation with randomization to BI after 2–3 courses of chemotherapy showed that patients who had complete response (CR), partial response (PR), minor response (MR), or no change (NC) of the diseases with CCRT benefited from BI with significantly reduced BM, prolonged response (R) duration and time to progression (TTP). (Proc. ASCO 5: Abstract 728, 1986). The value of BI remains unclear. Methods: Re-evaluation of previously mentioned 5 CCRT protocols was done to determine the effects on S, duration of R, TTP, and CRF with evaluations at 75th percentiles. Results: Of 138 patients (59 BI+), there was no significant difference between BI+ and BI- in terms of characteristics and response to CCRT. The effects of BI on S, duration of R, TTP, and CRF are as above. Conclusions: 1) BI significantly improved the duration of R,TTP, and CRF; 2) Although no S benefit was found in standard evaluation, BI patients had 37 weeks S advantage at 75th percentiles; 3) Patients who had CR, PR, or MR had benefited from BI and the benefits were more when evaluated at 75th percentiles; 4) The standard study of duration curves should be modified to look at a higher percentiles if the proposed treatment had low responses; 5) Awaiting for the results of RTOG 0214, our information could possibly favor BI in these patients. [Table: see text] No significant financial relationships to disclose.
Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Authors: Singer J. W. , Oldham F. B. , Bandstra B. , Sandalic L. , Bianco J. , Bonomi P. , Ross H. 
Published: March 2020

18036 Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared paclitaxel poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB by ELISA (ICON Labs). Values were assessed by quartiles and there was a clear breakpoint at the median. Pts were categorized as high or low CB based on values above or below the median (64 ng/ml). The effect of CB levels on survival was evaluated by log rank for pooled pts from the studies. Results: As detailed in the table , median survival for non-PPX-treated pts was worse if CB was high; in contrast, median survival for PPX-treated pts did not differ by CB level. Pts with high CB receiving PPX showed a trend towards better survival compared to those receiving control regimens. Conclusions: The data suggest that serum CB may be prognostic biomarker for NSCLC. Retrospective analysis suggests a trend towards improved survival in patients with high CB receiving PPX; prospective studies are required to confirm this observation. [Table: see text] No significant financial relationships to disclose.
Phase II study of weekly docetaxel and gemcitabine in relapsed patients (pts) with advanced, platinum-exposed non-small cell lung cancer (NSCLC)
Authors: Langer C. J. , Huang C. , Ruth K. , Shafer D. , Borghaei H. , Millenson M. , Mintzer D. , Staddon A. , Seldomridge J. , Tuttle H. , Treat J. 
Published: March 2020

18039 Background: Docetaxel (D) has, clear-cut therapeutic superiority compared to best supportive care, or ifosfamide/vinorelbine in relapsed NSCLC and, as a result, is the standard of comparison in the second line setting. In the pre-pemetrexed era, gemcitabine (G) in phase II studies also demonstrated activity in the salvage setting with favorable survival rates. We therefore mounted a phase II trial pairing these two agents in pts with progressive disease (PD) after prior platinum-based therapy. Methods: Pts with advanced NSCLC and ECOG PS 0–1 progressing either during or after prior platin-based therapy received D 40 mg/m2 days 1 and 8, in combination with G 800 mg/m2 days 1 and 8 every 3 wks. In the absence of dose limiting myelosuppression or other gr=3 toxicities, the dose of G was escalated on an intra-patient basis to 1 g/m2 days 1 and 8. Pts continued treatment until disease progression or unacceptable toxicity. Results: 35 pts were enrolled: 20 pts (57%) were male; 69% were ECOG PS 1; 57% had received prior XRT. Median age was 61 (range 30–79); median time from initial diagnosis to enrollment was 12.4 months. 170 cycles total were administered (median 4, range 1–16). Overall response rate was 23% (95% CI 12–39%). Median event free survival (EFS) was 5.7 months; median overall survival 12.5 mos; with 1 year survival rate of 51%, and 2 year survival rate 20%. Those enrolled within 12 months of initial diagnosis had poorer EFS compared to those beyond 12 months (log rank p=0.04). There were no treatment-related deaths. Typical grade = 3 toxicities included neutropenia (43%), neutropenic fever (9%) diarrhea (6%), pneumonitis (9%), LFT elevations (9%) and dermatitis (9%), including nail changes. Conclusions: Combination docetaxel and gemcitabine administered days 1 and 8 every 3 weeks in good performance NSCLC pts with PD after/during platinum-based therapy appears encouraging, and presents a viable option in this population. Proof of benefit vs. docetaxel alone requires phase III testing. No significant financial relationships to disclose.