bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutathione pathway genes predict quality of life (QOL) in lung cancer patients: A NCCTG-97–24–51 based study
Authors: Yang P. , Mandrekar S. , Hillman S. , Allen K. , Jett J. , Perez E. , Adjei A. 
Published: March 2020

18037 Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.
Gefitinib (G) plus interleukin-2 (IL-2) in previously treated patients with advanced non-small cell lung cancer (NSCLC)
Authors: Tomasello G. , Buti S. , Bosio G. , Stifani I. , Maestrelli M. , Brighenti M. , Porzio R. , Lazzarelli S. , Negri F. , Longarini R. , Passalacqua R. 
Published: March 2020

18042 Background: Previous studies in patients with NSCLC treated with IL-2 reported relatively long survival (Cancer 1994;73:1353–60) and a recent study indicated that lymphocytes are activated by G treatment (J Cancer Res Clin Oncol. 2006;132:719- 725.). In this study we explored the possible synergism between IL-2 and G in terms of response rate, survival and toxicity. Methods: From September 2003 to November 2006, 70 consecutive chemotherapy treated patients with advanced, progressive NSCLC received oral G 250 mg daily in a compassionate use program at a single institution. The first 39 patients included in the study received only G, the others 31 also received subcutaneous IL-2: 1 MUI/m2 twice a day on day 1 and 2, once a day on day 3, 4, 5 every week for 4 consecutive weeks with 4 week rest period. This is a phase II trial combined with a cohort design each having a different outcome event. All the evaluations were made using Recist criteria and according to the intention to treat principle. Results: The main patients characteristics and results are showed in the table below. Fifty-one (73%) patients received one prior chemotherapy regimen, while 17 (24%) received = two prior lines of treatment. *Median, months ±95% CI. §p value<0.05 Cox’s regression analysis, including PS, gender, smoke, skin toxicity, histology and use of IL-2, revealed that only skin toxicity [p<0.001; HR 0.29;CI 95% 0.16–0.54] and use of IL-2 [p<0.001; HR 0.33;CI 95% 0.18–0.60] were significantly associated with improvement in OS. Patients treated with IL-2 also showed grade 2–3 fever in 46%, fatigue in 21%, arthralgias in 13%, besides the known G- related toxicity. Conclusions: In this consecutive, non-randomized, series of patients, the use of IL-2 seems to increase the efficacy of G. Further randomized studies of TK inhibitors with IL-2 are warranted. [Table: see text] No significant financial relationships to disclose.
Exclusions to use of bevacizumab in elderly veterans with advanced non-small cell lung cancer (NSCLC)
Authors: Merza T. , Howard L. M. , Junagadhwalla M. , Gajra A. 
Published: March 2020

18046 Background: Bevacizumab (BEV) is a monoclonal antibody against VEGF approved for treatment of advanced NSCLC in the 1st line setting. BEV is being evaluated in other settings in NSCLC (2nd line, adjuvant). BEV is associated with a distinct toxicity profile including hemorrhage, delayed wound healing, viscus perforation, hypertension (HTN), and thrombosis which limits its use. At the VA medical center, we noticed poor accrual to trials with BEV. We retrospectively studied all patients diagnosed with NSCLC in the past 3 years to identify the factors that would exclude patients from participating in clinical trials with BEV. Methods: Patients were identified from our tumor registry and clinical data was reviewed. We used the exclusion criteria as per ECOG 4599 and an open industry sponsored trial (erlotinib ± BEV for 2nd line NSCLC) as listed in the table below. Results: A total of 106 male veterans with stage 4 NSCLC were identified with a median age of 72 years. Patients with squamous predominant histology (n=26) were excluded. Of the remaining 80 patients evaluated for use of BEV, 72 patients (90%) met 1 or more exclusion criteria. The following table displays the breakdown of exclusion criteria both non-specific and specific to BEV. Conclusions: Elderly veterans with NSCLC have multiple co-morbidities precluding use of cytotoxic chemotherapy. Use of BEV is further limited in this population. There is a need for agents with a favorable toxicity profile in the treatment of NSCLC. Clinical trials specific to the needs of this group of patients with poor PS and multiple co-morbidities are needed to improve participation and to offer newer therapies to the elderly veteran with lung cancer. [Table: see text] No significant financial relationships to disclose.
Expression of cyclin D3 confers resistance to erlotinib
Authors: Petty W. J. , Voelzke W. R. , Memoli V. A. , Dragnev K. H. , Urbanic J. J. , Rigas J. R. , Dmitrovsky E. 
Published: March 2020

18054 Background: Transcriptional repression of cyclin D1 occurs during responses to erlotinib (E) both in vitro and in vivo. Cyclin D3 has overlapping function with cyclin D1 but has distinct transcriptional regulation. Methods: The expression of cyclin D3 was compared in E sensitive cell lines (H358, H441) and an E resistant cell line (A549). Cyclins D1, D2, and D3 were independently overexpressed in E sensitive NIH 3T3 cells by plasmid transfection. Biopsy tissues from a proof-of-principal clinical trial of E were assessed for cyclin D3 expression. Results: A549 cells were resistant to E and expressed high levels of cyclin D3 RNA and protein compared to E sensitive cell lines. Overexpression of cyclin D1 and cyclin D3 conferred partial resistance to E in NIH 3T3 cells while cyclin D2 had no significant effect. Comparison of cyclin D3 immunostaining in tumor biopsies from patients before and after treatment with E revealed an increase in the percentage of cyclin D3 expressing cells following treatment with E. Conclusions: Cyclin D3 confers resistance to E in vitro and in vivo. Drugs such as retinoids and rexinoids that target cyclin D3 expression may prove useful for enhancing sensitivity to E. No significant financial relationships to disclose.
Phase I dose escalation, toxicity and dynamic contrast-enhanced (DCE) MRI imaging biomarker study of first line treatment with imatinib (I) and cisplatin (C) plus docetaxel (D) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Vlahovic G. , Foster T. L. , Andrews C. H. , Herndon J. E. , Sporn T. , Kelley M. J. , Dewhirst M. W. , Vujaskovic Z. 
Published: March 2020

18056 Background: Imatinib (I) inhibits activated PDGF-Rβ and down-regulates VEGF resulting in decreased angiogenesis and improved blood flow favoring enhanced tumor drug delivery in lung cancer xenoagrafts. Objectives: 1) determine the MTD for the combination of I and C plus D in NSCLC pts, 2) describe non-dose limiting toxicities (non-DLT), 3) evaluate for feasibility and changes in blood flow/permeability measurement by DCE-MRI after treatment with I, and 4) explore the relationship between measured DCE-MRI parameters and proangiogenic plasma tumor markers PDGF-BB, VEGF, PAI1, ANG2, OPN, and MMP1. Methods: Eligibility: NSCLC with tumor expression of p-PDGF-Rβ. DCE-MRI was performed before and after 7 daily doses of I alone (lead-in) followed by C plus D on day 1, every 3 weeks. Once daily I was given with each C plus D cycle, on days -5 to +2. Standardized hemodynamic parameters (Ktrans, Ve, Kep) were acquired from DCE-MRI. Enrolled patients’ plasma was analyzed by ELISA to determine plasma tumor markers’ level. Results: 14 enrolled pts (9 M, 5 F) were evaluable for toxicity and 13 for response. Six pts were treated at dose level 1 (C+D 60/60 mg/m2, and I 300 mg); one DLT (febrile neutropenia) was seen; there were no DLTs in cohort 2 (60/60 mg/m2 and I 400 mg; n=3), and two DLTs were observed in cohort 3 (70/70 mg/m2 and I 400 mg; n=5) - febrile neutropenia and grade 4 diarrhea. For all cohorts, grade 3 and 4 toxicities were: fatigue (7%), nausea (14%), neutropenia (14%), elevated creatinine (7%), and dispnea (7%). Two pts (15%) had partial response, and 6/13 pts had stable disease as their best response. DCE-MRI demonstrated trend in decrease of Ve after 7-day treatment with I (p=0.088). Exploratory analysis revealed a significant correlation of: both ANG2 and OPN with Ve (p=0.02 and 0.05 respectively), MMP1 with Kep (p=0.03), and VEGF with Ktrans (p=0.02). Conclusions: MTD for I and C plus D in chemo naïve NSCLC pts is 400 mg and 60/60 mg/m2, respectively. More, DCE-MRI is feasible in NSCLC pts. Phase II study is open and currently enrolling with continues exploration of DCE-MRI as a predictive imaging biomarker, collectively with tumor proangiogenic markers. No significant financial relationships to disclose.
Correlation of gefitinib efficacy and detection of new EGFR mutation variants in pre-treated patients (pts) with advanced non- small cell lung cancer (NSCLC)
Authors: Pallis A. , Voutsina A. , Kalikaki A. , Koutsopoulos A. , Souglakos J. , Christophylakis C. , Kentepozidis N. , Giassas S. , Mavroudis D. , Georgoulias V. 
Published: March 2020

18062 Background: The efficacy of tyrosine kinase inhibitors (TKIs) of EGFR is associated with well characterized mutations on the exons 18, 19 and 21 of EGFR gene. Less common mutations could be detected in these exons but their relationship with the clinical efficacy of TKIs has not been established yet. Methods: Genomic DNA was extracted from microdissected formalin-fixed paraffin-embeded tumor tissue from 86 pts enrolled in a gefitinib expanded access program. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Results: Classical EGFR mutations (CM) were detected in 9 (10.4%) pts and other mutations variants (MV) in 19 (22%) pts. Eight (42.1%) MV were observed in exon 18, 3 (15.8%) in exon 19 and 8 (42.1%) in exon 21. Tumor Growth Control (TGC) was achieved in 88.9% (3PR and 5SD) pts with CM, 63% (2PR and 10SD) pts with MV and in 45.9% (3PR and 25SD) pts with wild type EGFR gene (WT). There was no clear association between the presence of EGFR MV and the sex, histology or smoking history. The median TTP was 64 weeks (range:4- 80+), 20 weeks (range:6–140) and 16 weeks (range:4–176+) in pts with CM, MV and WT, respectively. Nine (47.3%) pts with EGFR MV had a TTP >24 weeks. The median survival was 78 weeks (range:5–94+), 70 weeks (range:10–142) and 36 weeks (range:4–176+) in pts with CM, MV and WT, respectively. Three patients bearing mutations in exons 18, 19, and 21 progressed despite gefitinib treatment suggesting that these mutations could be related to resistance to gefitinib. Conclusions: EGFR mutation variants could be associated with response or resistance to TKIs but their low incidence requires their evaluation in a largest cohort of patients. No significant financial relationships to disclose.
Subgroup analysis of African American patients from a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to P plus Cb in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)
Authors: Treat J. , Gonin R. , Edelman M. , Belani C. P. , Socinski M. , Catalano R. , Marinucci D. , Ansari R. , Comis R. , Obasaju C. 
Published: March 2020

18066 Background: A relationship between race and prognosis in patients with NSCLC has been suggested with African Americans (AA) having higher incidence and lower survival rates compared to whites (W) with a similar stage of disease. However, due to under representation of AA in clinical trials there is little data to substantiate this hypothesis. To investigate the possibility of a race effect on the efficacy and safety of standard chemotherapy doublet regimens in AA pts, we conducted a retrospective subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (stage IIIB/IV) NSCLC chemonaive patients with ECOG PS <2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome and toxicity data of AA pts vs. W pts were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 128 AA and 906 W pts were analyzed. There were no significant differences in the OS or TTP distributions in AA compared to W pts ( Table 1 ). The incidence and grade of hematologic toxicity in AA vs. W pts were comparable. AA demonstrated slightly lower incidences of Grade 3–4 constitutional (5.1% vs. 9.0%), hemorrhage (1.4 % vs. 2.5 %), and metabolic (4.4% vs. 7.0%) toxicities compared with W pts. Conclusions: Use of standard chemotherapy doublets as first-line chemotherapy in AA pts with advanced NSCLC demonstrated similar efficacy and safety compared to W pts treated under similar conditions. [Table: see text] No significant financial relationships to disclose.
Tumor specific antibodies for the early diagnosis of lung cancer
Authors: Pedchenko T. V. , Mernaugh R. , Massion P. P. 
Published: March 2020

18068 Background: The survival rates in lung cancer vary significantly by stage, the earlier the better. However, only 16% of patients are diagnosed at stage I. This implies an urgent need to identify a panel of biomarkers for the early detection of lung cancer in order to offer an improve chance for cure. We hypothesized that a unique phage-display recombinant antibody library approach will allow us to capture from serum and evaluate cancer antibodies as novel diagnostic biomarkers of non-small cell lung cancer. Methods: Immunoglobulins G (IgG) were purified from 3 groups of pooled serum: 10 diagnosed with adenocarcinoma, 10 squamous carcinomas, and 10 controls. A naïve rodent scFv (single chain fragment variable) phage-displayed recombinant antibody library (∼2.9 x 109 members) was used to select scFv specific for cancer human IgG. Individual bacterial colonies obtained after two rounds of subtractive biopanning on purified normal IgG and cancer IgG were picked and induced to express soluble E-tagged ScFv antibodies. An ELISA was used to screen ScFv for binding activity to pooled normal and cancer serum IgG. Single scFv clones that showed preferential binding to cancer IgG in ELISA were further validated for binding specificity by dot blot. ScFv were assayed against individual serum samples obtained from 120 normal, 60 adenocarcinoma, 56 squamous carcinoma, and 35 other, non-small cell, lung cancers. Dot blot signal intensity was quantified using Typhoon 8600 imaging system. Results: Seventy-five individual bacterial clones produced scFv that, by ELISA, distinguished purified normal from cancer IgG from pooled serum samples. Selected scFv antibodies show significantly higher binding activity to cancer-related IgG as compared to normal IgG. Twenty-five scFv were further validated for binding activity in individual human serum samples by dot blot assays. Ten scFv clearly differentiated cancer immunoglobulins from normal in human serum by dot blot, with preferential binding either to adeno- or squamous carcinoma. Conclusions: In this preliminary dataset, we identified scFv antibodies that interact with immunoglobulins present in human cancer serum samples. We show that this is a feasible and promising approach to discover cancer-specific immunoglobulins as candidate diagnostic biomarkers. No significant financial relationships to disclose.
Gemcitabine plus conventional-dose epirubicin versus gemcitabine plus cisplatin as first-line chemotherapy for stage IIIB/IV non-small cell lung carcinoma: A randomized phase II trial
Authors: Hsu C. , Cheng A. , Shih J. , Yu C. , Kuo S. , Lin C. , Huang T. , Yang P. , Yang C. 
Published: March 2020

18072 Background: Epirubicin is active for treatment of non-small cell lung carcinoma (NSCLC) but its optimal dose was undetermined. This study was designed to evaluate the efficacy and safety of gemcitabine plus conventional-dose epirubicin for stage IIIB/IV NSCLC. Methods: Patients with histological or cytological diagnosis of stage IIIB/IV NSCLC who had not received prior chemotherapy were eligible. Patients were randomized to GE (gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 and epirubicin, 70 mg/m2 on day 15) or GC (gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 and cisplatin, 80 mg/m2 on day 15). Treatment cycles were repeated every 4 weeks. Objective tumor response and toxicity were evaluated by using the World Health Organization criteria. Results: No significant difference in baseline characteristics between patients randomized to GC (n=41) and GE (n=39) arms were found. The objective response rate was 31.0% (95% C.I. 16.4% to 45.5) for GC and 37.2.0% (95% C.I. 22.2% to 52.3%) for GE. The median time-to-treatment-failure and overall survival were 6.1 months (95% C.I. 4.9 to 7.4 months) and 13.2 months (95% C.I. 8.9 to 17.5 months) for GC and 6.2 months (95% C.I. 5.2 to 7.2 months) and 21.2 months (95% C.I. 14.6 to 27.8 months) for GE, respectively. More grade 3/4 neutropenia (71.8%) was noted in GE than in GC (43.9%). Febrile neutropenia was also more common in GE (4 patients) than in GC (1 patient). However, delay of protocol treatment due to leukopenia was similar between the 2 arms. Data on the expresssion of the excission repair cross-complimentation 1 (ERCC1), evaluated by immunohistochemical study for patients with available tumor tissue, will be presented. Conclusions: Gemcitabine plus conventional-dose epirubicin is an effective and well-tolerated regimen for patients with stage IIIB/IV NSCLC. No significant financial relationships to disclose.
Phase I trial of vorinostat (V) in combination with pemetrexed (Pem) and cisplatin (CDDP) in patients with advanced cancer
Authors: Chen L. , Vogelzang N. J. , Blumenschein G. , Robert F. , Pluda J. M. , Frankel S. R. , Sharma S. 
Published: March 2020

18088 Background: Pem and CDDP are active agents in many tumor types, and the combination is approved as first line therapy in malignant pleural mesothelioma (meso). Vorinostat (V), an orally active histone deacetylase inhibitor, was shown to induce PR in 2 meso patients (pts) (Krug 2006, Kelly 2005). A Phase I trial was undertaken to determine the safety and maximum tolerated dose (MTD) of Pem+CDDP+V. Methods: Pts with advanced solid malignancies, adequate organ function, ECOG PS = 2, = 1 prior chemotherapy, >18 yrs of age, and at least 6 months from prior treatment with Pem+CDDP were eligible. Patients were treated on 21 day cycles. V was started 2 days before standard doses of CDDP (75 mg/m2) and Pem (500 mg/m2) and was given on 4 schedules: dose levels were: I-200 mg BID for 14/21 d, II- 300 mg BID for 3/7 d wk1, 2 wk rest, III-300 mg QD for 7/21 d, and IV- 400 mg QD for 7/21 d. Results: Twenty-two pts were treated: median age was 60 (range 31–81); 13M: 9F. Tumor types were NSCLC 8, meso 5, bladder 3, colorectal 2, other 4. Nineteen of 22 patients were evaluable for investigator determined response: 1 CR (5.3%), 1 PR (5.3%), 11 SD (57.9%), 6 PD (31.6%). Conclusions: Dehydration and fatigue were common DLTs on different schedules of Pem+CDDP+V. V 300 mg x 7 days was tolerable in this combination. Hints of clinical activity were observed in bladder cancer and sarcoma patients, and stable disease was seen in three mesothelioma patients. Alternative dose schedules of Pem + V are under investigation. [Table: see text] No significant financial relationships to disclose.
Phase II trial of vinflunine in patients with relapsed small cell lung cancer
Authors: Peyton J. D. , Spigel D. R. , Hainsworth J. D. , Yardley D. A. , Burris H. A. , Vazquez E. , Farley C. , Porter L. , Lunin S. , Greco F. A. 
Published: March 2020

18091 Background: Vinflunine (VFL) is a novel microtubule inhibitor of the vinca alkaloid class which has demonstrated significant preclinical activity in a small cell lung cancer (SCLC) model and antitumor activity in several other tumor types. This multicenter community- based trial was designed to examine the role of VFL in patients (pts) with relapsed SCLC. Methods: The primary endpoint is objective response rate (ORR). Eligibility criteria: previously treated SCLC (sensitive or refractory relapsed pts; limited to 1 prior platinum or non-platinum therapy for limited- or extensive-stage disease), ECOG PS 0–2, measurable disease, and informed consent. Treatment: VFL 320 mg/m2 IV over 20 minutes day 1 every 21 days for up to 6 cycles. Pts were restaged every 6 weeks. This 2-stage trial was designed to achieve a 20% ORR in platinum-sensitive pts (per RECIST criteria). Results: 29 pts were enrolled from 3/06 to 12/06 (trial ongoing, n=41 planned). Data are available for 16 pts in this analysis. Baseline characteristics: median age 64 years; male/female, 63%/37%; ECOG PS 0/1/2, 25%/50%/25%; and sensitive relapse, 50%. 3 partial response have been observed (ORR 19%, 95% CI 4%-46%). 3 pts (19%) had stable disease and 7 pts (44%) had progressive disease. 3 pts were not evaluable due to: treatment-related toxicity (sepsis; constipation); declining PS, 1 pt each. With a median follow-up of 5 months, the median progression-free survival and overall survival are 1.7 months and 3.6 months, respectively. Grade (G) 3/4 non-hematologic toxicity occurring in more than 1 pt: constipation, dyspnea, fatigue, and hyponatremia (13% each). G3/4 hematologic toxicity: leukopenia (44%), neutropenia (38%), and thrombocytopenia (6%). There have been no treatment-related deaths. Conclusions: VFL appears active as second-line treatment for SCLC. Additional assessment of myelosuppression is needed to better assess VFL’s role. Completion of accrual is anticipated by 4/07. No significant financial relationships to disclose.