bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of smoking history on survival outcome: An exploratory analysis of a phase III study of gemcitabine and cisplatin in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Nguyen B. , Paul S. , Posther K. , Sandler A. 
Published: March 2020

7141 Background: Exploratory analyses of data from phase II and phase III NSCLC studies of epidermal growth factor receptor (EGFR) inhibitors have shown that smoking history (specifically never smokers) is associated with positive clinical outcomes, indicating increased sensitivity to these agents. A phase III trial in chemonaïve patients (pts) with advanced NSCLC demonstrated that the regimen of gemcitabine-cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival [JCO 2000;18:122–30]. We analyzed data from this trial to examine the effect of smoking history on survival outcome. Methods: All pts entered in the study were combined (524 pts) in a subgroup analysis conducted to evaluate the effect of smoking history (smokers vs non-smokers at baseline; number of never smokers unknown) on survival. In addition, 220 pts with a history of smoking were grouped by the total number of pack-years (pk-yrs) smoked (≤37.5 vs >37.5 pk-yrs), and each group was analyzed with regard to survival relative to the group’s median number of pk-yrs. Results: There was no significant difference in median survival time between smokers (n = 220) and non-smokers (n = 304) (8.5 vs 8.1 months, respectively; hazard ratio [HR]: 0.97 [95% CI: 0.81–1.17]; p-value = 0.739). Although the 112 pts who smoked ≤37.5 pk-yrs had a median of 22.5 pk-yrs and the 108 pts who smoked >37.5 pk-yrs had a median of 55.5 pk-yrs, there was no significant difference in median survival time between the groups (9.2 vs 8.5 months, respectively; HR: 1.00 [95% CI: 0.75–1.34]; p-value = 0.9897). Conclusions: In pts with advanced NSCLC, analyses of survival outcomes for chemotherapy with the combination of gemcitabine-cisplatin or cisplatin indicate that survival is independent of smoking history (smokers vs non-smokers at baseline), unlike targeted therapies, such as EGFR inhibitors for which smoking history (specifically never smokers) is a clinical predictor of the sensitivity of these agents and of survival. [Table: see text]
Serial hypoxia imaging with 99mTc-HL91 SPECT to predict radiotherapy response in non-small cell lung cancer
Authors: Li J. , Li L. , Yu J. , Xing L. , Guo H. , Zhu H. , Sun X. , Yang G. 
Published: March 2020

7143 Background: To evaluate the relationship between 99mTc-HL91 (99mTc labeled 4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime) SPECT (single photon emission computed tomography) hypoxia imaging and the radiotherapy outcome and also to assess changes in tumor oxygenation during the course of treatment. Methods: 32 patients with pathologically proven non-small cell lung cancer received three-dimensional conformal radiotherapy were enrolled into the study. All patients were performed 99mTc-HL91 SPECT scanning at one or two days before radiotherapy. 18 patients were also performed during radiotherapy (30–40 Gy) and one or two days after radiotherapy. Anterior, posterior and lateral planar images were collected at 2 hours, 4 hours and 6 hours respectively after intravenous injection approximately 740MBq 99mTc-HL91. Regions of interest (ROIs) were drawn in the tumor and contralateral normal lung tissue and the radioactivity ratios of tumor to normal tissue (T/N) were calculated. Results: The relationship between T/N ratios at 4h images after injection which was shown as the best of three acquired images before radiotherapy and the response and over survival to radiotherapy were analyzed for all 32 patients. The results of 99mTc-HL91 imaging of 32 patients correlate well with radiotherapy response (P = 0.049) and also patient survival (P = 0.043). The average T/N value of 18 patients who receiving serial scanning was 1.57 ± 0.18, 1.44 ± 0.19 and 1.30 ± 0.14 respectively. There was significant statistic difference between these three groups (P = 0.000). Conclusions: HL91 SPECT imaging identified the hypoxia status and changes during radiotherapy in lung cancer. It was confirmed that hypoxia imaging with HL91 SPECT before treatment may predict radiotherapy response and patient survival. The relationship between T/N ratio and radiotherapy outcome in NSCLC [Table: see text] No significant financial relationships to disclose.
Evaluation of guilt, shame and depression in non-small cell lung cancer (NSCLC) relative to breast (BC) and prostate cancer (PC)
Authors: Schmidt N. K. , Else-Quest N. M. , Hammes L. , Eickhoff J. , Hyde J. , Schiller J. H. 
Published: March 2020

7158 Background: Most NSCLC is related to smoking, and thus is potentially avoidable. Prior qualitative studies suggest that stigma from a self-induced illness results in feelings of guilt and shame in NSCLC patients (pts). This study is a prospective quantative study of guilt, shame and depression in NSCLC pts relative to BC and PC pts. Methods: Stage IV NSCLC, BC, and PC pts completed 3 surveys over 6 months (T1–3). The survey was a 20 minute questionnaire, including standardized tests of shame, guilt, and depression, as well as several investigator designed questions (IDQ) and demographic data. Goal enrollment is 94 NSCLC pts, 47 BC pts and 47 PC pts, with 80% power to detect a 0.75 point difference in the State Shame and Guilt Scale (SSGS, scores 1 to 5). Data for the first 159 pts with T1 and T2 data are presented. Means of the pooled results for the SSGS and IDQ were compared via analysis of variance; impact of cancer (CA) and gender were performed via regression analyses. Results: 92 NSCLC, 41 PC, and 26 BC patients have been enrolled. 55% of participants are male, mean age is 66 years (35–87), and 67% are married. There is a diverse range of incomes and education. IDQ were combined into a composite score, “self-blame” (reliable, internal consistency score 0.76). Results at T2 are presented in the table. Multiple regression analysis performed on women found that type of CA predicted depression, mediated by shame and guilt. Conclusions: NSCLC is associated with increased levels of guilt and shame leading to depression, relative to BC and PC. This disparity is particularly striking amongst women with NSCLC. Guilt, shame and depression may hamper a pt’s ability to advocate for themselves and may affect treatment outcomes. Further investigation is warranted as to whether a targeted intervention may improve levels of stigma amongst NSCLC pts. Funding provided by an American Medical Association Seed Grant. [Table: see text] No significant financial relationships to disclose.
Sorafenib combined with carboplatin/paclitaxel for advanced non-small cell lung cancer: A phase I subset analysis
Authors: Schiller J. H. , Flaherty K. T. , Redlinger M. , Binger K. , Eun J. , Petrenciuc O. , O’Dwyer P. 
Published: March 2020

7194 Background: The EGFR is often overexpressed in advanced non-small-cell lung cancer (NSCLC) - a solid tumor associated with a poor prognosis. Oncogenic k-ras mutations and raised serum VEGF predict poor outcome in NSCLC. In vitro targets of sorafenib include Raf, which is downstream of EGFR and k-ras. Sorafenib also targets the VEGFR-2/-3 tyrosine kinases, involved in tumor angiogenesis. Preclinically, sorafenib targets the tumor and tumor endothelium to inhibit tumor growth. Methods: This subanalysis of a Phase I trial with a Phase II expansion in NSCLC was performed to evaluate the safety (adverse events graded by NCI-CTC 2.0) and preliminary anti-tumor activity (response by RECIST, PFS, TTP) of oral sorafenib combined with carboplatin/paclitaxel in 15 patients with advanced, progressive NSCLC. Carboplatin (AUC 6)/paclitaxel (225 mg/m2) was administered on Day 1, and sorafenib (100, 200, or 400 mg bid) on Days 2–18 of each 21-day treatment cycle. Results: Drug-related adverse events were reported by 73% (11/15) of patients, but were mostly grade 1–2 (53%) in severity; none was grade 4. The most common drug-related events at any grade were dermatologic (Hand-foot skin reaction [20%]; rash [60%]), and gastrointestinal (diarrhea [20%]; anorexia [13%]). There were no drug-related cardiovascular adverse events. Three patients reported grade 1–2 drug-related bleeding events (epistaxis n = 2; other n = 1). Of the 14 evaluable patients, four (29%) had a confirmed PR as best response, seven (50%) had SD, and three (21%) had PD. Therefore, the disease control rate (objective response plus SD) was 79%. Duration of response was 25 weeks. Median PFS was 34 weeks. Discussion: This sorafenib combination was well tolerated and showed promising preliminary anti-tumor activity in patients with advanced, progressive NSCLC. [Table: see text]
Prognostic role of promoter hypermethylation of death-associated protein (DAP) kinase and p16 genes in early-stage non-small cell lung cancer
Authors: Lu C. , Wistuba I. , Zhou X. , Bekele B. N. , Putnam J. B. , Correa A. , Mao L. 
Published: March 2020

7216 Background: Promoter hypermethylation is an epigenetic mechanism of gene silencing commonly observed in malignancies. Prior studies suggest that hypermethylation of DAP kinase and p16, genes involved in apoptosis and cell cycle regulation, respectively, are associated with poorer survival in NSCLC patients. In this study we investigate the prognostic role of DAP kinase and p16 promoter hypermethylation in a large cohort of early-stage NSCLC patients. Methods: Pathologic stage I and II NSCLC patients who underwent complete surgical resection between 1/97 and 12/01 at our institution and did not receive adjuvant therapy were identified. Formalin-fixed, paraffin-embedded tissue blocks were retrieved, and p16 and DAP kinase promoter methylation status was determined by methylation specific PCR. Two-sided statistical analyses were performed to determine associations between methylation status, clinicopathologic characteristics, and survival. Results: DAP kinase and p16 methylation status was observed in 36.3% (97 of 267) and 36.4% (95 of 261) cases, respectively. Subject characteristics: 55% female, 77% former/current smokers, 81% stage I, 19% stage II, 61% adenocarcinoma, 29% squamous carcinoma, 63% performance status (PS) 0, 37% PS 1,93% < 5% weight loss. Recurrent NSCLC and death occurred in 21.3% and 38% of cases, respectively. No significant associations were observed between DAP kinase methylation status and subject characteristics. P16 methylation was associated with moderate/high grade (p = 0.03). A higher frequency of p16 methylation was observed in ever vs never smokers (39% vs 28%, p = 0.17). Preliminary analyses do not demonstrate significant associations between methylation status and overall survival (p16 p = 0.13; DAP kinase p = 0.56) or disease-free survival (p16 p = 0.36; DAP kinase p = 0.71). Conclusions: In this relatively large cohort of early-stage NSCLC patients, we did not detect significant associations between p16 and DAP kinase promoter methylation and clinical outcome. Further subset analyses stratified by gender and histology will be performed. The prognostic role of these biomarkers in NSCLC remains unclear. No significant financial relationships to disclose.
Differential canonical pathways derived from microarrays using RNA from paraffin-embedded non-small cell lung cancer tissue
Authors: Joshi M. M. , Petersen R. P. , Conlon D. H. , Tanaka K. , Shimizu D. , Kuramochi H. , Williams M. , Danenberg P. V. , Danenberg K. D. , Harpole D. H. 
Published: March 2020

7226 Background: Several molecular targets have been approved for use in patients with non-small cell lung cancer (NSCLC) and several hundred are in various phases of investigation. However, the efficacy of these targets range from 5–15% of the overall population of NSCLC patients. Therefore, the challenge remains to appropriately match the most active target with the individual patient. Our goal was to investigate a novel strategy for identifying active pathways from formalin-fixed, paraffin-embedded (FFPE) NSCLC samples. Methods: Ten 5 um sections of FFPE tumor were collected from 66 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term (<2 year cancer death) survivors. Sixty samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. Resulting cRNA was hybridized to the U133 plus 2.0 GeneChip. A differentially expressed gene list between long and short survivors was determined. These data were also analyzed for differential canonical pathways using Ingenuity Pathway Analysis. Results: We identified the differential pathways indicated by the unique gene signatures between early stage patients surviving <2 yrs and >2 yrs for both adenocarcinomas and squamous cell carcinomas. Adenocarcinoma pathways that differed between short- and long-term survivors were: G2M DNA damage checkpoint, EGF, estrogen receptor, hypoxia, VEGF, PDGF, IL-6 JAK/Stat and neurotrophin/Trk signaling. In contrast, for squamous cell carcinomas the main differing pathways were: Wnt/b-catenin signaling and retinol metabolism. Conclusions: We have demonstrated the feasibility of generating differential canonical pathways from FFPE NSCLC specimens which may serve as a tool to guide selection of molecular targets for the individual patient. In addition, these pathways may be a rational method for selecting the correct subset of patients most likely to respond to agents being investigated in early phase clinical trials. These data require validation in a larger prospective study. [Table: see text]
Single-agent bortezomib in previously untreated multiple myeloma (MM): Results of a phase II multicenter study
Authors: Anderson K. , Richardson P. , Chanan-Khan A. , Schlossman R. , Munshi N. , Oaklander A. , Heffner L. , Hassoun H. , Avigan D. , Amato A. 
Published: March 2020

7504 Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM. Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count < 30 × 109/L, or grade > 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR) [Bladé criteria], time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m2 (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34). Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1–2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS. Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification. [Table: see text]
Dose-escalated CHOP plus etoposide (Hi-CHOEP) is not superior to base-line CHOEP in young good-prognosis patients with aggressive lymphoma: Results of a randomized DSHNHL trial
Authors: Pfreundschuh M. G. , Zeynalova S. , Duehrsen U. , Pflueger K. , Vrieling T. , Berdel W. E. , Mergenthaler H. , Einsele H. , Bentz M. , Schmitz N. , Loeffler M. 
Published: March 2020

7513 Background: The addition of etoposide to CHOP (CHOEP) resulted in improved outcome of young patients with good-prognosis aggressive lymphoma (NHL-B1 trial; Blood 2004, 104:626). In order to improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem cell support in a preceding dose-escalation study (Hi-CHOEP: C: 1400 mg/m2, H: 65 mg/m2, O: 2 mg, E: 175 mg/m2 × 3, P: 100 mg × 5) was compared to baseline CHOEP-21 in a randomized trial. Methods: Intention-to-treat-analysis comparing CHOEP-21 (n = 194) with Hi-CHOEP (n = 195) in 389 young (18–60 years) patients with good-prognosis (aaIPI = 0,1) aggressive lymphoma. Results: Despite excellent adherence to the protocol (median relative dose of myelosuppressive drugs CHOEP-21: 98%; Hi-CHOEP: 93%), CR/CRu (78.4% vs. 79.5%; p = 0.783), and progressions (12.4% vs. 9.7%; p = 0.409) were not significantly different. After 37 months median observation, there was no difference in the primary endpoint time to treatment failure (64% vs. 68%; p = 0.639) nor overall survival (83% vs. 86%; p = 0.849). Neither low-risk nor low-intermediate risk patients profited from Hi-CHOEP. In a multivariate analysis, elevated LDH and advanced stage (III&IV) were confirmed as independent risk factors for TTF and survival. Hi-CHOEP was considerably more toxic than CHOEP-21 (grade 3 & 4 leukocytopenia 100% vs. 87.2%, p < 0.001, thrombocytopenia 80.8% vs. 9.6%, p < 0.001; infections 19.7% vs. 5.4%, p ≤ 0.001; therapy associated deaths 2.6% vs. 0%). Conclusions: Due to its equal efficacy and lower toxicity, CHOEP-21 is to be preferred over dose-escalated Hi-CHOEP. Our results indicate that dose escalation (in contrast to dose-densification and/or addition of rituximab) does not hold promise for young good-prognosis patients with aggressive lymphoma. Supported by Deutsche Krebshilfe. [Table: see text]
Effect on survival of treatment associated deep vein thrombosis in newly diagnosed multiple myeloma patients
Authors: Zangari M. , Barlogie B. , Cavallo F. , Anaissie E. , Hollmig K. , Manns A. , Karri S. , Mohiuddin A. , Pineda-Roman M. , Bolejack V. , Tricot G. 
Published: March 2020

7549 Background: Cancer patients experiencing thromboembolic disease have a poor prognosis. We report the effect on survival of treatment-associated DVT in myeloma patients. Methods: 668 newly diagnosed patients with progressive or symptomatic MM were enrolled in our Total Therapy 2 study, which included induction phase with VAD, DCEP, CAD and DCEP followed by high dose chemotherapy and tandem transplants. Patients were randomly assigned to receive Thalidomide or not during the whole treatment. Both arms otherwise received identical chemotherapy. Patients were followed and when clinically indicated underwent radiological studies to confirm a suspected DVT. If present, they were treated with low-molecular weight heparin followed by warfarin. Results: With a median follow up of 47 months a total of 158 patients experienced DVT; the median age was 57 years, 59% were male, 24% were IgA, 197 patients (30%) had abnormal cytogenetics (CA) including 100 patients with deletion of chromosome 13. The baseline characteristics were balanced between patients with and without DVT, with the exception of female gender, which was more prominent in the non DVT group (32% vs 46%, p = .018) on thalidomide, whereas CRP ≥ 8 mg/dl (57% vs 33%, p = .001), and IL6 > 9 pg/ml (47% vs 14%, p < .001) were more frequently observed in the DVT group on no thalidomide. Within each arm of the trial no significant differences in prognostic factors for survival (chromosomal abnormalities, low albumin level, β2-microglobulin, CRP) were seen. DVT status did not affect EFS (p = .3) or OS (p = .3) for the entire group, but a statistically longer EFS (p = .03) was observed in patients who developed a thromboembolic episode in the non thalidomide arm. No effect on survival (EFS p = .3; OS p = .95) was seen in the thalidomide arm. Conclusions: Development of DVT in newly diagnosed myeloma patients treated with chemotherapy ± thalidomide, does not affect overall survival. Patients not exposed to thalidomide who developed thrombosis during chemotherapy had significantly longer EFS. Our observation supports a survival benefit associated with anticoagulation therapy in cancer patients. [Table: see text]
Point mutation of C-terminal region of CD20 molecule predicts rituximab-induced complement-dependent cytotoxicity and clinical response to rituximab in non-Hodgkin’s lymphoma
Authors: Terui Y. , Mishima Y. , Mishima Y. , Yokoyama M. , Hatake K. , Sugimura N. , Kojima K. , Sakurai T. , Takeuchi K. 
Published: March 2020

7563 Background: Although rituximab is commonly used as induction and maintenance therapy for malignant lymphoma, some patients become refractory to treatment and the mechanism of resistance is unclear. The aim of this study was to investigate the relationship between CD20 mutations and rituximab resistance. Methods: To investigate whether CD20 mutations affect response to rituximab, fresh CD19+ lymphoma cells were isolated from the lymph nodes, or bone marrow of 68 patients with NHL. The cells were subsequently sorted by flow cytometry. RNA was prepared from the isolated cells and RT-PCR was performed. The PCR products were sequenced, subcloned into an expression vector pTARGET, transfected into K562 cells. CD20 expression was examined by flow cytometry and laser scanning confocal microscopy. Results: In all 68 patients, overall response rate (CR+CRu+PR) to rituximab was 91.2% (62/68), but t four cases became PD after PR. DNA sequence analysis revealed that point mutations were mostly observed in three CD20 domains - extracellular/cytoplasmic domains, the third transmembrane domain and the C-terminal cytoplasmic domain. Two cases had point mutations in extracellular/cytoplasmic domains, one patient had point mutations in the transmembrane domain, four cases showed point mutations in the C-terminal cytoplasmic domain and six cases had non-specific CD20 mutations, which did not affect CD20 expression. 56 patients showed no mutations of CD20 gene. CD20 expression was very weak in patients with point mutations in the C-terminal cytoplasmic domain, whereas expression was increased in patients with point mutations in the transmembrane domain. Conclusions: Point mutations in CD20 may cause rituximab resistance and identification of CD20 mutations upon diagnosis may help to predict a patient’s response to rituximab. No significant financial relationships to disclose.