bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of MBL2 genotypes wtih infections and outcome after allogeneic stem cell transplantation
Authors: Papanicolaou G. A. , Mihu C. , Kadeishvili K. , Doll M. , Stokar D. , Buchbinder A. , Hsu K. , O'Reilly R. , Pamer E. G. , Satagopan J. 
Published: March 2020

7100 Background: Low MBL2 concentration and MBL2 genotype variants have been associated with an increased risk of infection. Our objective was to correlate MBL2 genotypes with specific infections and outcome of HSCT. Methods: 125 non- consecutive, non-selected HSCT were examined. Patients were classified as high or low risk group based on status of underlying disease. Antifungal prophylaxis consisted of fluconazole 400 mg daily. Patients on steroids received mould prophylaxis. There was no routine antibacterial prophylaxis. Microbiologically confirmed infections were recorded. Genotype was determined by PR-Melting Curve Analysis on blood or buccal swab specimens. MBL genotype was classified as wild-type: A/A (MBL-sufficient, MBL-S) or variant-type: A/O, O/O (MBL deficient, MBL- D). Patients were followed for up to 2 years. Analyses of categorical variables were performed using the Fisher exact test and the Log-Rank test for time to event. Results: Seventy-one (58.2%) patients were homozygous for wild-type MBL2 (AA), 43 (35.3%) were heterozygous (A/0) and 8 (6.5%) were homozygous for variant genotypes (OO). MBL-D group had higher incidence of fungal infections (20% vs 7%, p=0.05), and in particular Aspergillosis (12% vs 3%, p=0.05). MBL-D was associated with a trend for higher rates of bacterial infections (63% vs 46%, p=0.10) and total number of bacterial infections (p=0.10). Rates of respiratory and enteric viral infections or CMV were similar in MBL-D and MBL-S groups (41% vs 38%, p=0.9 and 58% vs. 54% p=1.0 respectively). Patients with MBL-D genotype were at a disadvantage in relapse-free (RFS) and overall survival (OS), (p<0.01 and p=.08). This disadvantage was also observed when stratified by disease risk groups. The estimated 2-year relapse-free survival rate was 30% compared to 53% for MBL-D vs. MBL-S patients (p<0.01). Conclusions: 1) Patients with variant MBL genotype (MBL-D) had a trend for increased incidence and number of bacterial infections. 2) MBL-D genotype and graft versus host disease were risk factors for aspergillosis. 3) MBL-D genotype was associated with worse overall survival and relapse free survival post HSCT. These data suggest that MBL-D patients have impaired immune function compared with MBL-S patients and is consistent with animal data. [Table: see text]
r-HuEPO 40,000 U one time/week before high-dose melphalan allows a tandem autologous peripheral stem-cell transplantation without red blood cell transfusion in multiple myeloma patients: A pilot study
Authors: Martino M. V. , Console G. , Massara E. , Moscato T. , Callea I. , Gatto F. , Pucci G. , Dattola A. , Spiniello E. , Iacopino P. 
Published: March 2020

7103 Purpose: To decrease red blood cell (RBC) transfusion requirements during a tandem high-dose melphalan (HDM) for multiple myeloma (MM) patients (PTS), we conducted a pilot study to assess the effect of high-dose of recombinant human erythropoietin (rHuEpo) started during chemotherapy before the first HDM and autologous peripheral blood stem-cell transplantation (APBSCT). Patients and Methods: After induction chemotherapy with VAD, 14 consecutive PTS with MM, stage III, median age 58 years (range 42–62), were mobilized with cyclophosphamide (3–4 g/m2) to collect peripheral blood stem cells (PBSC) and entered a study consisting of two HDM (200 mg/m2) with APBSCT. Enrolled patients received rHuEpo (40,000 U subcutaneously one time/week) as soon as their hemoglobin (Hb) level fell <11 g/dl during induction chemotherapy. rHuEpo was continued at the same dose during PBSC collection and was reintroduced at the time of discharge after the first transplant up to the admission for the second one. If the Hb level exceeded 13 g/dl at any time, rHuEpo was withheld until the concentration decreased to <11 g/dl, at which time it was restarted. Results were compared to those of 20 tandem HDM and APBSCT performed in 15 consecutive historical MM controls matched for hematological parameters. Results: rHuEpo increased the hemoglobin (Hb) level from 10.1 ± 2.5 g/dl at diagnosis to 12.8 ± 2 g/dl at the time of the first HDM; no major adverse effects occurred. Compared to historical controls (46.6%, 7/15), RBC transfusion requirements were significantly lower for rHuEpo recipients (6.6%, 1/14) (P=0.00001). After the tandem HDM and APSCT, fewer RBC transfusions were needed: 3.3 and 1 RBC units for controls and rHuEpo recipients, respectively (P=0.006). Conclusion: The administration of high dose of rHuEpo during induction chemotherapy and interval beetween the first and second HDM cycle permit the realitazion of tandem chemotherapic program with a reduction of blood product support. No significant financial relationships to disclose.
Efficacy and safety of axitinib (AG-013736; AG) in patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase II trial
Authors: Schiller J. H. , Larson T. , Ou S. I. , Limentani S. A. , Sandler A. B. , Vokes E. E. , Kim S. , Liau K. F. , Bycott P. W. , Olszanski A. J. 
Published: March 2020

7507 Background: A correlation between vascular endothelial growth factor (VEGF), microvessel density, and prognosis has been reported in pts with NSCLC. AG is a small molecule inhibitor of the receptor tyrosine kinases, with picomolar potency against VEGFR 1, 2 and 3 and nanomolar potency against PDGFR-β and KIT. This is an open-label, multicenter phase II study examining the efficacy and safety of AG in pts with advanced NSCLC. Methods: Pts with stage IIIB or metastatic NSCLC received AG 5 mg BID. Eligibility criteria included measurable disease and ECOG performance status of 0 or 1. A Simon 2-stage minimax design was used with 18 pts in the first stage plus an additional 14 in the second stage if 1/18 pts responded. The primary endpoint was response rate (RR) according to RECIST. Results: A total of 32 pts were enrolled: median age was 66 yrs (39–80); histologies were adenocarcinoma (75%), squamous cell carcinoma (9%), and not otherwise specified (16%); 56% male/44% female; 72% received prior chemotherapy, 47% prior surgery, 47% prior radiotherapy, 9% investigational therapy, 3% immunotherapy, and 13% were treatment-naïve. Mean duration of treatment was 93 days (1–271). Three (9.4%) investigator confirmed responses were reported with a 95% confidence interval (CI) of 2, 25. Median duration of response was 9.4 months (mo). Median survival was 12.8 mo (95% CI: 9.9 mo, undefined) and progression-free survival was 5.8 mo (95% CI: 3.8 mo, 10.2 mo). 26 (81%) pts discontinued treatment: lack of efficacy 19 pts (59%), adverse events 5 pts (16%), death 1 pt (3%), and withdrawal of consent 1 pt (3%). Grade 3/4 toxicities (=5%) were fatigue (22%), diarrhea (6%), hypertension (6%) and hyponatremia (6%). Conclusions: AG demonstrates single- agent activity in pts with advanced NSCLC. Therapy is well tolerated with manageable toxicity in this population. Further investigation in this setting is warranted. [Table: see text]
Cisplatin (Cis)/etoposide (VP16) compared to cis/irinotecan (CPT11) in extensive-stage small cell lung cancer (E-SCLC): Pharmacogenomic (PG) and comparative toxicity analysis of JCOG 9511 and SWOG 0124
Authors: Lara P. , Redman M. , Lenz H. , Gordon M. , Shibata T. , Fukuda H. , Tamura T. , Saijo N. , Natale R. , Gandara D. 
Published: March 2020

7524 Introduction: J9511 demonstrated a significant survival benefit for Cis/CPT11 over Cis/VP16 in Japanese patients (pts) with E-SCLC (Noda, et al. NEJM 2002). S0124 is the confirmatory North American phase III trial (accrual completed) using the identical J9511 protocol. We hypothesized that toxicities would differ between North American & Japanese pts due in part to differences in the distribution of genetic polymorphisms involved in chemotherapy metabolism. Methods: Toxicity data were compared among 706 pts enrolled in J9511 & S0124 receiving common treatment using a logistic model adjusted for age, sex, and performance status (PS). Select polymorphisms of the UGT1A1, ABCB1, & OATP genes in genomic DNA were evaluated in 142 pts in S0124 only (67 Cis/CPT11; 75 Cis/VP16). Associations between toxicity & genotype within each arm were assessed using logistic regression. Results: Pt demographics for J9511 & S0124 respectively: Mean age − 61 & 62 years; Male sex − 131 (86%) & 315 (57%); PS 0 − 19 (13%) & 173 (31%); PS>0 − 133 (87%) & 372 (68%). Comparative toxicities (≥ grade 3) are summarized ( table ). PG analysis in S0124 pts: ABCB1 (C3435T) T/T was associated with an increased risk of CPT11 grade 3+ diarrhea (p=0.04) versus C/C and C/T. UGT1A1 (G3156A) A/A was associated with increased risk of CPT11 neutropenia (p=0.009) & leukopenia (p=0.05). UGT1A1*28 TA7, typically associated with increased CPT11 toxicity, was seen in only 4 pts (2 Cis/CPT11; 2 Cis/VP16); thus no correlation was done. No gene tested was associated with VP16 toxicity. Conclusions: Significant differences in treatment-related myelosuppression exist between J9511 and S0124 pt populations. Certain polymorphisms in genes involved in CPT11 metabolism are significantly associated with CPT11 toxicities in S0124. Additional analyses are ongoing. These results support the hypothesis that toxicities may be associated with distribution of genetic polymorphisms. No significant financial relationships to disclose. [Table: see text]
Induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone for unresectable stage III non-small cell lung cancer (NSCLC): Randomized phase III trial
Authors: Kim S. , Kim M. , Choi E. , Sohn H. , Lee D. , Suh C. , Lee J. , Yang H. , Hong J. , Kim W. 
Published: March 2020

7528 Background: We conducted a prospective randomized phase III trial comparing induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) versus immediate CCRT to evaluate whether the addition of induction chemotherapy would result in improved survival. Methods: Patients with unresectable stage III NSCLC, ECOG PS 0–1, and weight loss up to 10% were eligible. They were randomized to receive either induction chemotherapy followed by CCRT (arm A) or immediate CCRT (arm B) after stratification for stage (T4N0–2, T1–3N3, T4N3, and stage IIIA), histology (squamous vs non-squamous), and SCLN positivity. Induction chemotherapy consisted of two cycles of gemcitabine (1,000 mg/m2 D1, D8) and cisplatin (70 mg/m2 D1) q 21days. Chemotherapy during CCRT consisted of 6 cycles of weekly paclitaxel (50 mg/m2) and cisplatin (20 mg/m2). Radiation therapy performed with hypofractionated scheme (2.2 Gy/fraction, once a day) and total dose was 66 Gy. Irradiated volume encompassed gross tumor plus 1.0 cm margin. Results: Between March 2003 and June 2006, 134 patients were enrolled. 92% of patients were male and 60% were age 60 or older. Objective tumor response was obtained in 38% after induction chemotherapy. Response rates after completion of CCRT were 72% (95% CI, 61%–83%) on arm A and 79% (95% CI, 69%–89%) on arm B. Grade 3/4 toxicities during induction chemotherapy consisted mainly of neutropenia (11%/3%). During CCRT, grade 3/4 neutropenia was noted in 8%/5% (arm A) versus in 8%/0% (arm B), grade 3 anemia was 8% vs 0%, grade 3 thrombocytopenia 5% vs 0%, and grade 3 esophagitis 16% vs 16%. At median follow-up of 28 months, median survival was 12.6 months (95% CI, 8.6–16.7 months) on arm A versus 18.2 months (95% CI, 11.7–24.8 months) on arm B (P=0.18). Two year survival estimates was 25% (15%–35%) and 43% (31%–55%), respectively. Median progression free survival was 7.5 months (95% CI, 5.6–9.4 months) on arm A and 11.6 months (95% CI, 9.6–13.6 months) on arm B (P=0.04). Conclusions: The addition of induction chemotherapy to CCRT failed to increase the survival of unresectable stage III NSCLC over immediate CCRT. Moreover, the progression free survival was inferior to immediate CCRT. No significant financial relationships to disclose.
Erlotinib as initial therapy in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2: A SWOG phase II trial (S0341)
Authors: Hesketh P. J. , Chansky K. , Wozniak A. J. , Mack P. , Lara P. N. , Franklin W. A. , Hirsch F. R. , Crowley J. , Gandara D. R. 
Published: March 2020

7536 Background: Patients (pts) with advanced NSCLC and PS 2 have an inferior survival compared with good PS pts. Single agent and combination chemotherapy have been used with modest success with toxicity often limiting treatment. Targeted agents such as the EGFR tyrosine kinase inhibitor erlotinib (E) offer an alternative which may confer comparable benefit with better tolerance. This phase II trial of E in unselected chemotherapy-naive pts with advanced NSCLC and PS 2 was performed to obtain preliminary data regarding efficacy and EGFR biology in this pt population, and to set the stage for a subsequent randomized trial of E vs.chemotherapy, in pts selected for EGFR expression. Methods: Eligibility: stage IIIB (pleural effusion)/IV NSCLC; measurable disease; PS 2; no prior chemotherapy/biologic treatment for NSCLC. Treatment: E 150 mg orally daily. Molecular correlative studies:EGFR protein expression (IHC), gene copy (FISH), mutation analysis. Results: Pts: 82; 73 eligible; 72 fully evaluable; age (median) 74.4; M/F 47%/53%; current/former smoker 91%; stage IIIB/V 12%/88%; adenoca 54%. Treatment was well tolerated. Five pts (7%) had a grade 4 toxicity (fatigue 3 pts; dyspnea 2 pts). Most common grade 3 toxicities: fatigue 9 pts (13%); rash 7 pts (10%); diarrhea 5 pts (7%); anorexia 5 pts (7%). There was 1 possible treatment related death due to pneumonitis. One complete (1%) and 5 (7%) partial responses were noted. Stable disease was seen in 25 pts (35%) for an overall disease control rate (DCR) of 43% (31 pts). Progression free survival: 2.1 months (95% CI 1.5 –3.1); Median survival: 5.0 months (95 % CI 3.5 –7.3). One year survival: 22% (95% CI 12 –32%). Analysis of molecular correlates is ongoing. Conclusions: Single agent erlotinib is a well tolerated treatment for chemotherapy- naive patients with advanced NSCLC and PS 2 with an overall DCR of 43% and median survival of 5 months. These efficacy results are comparable to the outcome seen in SWOG trial S0027 in PS 2 pts employing sequential vinorelbine and docetaxel. We hypothesize that pt selection by an EGFR biomarker strategy will improve results with E, and that E will be superior to chemotherapy in this selected population.This trial design is under development within SWOG at present. [Table: see text]
Randomized phase II study of vandetanib (VAN) alone or in combination with carboplatin and paclitaxel (CP) as first-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Heymach J. , Paz-Ares L. , De Braud F. , Sebastian M. , Stewart D. J. , Eberhardt W. , Herbst R. S. , Krebs A. , Langmuir P. , Johnson B. E. 
Published: March 2020

7544 Background: VAN (ZD6474) is a once-daily oral agent that selectively inhibits VEGFR, EGFR and RET signaling. This randomized phase II trial investigated VAN alone or in combination with CP vs CP. Methods: Eligible patients (pts) had previously untreated locally advanced or metastatic (IIIB-IV) NSCLC. The primary objective was to determine whether VAN (300 mg/day) ± CP (C, target AUCss = 6 mg/ml·min; P; 200 mg/m2 iv) prolonged progression-free survival (PFS) vs CP (75% power to detect 30% prolongation; 1-sided P=0.2). An initial run-in phase had established VAN 300 mg/day as an appropriate dose to be given with CP. Results: A total of 181 pts (median age 61 yrs, range 27–83) received VAN (n=73), VAN + CP (n=56) or CP (n=52). The primary objective was met, with VAN + CP prolonging PFS vs CP (HR = 0.76, 95% CI 0.50–1.15; P=0.098): median PFS = 24 wks (VAN + CP) and 23 wks (CP). The VAN monotherapy arm was stopped early after a planned interim PFS analysis met the criterion for discontinuation (HR > 1.33 vs CP). The objective response rates were 32%, 25% and 7% for VAN + CP, CP and VAN, respectively. Overall survival (OS), a secondary endpoint, was not significantly different between pts receiving VAN + CP or CP (HR = 1.07, 95% CI 0.63–1.81; P=0.595). Exploratory subgroup analyses suggest advantages in PFS and OS for VAN + CP vs CP for the 56 female pts. There was a higher incidence of some adverse events with VAN + CP vs CP, including rash (64% vs 33%), diarrhea (53% vs 32%), asymptomatic QTc-related events (22% vs 4%) and hypertension (32% vs 4%). Pts receiving VAN + CP, including 7 who entered with CNS metastases and 11 with squamous histology, did not experience any intracranial bleeding, or hemoptysis of CTC grade 2 or higher. A biomarker analysis, including circulating endothelial cells and 35 plasma angiogenic factors and cytokines, suggests several potential markers predictive of clinical outcome and will be reported separately. Conclusions: In this randomized phase II trial of 1st-line advanced NSCLC, VAN + CP met the primary endpoint of prolonging PFS vs CP alone but did not provide a detectable survival advantage. No significant financial relationships to disclose.
Phase II study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Spira A. I. , Iannotti N. O. , Savin M. A. , Neubauer M. , Gabrail N. Y. , Yanagihara R. , Datta K. K. , Zang E. A. , Fields S. Z. , Das A. 
Published: March 2020

7546 Background: Eribulin is a structurally-simplified, fully synthetic analog of the marine sponge natural product halichondrin B. Eribulin inhibits microtubule dynamics via a mechanistically novel mode of action. Methods: An open-label, single-arm, Phase II study of eribulin was conducted in patients with advanced NSCLC (ECOG of 0 or 1) who were treated with platinum-based doublet chemotherapy and stratified by prior taxane exposure. A total of 103 patients (83 with prior taxanes and 20 taxane naïve) were treated with eribulin (1.4 mg/m2), administered as a bolus infusion over 2 –5 minutes on Days 1, 8, and 15 of a 28-day cycle (N=77). Due to delays or skipped doses secondary to myelosuppression at Day 15 with recovery by Day 21, the protocol was amended to a schedule of Days 1 and 8 of a 21-day cycle (N=26). The primary efficacy endpoint was objective response rate. Independent radiologic review was used to confirm responses. Results: Of 106 enrolled patients, 103 received eribulin. Median age was 65 years and median number of prior therapies was 2, including taxanes (81%), gemcitabine (40%), pemetrexed (23%), and EGFR inhibitors (34%). Median number of cycles administered was 3 (range 1–15). Drug related toxicities included neutropenia grade 3 (23%) and 4 (26%), febrile neutropenia (4%), grade 3 fatigue (11%), grade 3 nausea (2%), and peripheral neuropathy grade 1/2 (37%) and 3 (2%). Based on RECIST criteria, the overall response rate (all partial responses) was 9.7% (95% CI: 4.0–15.4 %), with 10.8% PR in taxane pre-treated, and 5% PR in taxane naïve patients. Overall disease control rate (PR + SD) was 55.3%. 12-week progression free survival (PFS) rate was 53.0% (95% CI: 42.6–63.3%) and median PFS was 102 days (range 1–408+). Median duration of response was 176 days (range 50–291+), and median overall survival was 287 days (range 16–423+). The one year survival rate was 46.4% (95% CI: 34.9–58.0%). Conclusions: In this group of NSCLC patients who were treated with a median of two prior therapies, consisting in the majority of cases of two cytotoxic regimens, eribulin demonstrated an overall PR rate of 9.7% (10.8% in the taxane pre-treated) and 9.6 months median survival. No significant financial relationships to disclose.
High insulin-like growth factor 1 receptor (IGF1R) expression is associated with poor survival in surgically treated non-small cell lung cancer (NSCLC) patients (pts)
Authors: Merrick D. T. , Dziadziuszko R. , Szostakiewicz B. , Szymanowska A. , Rzyman W. , Jassem E. , Jassem J. , Franklin W. A. , Bunn P. A. , Hirsch F. R. 
Published: March 2020

7550 Background: IGF1R represents a novel molecular target in NSCLC. We aimed to evaluate the association between IGF1R expression, clinical characteristics and survival in operable NSCLC pts. Methods: 184 consecutive surgically treated pts (median follow up of 32 months [range: 13–51 months]) were included in the study. There were 23% females, 55% pts with squamous cell carcinoma, 28% with adenocarcinoma, 3% with large cell carcinoma, 13% with mixed carcinoma and 1% with other types, 5% were never-smokers. Median age was 64 years (range: 37–85 years). Pathological stage I was diagnosed in 41%, stage II –22%, stage III –33% and stage IV –4% pts. Induction or adjuvant treatment was not routinely used. IGF1R was evaluated in tissue microarray by immunohistochemistry and scored by two observers according to H-score, taking into account proportion of cells with positive staining times staining intensity (scale 0–400). Results: IGF1R IHC expression was low in analyzed samples (median H-score 20, range: 0–223). Higher IGF1R score was observed in adenocarcinomas vs. squamous-cell carcinomas (p=0.02) and never-smokers vs. smokers (p=0.02). IGF1R score did not depend on stage (p=0.98) and sex (p=0.83). When analyzed as a continuous variable, IGF1R score tended to associate with worse survival in the entire cohort (p=0.10), and was significantly associated with inferior survival in patients with complete (R0) resections (p=0.04). When categorized with cut-off point of 50 (30% of patients positive), IGF1R expression was again associated with poor survival (p=0.05). This association was confined to pathological stage I (hazard ratio, HR=3.07; 95% confidence interval, CI=1.41–6.70, p=0.005) vs. all other stages (HR=1.03; 95% CI=0.63–1.70, p=0.90), and to patients with adenocarcinoma histology (HR=2.67; 95%CI=1.17–6.70, p=0.02 vs. all other histologies (HR=1.28; 95%CI=0.79–2.11, p=0.32). Conclusion: In this cohort of operable NSCLC pts, high IGF1R expression was associated with never-smoking history, adenocarcinoma histology, and poor survival, particularly in stage I disease and in patients with adenocarcinoma. These results support involvement of IGF pathway in the progression of early-stage NSCLC. No significant financial relationships to disclose.