bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor cell (CTC) as a significant clinical marker in epithelioid-type malignant pleural mesothelioma (MPM).
Authors: Yoneda Kazue , Tanaka Fumihiro , Fukuda Shunichi , Orui Hayato , Hashimoto Masaki , Takuwa Teruhisa , Okumura Yoshitomo , Matsumoto Seiji , Kondo Nobuyuki , Sato Ayuko , Tsujimura Tohru , Tsubota Noriaki , Fukuoka Kazuya , Nakano Takashi , Hasegawa Seiki 
Published: March 2020

7080 Background: Circulating tumor cell (CTC) is a surrogate of distant metastasis, and our preliminary study suggested that CTC detected by an EpCAM-based immuno-magnetic separation system (“CellSearch”) was a useful clinical marker in the diagnosis of malignant pleural mesothelioma (MPM) (Tanaka F. et al ASCO 2008). Methods: Patients who presented at our institute to receive pleural biopsy with suspicion of MPM were prospectively enrolled. CTCs in 7.5mL of peripheral blood were quantitatively evaluated with the CellSearch system. Results: Among 136 eligible patients, 104 were finally diagnosed with MPM, and 32 were with non-malignant diseases (NM). CTC was positive (CTC≥1) in 32.7% (37/104) of MPM pts, and in 9.4% (3/32) of NM pts (p=0.011). CTC-count was significantly higher in MPM (range, 0-9) than in NM (range, 0-1; p=0.007). According to a ROC curve analysis, the CTC-test provided a significant diagnostic performance in discrimination between MPM and NM (AUC= 0.623; P=0.036). Among MPM pts, CTC-positivity and CTC-count were significantly increased with tumor progression (p=0.026 and p=0.008, respectively). For all MPM pts, there was no significant difference in overall survival between CTC-positive and negative pts. However, in a planned subset analysis, CTC was a significant factor to predict poor prognosis (median survival time, 8.0 months for CTC-positive pts, and 20.3 months for negative pts; p=0.012) in pts with epithelioid-type MPM in which CTC was exclusively positive; a multivariate analysis confirmed that CTC, along with PS, was an independent prognostic factor (HR=2.38; P=0.006). Conclusions: CTC was a significant diagnostic marker in discrimination between MPM and NM. CTC-positivity was a significant and independent prognostic factor to predict a poor prognosis of epithelioid MPM. [Table: see text]
Randomized phase II study of recombinant human endostatin in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer (NCT00912392).
Authors: Lu Shun , Li Lu , Luo Yi , Zhang Li , Chen Zhiwei , Gang Wu , Chen Ping , Huang Cheng , Guo Shuliang , Zhang Yiping , Song Xiangqun , Lv Meijun , Li Wei , Hu Chunhong , Hu Cheng-ping 
Published: March 2020

7091 Background: Endostar (recombinant human endostatin) is a novel antiangiogenesis drug developed in China for non-small cell lung cancer (NSCLC). Because of promising efficacy signals, we performed a randomized phase II trial to assess the efficacy and safety of adding endostar to first-line standard chemotherapy for treatment of chemonaive extensive-stage small-cell lung cancer (SCLC). Methods: Extensive-stage SCLC patients with a performance status 0-2 were randomly assigned to endostar group (endostar 7.5mg/m2 D1-D14 with carboplatin AUC=5 plus etoposide 60mg/m2 D1-D5 of a 21-day cycle for six cycles) or the control group (the same dose of carboplatin plus etoposide). Patients in endostar treatment group with CR, PR and SD were treated with single-agent endostar until progression or unacceptable toxicity. The primary end point is progression-free survival (PFS). The secondary end points are overall survival (OS) and response rate (RR). Results: 140 patients were enrolled from June 2009 to June 2011, and 137 patients were included in full analysis set. 68 patients were randomly assigned to the endostar treatment and 69 patients to the control group. Median age was 57 years and 80.9% for male in the endostar group while median age was 58 years and 85.5% for male in the control group. Median PFS was similar for endostar and control group (6.2 v 5.9 months, P=0.163, HR 0.762; 95%CI 0.519-1.119). Median overall survival (OS) was also similar for both groups (12.4 v 12.3 months, P=0.475, HR 0.835; 95%CI 0.508-1.371). Overall RR were 76.5% for endostar group and 68.1% for the control group (p=0.275). 20 patients in the endostar group completed six cycles of therapy and subsequently treated with single-agent endostar as maintenance therapy and the median PFS and OS were 6.8 and 12.4 months respectively. The rate of ≥ 3 grade adverse events occurred in both groups was similar and no new or unexpected safety signals for endostar were observed. Conclusions: The addition of endostar to carboplatin plus etoposide for treatment of extensive stage SCLC didn’t improve the PFS significantly, with an acceptable toxicity profile. And no improvement in OS was observed.
ABEL trial: A phase II randomized trial adding bemiparin (B) to chemo-radiotherapy (CT-RT) in limited-stage small cell lung cancer (SCLC)—Final results.
Authors: Massuti Bartomeu , Lecumberri Ramon , Lopez Vivanco Guillermo M , Font Albert , Gonzalez-Billalabeitia Enrique , Marti-Ciriquian Juan Luis , Gómez-Codina Jose , Domine Manuel , Bover Isabel , Isla Dolores , Galan Antonio , Gurpide Alfonso , Vicente Vicente , Rosell Rafael , Monreal Mayte , Rocha Eduardo 
Published: March 2020

7095 Background: Low molecular weight heparins (LMWH) could improve therapeutic outcomes in patients with advanced cancer. Heparin binding growth associated molecule is a member of growth factors involved in proliferation, angiogenesis and metastases in SCLC. LMWH associated with CT increase survival in cancer patients (Cochrane DB Systematic Reviews 2011). LMWH do not increase hemorrhagic events when used in neoplastic patients. Methods: Open randomized phase II multicentric trial to assess efficacy and safety of adding bemiparin to standard CT-RT in patients with SCLC with limited disease. CT: Cis/carboplatin + etoposide x 4-6 cycles. Concurrent early thoracic RT (45-50 Gy) and prophylactic cranial irradiation in case of response. Patients (p) were randomly allocated to addition of B at daily subcutaneous dose of 3.500 UI during 26 weeks. Primary end-point: progression free survival (PFS). Secondary end-points: response (RECIST), safety profile (CTC), venours thromboembolic (VTE) and hemorrhagic events incidence and overall survival (OS). Sample size 130 p. Preplanned interim analysis after inclusion 30 p. Results: From October-05 to January/10 39 p were included. Study was closed after interim analysis due to poor recruitment. 38 evaluable p. ITT analysis: 20 CR-RT + B vs 18 CT-RT. No significant disbalance in patient characteristics and prognostic factors. Median PFS 58.6 weeks (CT-RT+B) vs 38.8 w (CT-RT) (HR 2.576; Log-rank p=0,018). RR: 65% (CT-RT+B) vs 55% (CT-RT) (NS); Median OS 161.8 w (CT-RT+B) vs 49.3 w (CT-RT) (HR 2.96; Log-rank p=0,012). 2-year survival rate: 68.6% (CT-RT+B) vs 29.4% (CT-RT) (p=0,0042). Safety: G3-4 AE: 50% vs 67%; bleeding events: 10% vs 27% (NS); thrombocytopenia 15% vs 50% (p=0.024); VTE: 0 vs 22% (p=0.041). Conclusions: Addition of B (3.500 u/daily s.c. during 26 w) to CT-RT in SCLC with LD significantly increases PFS and OS. B does not increase hemorragic events and significantly reduces VTE. In spite of early closure of the trial due to poor accrual, these results warrants further research in this approach trying to improve current outcomes of SCLC. ClinicalTrials.gov Id: NCT00324558.
Investigation of PARP1 as a therapeutic target in small cell lung cancer.
Authors: Byers Lauren Averett , Nilsson Monique B. , Masrorpour Fatemeh , Wang Jing , Diao Lixia , Bhardwaj Vikas , Welsh James , Girard Luc , Coombes Kevin R. , Weinstein John N. , Lippman Scott Michael , Glisson Bonnie S. , Minna John D. , Heymach John 
Published: March 2020

7096 Background: Small cell lung cancer (SCLC) is an aggressive malignancy that differs from non-small cell lung cancer (NSCLC) in its metastatic potential and response to treatment. To date, no molecularly-targeted agent has prolonged survival of SCLC patients. Using a proteomic approach, we previously identified high expression of the DNA repair protein poly (ADP-ribose) polymerase 1 (PARP1) in SCLC cell lines and tumors. Here we test in vitro sensitivity of SCLC to PARP inhibition or knockdown. Methods: Cell lines were treated with PARP inhibitor olaparib or AG014699 for 14d +/- chemotherapy. Relative cell viability was assessed by cell count. siRNA against PARP1 was compared with scrambled siRNA and mock transfected cells. To assess DNA repair, RAD51 foci were counted after 1µM or 5µM olaparib and after 8Gy irradiation (RT). Results: SCLC cell lines were highly sensitive to PARP inhibition by olaparib (IC50s <0.5 µM for H69; ≤2µM in H524, H82, and H526) and AG014699 (IC50s <0.5 µM for H82, H69, and H524; 2.2 µM for H526 and H841). In contrast, A549 (NSCLC) was resistant to both drugs (IC50s >8µM). Because BRCA1/2 and PTEN mutations are associated with greater sensitivity to PARP inhibitors, we compared SCLC sensitivity with that of BRCA1-mutated (HCC1395) and PTEN-mutated (MDA-MB-468) breast lines. As expected, HCC1395 and MDA-MB-468 were sensitive to both PARP inhibitors. Remarkably, however, SCLC cell lines were as sensitive or more so. Combination of olaparib with topotecan or irinotecan (commonly used in SCLC) decreased tumor cell viability more than either agent alone (p <0.03). Consistent with the drug studies, knockdown of PARP1 by siRNA decreased growth of SCLC compared with that of controls. RAD51 foci increased in SCLC after olaparib treatment (>4-fold) and RT (>18-fold). Conclusions: SCLC lines were as sensitive to PARP inhibition as BRCA1- or PTEN-mutated breast cancer lines. Moreover, PARP inhibition enhanced the effect of chemotherapy on SCLC lines. Increased formation of RAD51 foci in SCLC cells after olaparib or RT suggests a deficiency in homologous recombination that may account for the sensitivity to PARP inhibitors. These results support the investigation of PARP inhibition as a novel therapeutic approach in SCLC lung cancer.
A prospective, phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors.
Authors: Park Silvia , Park Keunchil , Ahn Myung-ju , Ahn Jin Seok , Sun Jong-Mu , Ahn Hee Kyung , Lee Su Jin , Maeng Chi Hoon , Hwang Deok Won 
Published: March 2020

7104 Background: Thymic epithelial tumors (TETs), thymoma and thymic carcinoma, are the most common tumor of the anterior mediastinum. Initial complete resection is the most powerful prognostic indicator of survival. However, it is obviously related to stage. Here, we report the result of a prospective phase II study of neoadjuvant docetaxel/cisplatin in patients with locally advanced TETs. Methods: In this open-label, phase II, nonrandomized study, patients with histologically proven, Masaoka stage III/IV TETs at presentation were enrolled. Patients received docetaxel 75mg/m2 I.V for 1 hr, followed by I.V cisplatin 75mg/m2 over 1.5hr on day 1 of every 3 week. After 3 cycles of chemotherapy, subsequent surgical resection was performed, if resectable. Results: From March 2007 to July 2011, a total of 27 TETs patients were entered into the trial. The median age was 54 (range, 15-68), and Masaoka stage at presentation was III (n=8, 29.6%), IVA (n=17, 63.0%), and IVB (n=2, 7.4%). Histologic type by the WHO includes type B1 (n=2, 7.4%), B2 (n=3, 11.1%), B3 (n=5, 18.5%), and thymic carcinoma designated as type C (n=16, 59.3%). After completion of neoadjuvant chemotherapy, 17 (63.0%) achieved PR and 10 (37.0%) had SD. Nineteen patients (70.4%) underwent surgical resection, and 8 patients did not (surgeons’ decision, n=5; patients’ refusal, n=2; radiation therapy, n=1). Of the 19 patients undergoing surgical resection, 17 (89.5%) had complete resections and 2 (10.5%) did not. Major side effects of chemotherapy include grade 3 anorexia (n=1), nausea (n=2), diarrhea (n=3), alopecia (n=1). After completion of surgical resection, adjuvant therapy was performed as follows: radiotherapy (RT, n=8), chemotherapy (CTx, n=6), radiotherapy with chemotherapy (RT + CTx, n=2) and observation (n=3). Overall, 4yr OS and PFS was 79.4% and 40.6%. Patients with complete resection showed 93.8% of 4yr OS and 50.2% of 4yr PFS whereas patients without complete resection showed 47.6% of 4yr OS and 26.7% of 4yr PFS, respectively (OS, p=0.06; PFS, p=0.27). Conclusions: Neoadjuvant docetaxel/cisplatin was well tolerated and feasible, and improved the surgical respectability in patients with advanced TETs.
Factors affecting survival of patients with Masaoka stage IV thymic epithelial tumors (TET).
Authors: Suleiman Yaman , Radovich Milan , Rojas Luis , Porter Ryan Frederick , Conces Madison , Shirar Kristen Leigh , Nelson Robert P , Spittler Aaron John , Siddiqui Bilal Karim , Burns Matthew , Badve Sunil S. , Schneider Bryan P. , Loehrer Patrick J. 
Published: March 2020

7107 Background: Thymoma and thymic carcinoma (TC) are rare tumors, but represent the most common neoplasms of the anterior mediastinum. The vast majority of TET present in early stages with little data existing on factors influencing survival in patients with advanced or stage IV disease. Methods: A retrospective analysis was performed on patients with confirmed TET (histology and with tissue blocks) seen at IUSCC diagnosed between 1976 and 2011. Patient demographics including Masaoka stage, histology, and sites of metastasis were linked with progression free survival (PFS) and overall survival (OS). Results: Our analysis included 102 patients with stage IV TET: 50 presented de novo and 52 developed stage IV disease following primary treatment. When stratified by tumor histology (thymoma or TC), patients with TC had considerably poorer PFS (p=1.87x10-7) and OS (p=7.72x10-8). The median PFS for TC was 13 months (range 4 to 39) and the MST was 36 months (range 4 to 115). PFS at 5-years was 21% and 0% but the five-year OS was 84% and 29% for thymoma and TC, respectively. Ten year OS was 55% for patients with thymoma and 0% for those with TC. Pleural (>3 vs. <3) metastases were significantly associated with a better PFS (p=0.036) and OS (p=0.0003). The PFS and OS of patients with lung nodules trended with those with pleural metastasis. Patients with pleural metastasis and lung nodules sites did considerably better than those with visceral disease (PFS, p=0.004, OS, p=2.09x10-5). Conclusions: Patients with TC have significantly poorer PFS and OS when compared to thymoma confirming that TC is a distinct clinical entity from thymoma. Patients with thymoma may have prolonged survival, despite having residual disease. Although current staging places patients with pleural metastasis (Masaoka stage IVA) and those with lung nodules (stage IVB) as separate categories, our data would suggest that those with lung nodules have similar survival with those who have pleural metastasis.
Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC).
Authors: Janne Pasi A. , Shaw Alice Tsang , Pereira Jose Rodrigues , Jeannin Gaelle , Vansteenkiste Johan , Barrios Carlos H. , Franke Fabio A. , Grinsted Lynda , Smith Paul D. , Zazulina Victoria , Smith Ian C. , Crino Lucio 
Published: March 2020

7503 Background: KRAS mutations are the most common (~20%) oncogenic alteration in NSCLC. There are no effective targeted therapies for this subset of NSCLC. Selumetinib (AZD6244, ARRY-142866) inhibits MEK1/2 signaling downstream of KRAS. We prospectively evaluated SEL + DOC vs DOC + placebo in advanced KRAS mutant NSCLC based on preclinical observations (NCT00890825). Methods: Patients (pts) with stage IIIB-IV, KRAS mutant NSCLC, who had received prior chemotherapy, received iv DOC 75 mg/m2, and po SEL 75 mg or placebo BD. The primary endpoint was overall survival (OS); secondary endpoints included: progression-free survival (PFS), objective response rate (RR), duration of response, change in tumor size, proportion of patients alive and progression-free at 6 mo, and safety and tolerability. Results: Between April 2009 and June 2010, 422 pts were screened across 67 centers in 12 countries; 113 had KRAS mutant NSCLC and 87 were randomized (DOC, 43; SEL/DOC, 44). Baseline characteristics were balanced (DOC vs SEL/DOC): WHO PS 0, 49%/48%; Female, 54%/52%; KRAS codon 12, 90%/93%. Median number of cycles: DOC, 4; SEL/DOC, 5. Most frequent grade 3/4 hematologic toxicity (DOC vs SEL/DOC): neutropenia (54.8%/67.4%), febrile neutropenia (0%/15.9%); most frequent grade 3/4 non-hematologic toxicity: dyspnea (11.9%/2.3%) asthenia (0%/9.1%), respiratory failure (4.8%/6.8%), acneiform dermatitis (0%/6.8%). Discontinuation due to AEs was similar: 18.2% SEL/DOC vs 11.9% DOC. OS was longer for SEL/DOC vs DOC (9.4 mo vs 5.2 mo; 56 events, median follow-up 219 days) but did not reach statistical significance; hazards were non proportional (HR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069). All secondary endpoints, including RR (DOC 0%, SEL/DOC 37%; p<0.0001) and PFS (DOC 2.1 mo, SEL/DOC 5.3 mo; 71 events; HR = 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138), were significantly improved for SEL/DOC vs DOC. Conclusions: This is the first prospective study to demonstrate a clinical benefit of a targeted therapy (SEL + DOC) for patients with KRAS mutant cancer of any type. Our findings could have implications for the treatment of NSCLC and other KRAS mutant cancers.
Discovery of recurrent KIF5B-RET fusions and other targetable alterations from clinical NSCLC specimens.
Authors: Capelletti Marzia , Lipson Doron , Otto Geoff , Yelensky Roman , Ercan Dalia , Kim Jhingook , Sasaki Hidefumi , Kim Hyeong Ryul , Park Seung-Il , Ross Jeffrey S. , Stephens Philip , Cronin Maureen T. , Janne Pasi Antero 
Published: March 2020

7510 Background: Many NSCLCs have driving oncogenic alterations including in EGFR, KRAS, ERBB2, BRAF, ALK and ROS1. Clinically effective drugs are approved for EGFR and ALK and clinical trials are underway for other genomic targets. Thus having a means of identifying genomic alterations in routine formalin fixed paraffin embedded (FFPE) clinical specimens is critical. Methods: We sequenced 24 FFPE NSCLC specimens with a next generation sequencing (NGS) assay that captures and sequences 2574 coding exons of 145 cancer relevant genes plus 37 introns from 14 genes often rearranged in cancer. Tumors from 643 additional patients were genotyped for KIF5B-RET. Results: We identified 50 alterations in 21 genes with at least one in 83% (20/24) of tumors (range 1-7). In 72% (36/50) of NSCLCs, at least one alteration was associated with a current clinical treatment or targeted therapy trial, including mutations in KRAS, BRAF, EGFR, MDM2, CDKN2A, CCNE1, CDK4, NF1 and PIK3CA. We also found an 11,294,741 bp pericentric inversion on chromosome 10 generating a novel gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET (K15:R12) in a Caucasian never smoker. This fusion gene contains the kinesin motor and coiled-coil domains of KIF5B and the entire RET tyrosine kinase domain. In 643 additional tumors we identified 11 fusion positive patients who were all wild type for known oncogenes (frequency of 6.3% (10/159)). Four unique KIF5B-RET variants were found: 8 K15:R12, 3 K16:R12, 1 K22:R12 and 1 K15:R11. We introduced K15:R12 into Ba/F3 cells and observed IL-3 independent growth consistent with oncogenic transformation. KIF5B-RET Ba/F3 cells were sensitive to sunitinib, sorafenib and vandetinib, multi-targeted kinase inhibitors that inhibit RET, but not gefitinib, an EGFR kinase inhibitor. Sunitinib, but not gefitinib, inhibited RET phosphorylation in these cells. Conclusions: We identified both known and novel genomic alterations from NSCLC FFPE specimens using a single test. Our findings suggest that RET inhibitors should be tested in prospective clinical trials in NSCLC patients bearing KIF5B-RET rearrangements and that NGS is a feasible approach to stratifying patients for treatment based on their genomic profiles.
A randomized double-blind trial of carboplatin plus paclitaxel (CP) with daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo (PLA) in patients (pts) with previously untreated advanced non-small cell lung cancer (NSCLC): NCIC Clinical Trials Group study BR29.
Authors: Laurie Scott Andrew , Solomon Benjamin J. , Seymour Lesley , Ellis Peter Michael , Goss Glenwood D. , Shepherd Frances A. , Boyer Michael J. , Arnold Andrew Michael , Clingan Philip , Laberge Francis , Fenton Dave , Hirsh Vera , Zukin Mauro , Stockler Martin R. , Lee Christopher W. , Chen Eric Xueyu , Montenegro Alexander , Ding Keyue , Bradbury Penelope Ann ,   NCIC Clinical Trials Group
Published: March 2020

7511 Background: In NCIC CTG study BR24, CED 30 mg/d + CP increased objective response rate (RR) and progression-free survival (PFS), but there were concerns regarding toxicity in some pts. BR29 tested a lower dose of CED 20 mg/d limiting accrual to pts without significant weight loss/hypoalbuminemia. Methods: Consenting, eligible adult pts with advanced incurable NSCLC of any histology were randomized to receive CED 20 mg/d or PLA with up to 6 cycles of C (AUC = 6) P (200 mg/m2); non-progressing pts continued CED/PLA after CP until progression, unacceptable toxicity or pt request. The primary endpoint was overall survival (OS). An interim analysis (IA) for PFS was planned after 170 events in the first 260 pts; the study would continue if the hazard ratio (HR) for PFS was < 0.7. Accrual continued until the required number of events was reached then held pending IA. Results: The trial was halted when the IA (n=260) revealed a HR for PFS of 0.89 (95% CI 0.66-1.20). A final analysis including all 306 randomized pts (median age 62, male 55%, PS 0 26%, PS 1 74%, adenocarcinoma 64%, squamous 13%, other histology 23%. RR was significantly higher with CED (52% vs 34 %, p = 0.001). For CED/PLA, respectively, median OS and PFS were 12.2/12.1 [HR: 0.95 (0.69-1.30, p=0.74)] and 5.5/5.5 months [HR: 0.91 (0.71-1.18, p=0.5)]. Grade >3 hypertension (15% vs 3%, p=0.0002), anorexia (7% vs 1%, p=0.02) and diarrhea (16% vs 1%, p<0.0001) were all significantly increased with CED; there were 2 deaths possibly-related to CED [1 each hemorrhage, leukoencephalopathy (prior radiation)]. Conclusions: Adding a lower dose of CED to CP increased RR and toxicity, but not PFS or OS.