bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vorinostat (V) intratumoral levels and biomarker response in a window of opportunity trial in patients with resectable aerodigestive tract cancer.
Authors: Dragnev Konstantin H. , Beumer Jan Hendrik , Anyang Bean , Ma Tian , Galimberti Fabrizio , Erkmen Cherie Parungo , Nugent William , Rigas James R. , Abraham Kathryn , Johnstone David , Memoli Vincent , Dmitrovsky Ethan 
Published: March 2020

7022 Background: Aerodigestive tract cancer (ADT) is the leading cause of cancer-related death in the US. New effective treatments are needed. Among a panel of drugs causing growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor V was found most potent. To translate studies into the clinic, a window of opportunity trial of V was conducted. Methods: Pts with resectable ADT received 400 mg V once daily orally for 7 days prior to surgical resection. Serum samples were obtained before the last V dose and at the time of biopsy. Tumor tissue was immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. Post- versus pre-treatment tumor biopsies were scored for necrosis, acute and chronic inflammation, and immunohistochemical changes in Ki-67, cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent resection and had adequate pretreatment samples. Median age 66, 4 women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and tumor (7pts) concentrations above the detection limits. There was considerable interindividual variation in plasma V concentrations (7.3-192.4 ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation in the post-treatment biopsies. Most cases with KRAS mutations had biomarker responses. Changes in multiple biomarkers were observed across the range of intratumoral V levels. Conclusions: This is the first report of V concentrations in human tumors. Preoperative treatment with V achieved intratumoral concentrations comparable to serum with evidence of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses in resected ADT. The results demonstrate the value of window of opportunity trials in the investigation of novel cancer therapeutics.
The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients.
Authors: Krasnik MARK , Lüchtenborg Margreet , Jakobsen Erik , Linklater Karen , Mellemgaard Anders , Møller Henrik 
Published: March 2020

7026 Background: TNM classification has been the traditional cornerstone of decision-making in treatment choices of lung cancer. In addition to TNM stage and lung function, there is no other objective information to support this decision. Severe comorbidity affects overall survival, and may be an independent prognostic factor. In this study we quantified the effect of comorbidity on stage-specific survival in resected non-small cell lung cancer (NSCLC) patients in a large population-based setting. Methods: Among 3,152 NSCLC patients from the Danish Lung Cancer Registry who underwent surgical resection between 1 January 2005 and 31 December 2010, mortality hazard ratios were calculated during three consecutive time periods following surgery (0-1 month, 1 month - 1 year and >1 year) according to Charlson comorbidity score (CCS 0, 1-2, 3+), ECOG performance status, lung function, age, sex, pathological T and N stage according to the revised 7th edition TNM lung cancer staging system, using Cox proportional hazard modelling. The Kaplan-Meier method was used to describe stage-specific survival according to the Charlson comorbidity score. Results: Increasing severity of comorbidity was independently associated with significantly higher death rates throughout the three periods of follow-up [HR1.18 for CCS 1-2 and 2.06 for CCS 3+ in 0-1 month, 1.13 for CCS 1-2 and 1.57 for CCS 3+ during 1 month - 1 year and 1.14 for CCS 1-2 and 1.84 for CCS 3+ after 1 year]. Stage-specific five-year survival in patients with severe comorbidity (CCS 3+) was significantly lower than in patients without comorbid disease [e.g., 38% (95% CI 23-53%) for pT1 and CCS 3+ vs. 69% (62-75%) for pT1 and CCS 0]. Conclusions: This study shows that severe comorbidity affects survival of NSCLC patients undergoing surgical resection by as much as a single stage increment. As the survival of NSCLC patients after different treatment regiments is mainly based on the TNM classification, further research is necessary to fully identify which patients are most likely to benefit from surgery, but also to provide a basis for developing a better prediction instrument for the survival after combination treatment involving radiotherapy and chemotherapy.
Amatuximab, a chimeric monoclonal antibody to mesothelin, in combination with pemetrexed and cisplatin in patients with unresectable pleural mesothelioma: Results of a multicenter phase II clinical trial.
Authors: Hassan Raffit , Jahan Thierry Marie , Kindler Hedy Lee , Bazhenova Lyudmila , Reck Martin , Pastan Ira , Ellis Alison , Fatato Penny Marie , Heyburn John , Schweizer Charles , Parno Jeff , Wallin Bruce 
Published: March 2020

7030 Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in many cancers including malignant mesothelioma (MM). Based on safety of amatuximab in phase I clinical trial and pre-clinical studies showing synergy in combination with chemotherapy, a single arm phase II study of amatuximab plus pemetrexed (P) and cisplatin (C) was initiated in pts. with MM. Methods: Eligibility criteria included pts. with unresectable epithelial or biphasic pleural MM, no prior chemotherapy and KPS > 70%. Pts. received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 and C 75 mg/m2 (PC) given on day 1, of each 21 day cycle for 6 cycles. Pts. with objective response or stable disease received amatuximab monotherapy until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), objective response rate and safety of amatuximab with PC. Results: From 2/2009 to 10/2010, 89 pts. were enrolled at 26 sites. Pt. characteristics: median age 67 yrs. (range 46-80), 78% male, 70% with KPS >90%, 89% epithelial MM, 11% biphasic MM and 88% had stage III/IV disease. Median number of PC plus amatuximab cycles was 5 (range 1-6) and 56 (63%) pts. received single agent amatuximab. In addition to the expected toxicity from PC, hypersensitivity reactions (12.4%; Grade 3/4=4.5%) from amatuximab were noted. By independent radiological review 30 (39%) pts. had partial response and 39 (51%) had stable disease. PFS at 6 months was 52% (95% CI: 39.5-63.5) with a median PFS of 6.1 months (95% CI: 5.4-6.5). As of 1/10/12 the median OS was 14.5 months (95% CI: 12.4-18.5) with 31 pts. still alive and 7 pts. receiving maintenance amatuximab. Conclusions: Amatuximab in combination with PC was generally well-tolerated in this study with 90% of pts. having an objective tumor response or stable disease by independent radiological review. Although PFS is not significantly different from historical results of PC alone, the median OS is 14.5 months with 35% of pts. still alive. Updated OS and biomarker data will be presented at the meeting.
Next-generation sequencing of thymic malignancies.
Authors: Radovich Milan , Porter Ryan Frederick , Conces Madison , Suleiman Yaman , Badve Sunil S. , Kesler Kenneth , Schneider Bryan P. , Loehrer Patrick J. 
Published: March 2020

7032 Background: Thymic malignancies are rare with ~500 cases in the US per year. Apart from standard chemotherapy, treatment options are limited. Further, the challenge of histologic subtyping of these tumors along with an inadequate understanding of the transcriptional biology is a hindrance to the development of targeted therapies. Methods: Thymic malignancies and normal tissues were obtained from the Indiana University Simon Cancer Center. The WHO subtypes of our samples include: (4) type A, (2) A/B, (1) B2, (5) B3, (1) C, and (3) normal tissues. RNA was sequenced on a Life Technologies SOLiD sequencer. For gene expression, reads were mapped to the genome using BioScope and outputs imported into Partek GS. In Partek, statistical comparison of gene expression as well as PCA & clustering analyses were performed. Results: Unsupervised hierarchical clustering of gene expression values revealed 100% concordance between gene expression clusters and WHO subtype. A subsequent unsupervised clustering of 705 pre-miRNAs also showed substantial concordance between clusters and subtype. By analyzing the dendrograms, A & A/B tumors were significantly different from B type tumors, as well as C and normal. A substantial differentiator was a large cluster of overexpression in A&A/B tumors that was nearly absent in the others on chr19q13.42 corresponding to the miR-515 cluster (43 miRNAs). When comparing A & A/B tumors vs. B type tumors, 1334 genes are differentially expressed (258 downregulated) (FDR<5%). 95/258 genes are predicted to be downregulated by the miR-515 cluster including several transcription factors and tumor suppressors. When looking at mutations, we detected no recurrent gene fusions, though we are detecting several point mutations and small insertion deletions. These are being followed up by exome sequencing. Conclusions: Analyses reveal that RNA-seq can be used to accurately subtype Thymic Malignancies and the development of an expression based diagnostic is feasible. Further, these data support that the main differentiator of thymomas may lie in the expression of a single miRNA cluster. In addition, several mutations in key pathways are implicated. Ongoing analyses include: alternative splicing, noncoding RNAs, viral analysis and exome sequencing.
A prospective phase II study of induction erlotinib therapy in stage IIIA-N2 non-small cell lung cancer.
Authors: Zhong Wenzhao , Yang Xuening , Liao Riqiang , Nie Qiang , Su Jian , Chen Zhihong , Zhang Xuchao , An Shejuan , Zhou Qing , Yang Jinji , Wu Yi Long 
Published: March 2020

7039 Background: Stage IIIA NSCLC represents a heterogeneous group of patients with ipsilateral mediastinal (N2) lymph nodes involvement. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide dramatic responses in patients with non-small cell lung cancer (NSCLC) carrying EGFR mutations. The purpose of this study is to evaluate the role of induction EGFR-TKI therapy in IIIA-N2 NSCLC. Methods: Patients with resectable NSCLC of stage IIIA-N2 were assigned to either induction erlotinib arm or induction gemcitabine/carboplatin(GC) arm based on the EGFR mutations analysis (NCT00600587) . Study Design: Phase II, factorial Assignment, Safety/Efficacy; Primary outcome measures: Response to Induction Therapy; Estimated enrollment: 5 cases with partial response in the erlotinib arm. Results: From January 2008 till June 2011, 24 patients with IIIA-N2 NSCLC diagnosed by mediastinoscopy or PET/CT have been enrolled. Twelve cases with EGFR mutation were assigned to the erlotinib arm (30-42 days), while 12 cases harboring wild-type EGFR received the GC regimen (3 cycles). The primary end point of the response rates were 58% (7/12) for the erlotinib arm and 33% (4/12) for the GC arm (P=0.49). The pathological N2 complete response rates were 17% for the erlotinib arm and 25% for the GC arm (P=0.64). In the erlotinib arm, the most common failure model after initial therapy was distant metastases (9/10), especially brain metastases (3/9). The median progression free survival time was 7 months for the erlotinib arm and 9 months for the GC arm (P=0.27). The median overall survival was 27 months for the erlotinib arm and 23 months for the GC arm (P=0.52). In addition, four cases in the erlotinib arm got partial response to the 2nd EGFR-TKI therapy after progression to erlotinib induction therapy and the following thoracotomy. Conclusions: Induction erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy. Distance metastases were major failure model. A multicenter, randomized, phase II study evaluating efficacy and safety of erlotinib vs GC as neoadjuvant therapy for stage IIIA-N2 NSCLC patients with EGFR mutations (NCT01407822) is currently recruiting participants.
Matched-pair comparison of outcome of patients with clinical stage I non-small cell lung cancer treated with resection or stereotactic radiosurgery.
Authors: Shelkey Julia , Fakiris Achilles , DeCamp Malcolm M. , Medford-Davis Laura Nyshel , Flickinger John Charles , Recht Abram , Liss Adam , Belani Chandra Prakash , Deluca Jill , Maheshwari Neelabh , Varlotto John M. 
Published: March 2020

7040 Background: Stereotactic body radiotherapy (SBRT) is an alternative to surgery alone for certain patients with clinical stage I non-small cell lung cancer (NSCLC), but comparing their effectiveness is difficult because of differences in patient selection and staging. Methods: Two databases were combined which contained 132 patients treated by lobectomy (LR) and 48 by sublobar resection (SLR) and 137 patients managed with SBRT after negative staging between 1999-2009. We compared rates of overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) between patients treated with surgery and SBRT to each other and in relation to possible prognostic factors. We then performed a matched-pair analysis comparing surgery and SBRT results. Median follow-up for the entire study population was 25.8 months. Results: On univariate analysis, OS was significantly correlated with histology, the Charlson Comorbidity Index, tumor size, aspirin use, and use of SBRT; DFS was correlated only with histology; and no variable was significantly correlated with LRC. Multivariate analysis found improved OS in patients with adenocarcinoma and those undergoing surgical resection. The NSCLC “not otherwise specified” histology was associated with poorer DFS. Overall survival was significantly poorer for SBRT patients in the matched-pair analysis than for patients treated with surgery, but DFS and LRC were not significantly different between these groups. Conclusions: Our retrospective study has demonstrated similar LRC and DFS in patients treated with SBRT or surgery, but worse OS in the former group, when patients were matched for prognostic factors. Our investigation suggests that randomized trials are needed to eliminate selection bias in treatment assignment in order to accurately compare outcomes between these approaches.
Comparative effectiveness of five treatment strategies for early-stage non-small cell lung cancer in the elderly.
Authors: Shirvani Shervin Mohajer , Jiang Jing , Chang Joe Y. , Gomez Daniel Richard , Welsh James , Swisher Stephen , Buchholz Thomas A. , Smith Benjamin D. 
Published: March 2020

7062 Background: Early-stage lung cancer incidence among older adults is expected to increase due to demographic trends and CT-based screening, yet optimal treatment in the elderly remains controversial. Using the SEER-Medicare cohort spanning 2001-2007, we determined survival outcomes associated with five strategies used in contemporary practice. Methods: Treatment strategy and covariates were determined in 10,923 patients age≥66 with stage IA-IB non-small cell lung cancer. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for lobectomy, sublobar resection, conventional radiation, stereotactic body radiotherapy (SBRT) and observation. In a second analysis, propensity-score matching was used for pairwise comparison of SBRT with other strategies. Results: Median age was 75 years and 29% had substantial comorbidity. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SBRT (1.1%). In unmatched Cox regression with median follow up of 3.2 years, SBRT was associated with the lowest risk of death within six months of diagnosis (HR 0.47; 95%CI 0.37-0.61; referent is lobectomy). After six months, sublobar resection and SBRT were associated with similar overall survival (P=0.51) and were both modestly worse than lobectomy. With propensity-score matching, survival after SBRT was similar to lobectomy (HR 0.90; 95%CI 0.64-1.27). Conventional radiation and observation were associated with poor outcomes in all analyses. Disease-specific survival outcomes followed similar trends. Conclusions: This population-based experience provides strong support of SBRT as an alternative to surgery or conventional radiation for select patient populations. Evaluation of this new therapy in randomized trials is urgently needed.
Prospective study of tumor suppressor gene (TSG) methylation as a prognostic biomarker in surgically resected non-small cell lung cancer (NSCLC).
Authors: Azzoli Christopher G. , Drilon Alexander Edward Dela Cruz , Sugita Hirofumi , Sima Camelia S. , Huang Eric , Danenberg Peter V. , Kris Mark G. , Rusch Valerie W. 
Published: March 2020

7066 Background: In the New England Journal of Medicine, Brock et al. (2008) published a nested case-control study which tested the association between early recurrence of NSCLC after surgical resection, and TSG promoter methylation in tumor and lymph nodes detected by methylation-specific PCR (MSP). They reported that promoter methylation of the TSGs p16, CDH13, RASSF1A, and APC was significantly associated with early recurrence in 51 patients with stage I NSCLC compared to matched patients without early recurrence. We attempted to confirm these findings. Methods: In a prospective study, fresh frozen tumor tissue was acquired after surgical resection in 107 patients with stage I-IIIA NSCLC between 2003-2008. The promoter methylation status of the same 4 genes examined by Brock, et al (p16, CDH13, RASSF1A, APC), as well as 6 additional TSGs (MGMT, WIF-1, METH-2, GSTP1, SOCS3, DAPK) were assessed in the tumor tissue using quantitative MSP (MethyLight assay), with any amount of methylation scored as positive. Methylation status was correlated with clinical features, pathologic stage, disease-free survival (DFS), and overall survival (OS). Results: No significant associations were observed between promoter methylation of individual TSGs and DFS. No significant associations were observed between the number of methylated TSGs and DFS, or OS. Increased RASSF1A methylation was observed in poorly-differentiated and undifferentiated tumors compared to tumors that were well- or moderately-differentiated (p=0.031). Increased WIF-1 methylation and GSTP1 methylation were associated with increasing T (p=0.01) and N stage (p=0.028), respectively. Squamous cell carcinomas (SQCCs) were characterized by increased p16 methylation (p=0.0314) and decreased APC methylation (p=0.0146) compared to tumors of non-SQCC histologies. Conclusions: In this prospective study, we did not confirm that the promoter methylation of p16, CDH13, RASSF1A, and APC, or 6 other TSGs, was prognostic for early recurrence in surgically resected NSCLC.
Expression pattern and biologic relevance of Bcl-2 and Mcl-1 in pulmonary neuroendocrine tumors.
Authors: Chowdry Rajasree Pia , Sica Gabriel , Chen Zhengjia , Goodman Aaron , Kim Sungjin , Deng Xingming , Curran Walter John , Gal Anthony A , Khuri Fadlo Raja , Ramalingam Suresh S , Owonikoko Taofeek Kunle 
Published: March 2020

7097 Background: Bcl-2 protein overexpression is frequently described in small cell lung cancer (SCLC) but the biological relevance remains unclear. To better elucidate the role of Bcl2 dysfunction in SCLC, we assessed the total and the biologically relevant phosphorylated forms of the anti-apoptotic Bcl2 family members (Bcl2, pBcl-2, Mcl-1, pMcl-1) in pulmonary neuroendocrine (NE) tumors. Methods: We analyzed archival samples of pulmonary carcinoid, SCLC and large-cell NE carcinoma (LCNEC) by immunohistochemistry (IHC) using specific antibodies. Protein expression was assessed by light microscopy using standard scoring of intensity (0, 1, 2 and 3) and percent cell staining and correlated with age, gender, smoking status, tumor type, stage and survival. Significant differences in expression pattern and correlation with clinical variables were assessed by Wilcoxon two-sample test, t-test, ANOVA, Spearman and Pearson correlation coefficients and Cox regression model. Results: We retrieved 77 cases: carcinoid (16) SCLC (41) and LCNEC (20); median age (61 yrs), gender (62% females). Bcl2 and pBcl2 expression was higher in SCLC and LCNEC compared to benign carcinoid tumor. pBcl-2 showed stronger correlation with adverse features including smoking, malignant histology, higher stage at diagnosis and worse survival. No significant association of Mcl1 or pMcl-1 expression with clinical or pathologic parameters. Conclusions: pBcl-2 expression pattern and correlation with adverse prognostic features indicate a key role in SCLC biology and relevance as a therapeutic target. [Table: see text]
A 19-gene prognostic GEP signature (DecisionDx-Thymoma) to determine metastatic risk associated with thymomas.
Authors: Gokmen-Polar Yesim , Goswami Chirayu Pankaj , Cook Robert W. , Oelschlager Kristen M. , Maetzold Derek , Vladislav Ioan Tudor , Shirar Kristen L , Kesler Kenneth , Loehrer Patrick J. , Badve Sunil S. 
Published: March 2020

7106 Background: The treatment of thymomas is predominantly based on the stage of disease. Histologic classification is of limited value as all types of thymomas can give rise to metastases. In order to better predict the metastatic behavior of these tumors, we performed genome-wide gene expression analysis and identified a set of genes associated with presence or absence of metastases. In the current study, we sought to further develop and validate the gene signature using quantitative RT-PCR analysis. Methods: Thymomas with archived blocks and long-term follow-up data were reviewed. This training set study consisted of 50 cases, including 34 cases on which the discovery microarray analysis had been performed. RNA was extracted from 5 x 10-micron thick sections in a CAP-accredited CLIA certified laboratory and analyzed by RT-PCR using custom TLDA cards on an ABI7900HT instrument. Expression data and biostatistical analysis were performed using GeNorm and JMP Genomics (SAS). Predictive modeling using Partition Tree Analysis (PTA) and Logistic Regression Analysis (LRA) was performed. Metastasis-free survival (MFS) was assessed using Kaplan-Meier analysis. Results: A 19-gene expression profile (GEP) signature was developed using a cohort of 50 thymomas for predicting metastasis. PTA yielded ROC of 0.97 (met. accuracy = 96%, non-met. accuracy = 81%), while LRA yielded ROC of 0.895 (met. accuracy = 87%, non-met. accuracy = 85%). PTA classification showed 5-year MFS rates of 100% and 31% for predicted low risk (Class 1) and high risk (Class 2) of metastasis (median MFS = NR and 4.1 yrs, resp., P<0.0001 Log-Rank), respectively. LRA showed 5-year MFS rates of 100% and 17% for predicted Class 1 and high risk Class 2 of metastasis (median MFS = NR and 2.9 yrs, resp., P<0.0001 Log-Rank), respectively. Analysis of additional cohorts is ongoing. Conclusions: We have successfully completed development of a 19-gene signature (DecisionDx-Thymoma) that appears to predict metastatic behavior of thymomas more accurately than traditional staging. If validated in larger cohort, this signature will provide insight for the future management of patients with this rare malignancy.