bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of t(11;14) expression by FISH in patients with newly diagnosed multiple myeloma in the era of novel therapies.
Authors: Gonzalez Velez Miguel , Parrondo Ricardo Daniel , Andrews Tracy , Duma Narjust , Richter Joshua Ryan , Vesole David H. , Siegel David Samuel DiCapua , Biran Noa 
Published: September 2018

e19525 Background: Rearrangements of the immunoglobulin heavy chain (IGH) on chromosome 14 are identified by FISH in about 15-20% of patients (pts) with newly diagnosed multiple myeloma (MM). Historically there is variation on the significance on prognosis of these rearrangements: typically, t(4;14), t(14;16) and t(14;20) have high risk (HR), and t(11;14) have standard risk (SR). A recent study (Kaufman et al, Leukemia. 2016 30:633-9) suggests that t(11;14) may confer a worse prognosis We report the prognostic significance of t(11;14) in a single-institution MM cohort. Methods: 87 pts with t(11;14) by CD 138 selected FISH at diagnosis were identified, pts without symptomatic MM were excluded. Cox regression was used for statistical analysis. Progression free survival (PFS), and overall survivals (OS) from diagnosis and post autologous stem cell transplant (ASCT) were analyzed by Kaplan-Meier. Results: Median age at diagnosis was 62 years, 45 pts (52%) were male, and 24 pts (27%) had ISS 3. All pts received either a proteasome inhibitor or an immunomodulatory agent, and 42 (48%) received triplet treatment as induction. Sixty-nine (79%) pts had ASCT, and overall response rate (ORR, partial response or better) post ASCT was 73%. For pts with HR FISH (defined as t(14;16), p53 del, 1q21 gain or 1p del) compared to SR FISH, the ORR post ASCT was 70% vs 77% (p = 0.67). OS from diagnosis was 93% at 3 years, 74% at 4 years and 51% at 5 years. Seven patients (8%) developed plasma cell leukemia, and there was no association between HR and SR FISH (p = 0.66). In multivariate analysis, ISS stage was an independent risk factor for mortality; pts with stage 3 had 7.3 times (CI: 1.16-36.4) and 5.7 times (CI: 1.63-20.0) the risk of mortality than pts with stage 1 and 2. Having an ASCT reduced mortality by 87% (CI: 0.04-0.41). Conclusions: Despite the use of novel therapies the OS at 5 years of our pts with MM was not significantly improved compared to SEER data from 1992-2013 (51% vs 48.5%). Pts with t(11;14) who had ASCT had increased survival compared to those who did not. Our results suggest that t(11;14) may confer a worse prognosis. Further prospective studies evaluating the risk of t(11;14) are warranted.
Stromal infiltrating CD8+ and CD20+ lymphocytes and CD204+ M2 macrophages but not PD-L1 expression on tumor cells are prognosticators for patients with resectable thymic carcinoma.
Authors: Sato Jun , Motoi Noriko , Kitano Shigehisa , Yamamoto Noboru , Watanabe Shunichi , Ohe Yuichiro , Hiraoka Nobuyoshi 
Published: September 2018

e20002 Background: Thymic carcinoma (TMCA) is a rare malignant disease, and standard systemic chemotherapy has not been established. Tumor microenvironment (TME) that consists of tumor cells (TCs), tumor-infiltrating immune cells (TIICs) and stromal cells is thought to be an important biological feature of cancer behavior. The aim of this study was to analyze TME of TMCA, focusing the TIICs’ characteristics and the PD-L1 expression in the TC and TIIs and their impact on the clinical outcome. Methods: Fifty-one TMCA specimen with median observation period 33.8 months (range: 0.2-351) were collected. We evaluated the immunohistochemical profile of TIIs using antibodies against CD8, CD20 and FoxP3 for TIICs, CD204 for tumor-associated macrophages (TAMs), and PD-L1(SP142) expression of both TIICs and TCs using representative FFPE specimen. The density (median positive cell number per 1 mm2) of TIICs or TAMs was evaluated in intraepithelial (IE) and tumor stromal (TS) areas separately by using an automated image analyzer. Statistical analysis was performed using SPSS (version 24) and used p < 0.05 as significant level. Results: 51.9% (n = 26) had recurrent disease, and 31% (n = 16) survive without tumor. Of recurrent group, the density of CD8+ (54.5 vs 432) and CD20+ (35.9 vs. 516) TIIs, as well as the CD8+/CD204+, CD20+/CD204+ ratio in TS were significantly lower and FOXP3+ (590 vs 176) in TS was higher than that of non-recurrent group (Mann-Whitney U-test, two-sided). In the IE area, the lower CD20+/CD204+ ratio associated with recurrence. The CD20 and FOXP3 TIIs in TS also associated with the overall survival. There was no significant association between CD204 or PD-L1 expression and patients’ outcome. Conclusions: Our retrospective study showed the density of CD8+, CD20+ and FOXP3+ stromal-infiltrating lymphocytes and CD204+ M2 macrophage were prognostic factors for patients with resectable TMCA. Host immune reaction in TME might be one of the important prognostic factors for TMCA.
Immunohistochemical staining for programmed cell-death ligand 1 (PD-L1) in malignant thymoma and thymic carcinoma.
Authors: Shimanovsky Alexei , Cartun Richard , Fiel-Gan Mary , Mandich Daniza , Earle Jonathan , Salner Andrew L. , Collins Katrina , Otterson Gregory Alan , Chu Benjamin F. 
Published: September 2018

e20003 Background: Recent development of anti-PD-1/L1 antibodies has demonstrated activity in various neoplasms. Thymic malignancies (TMS) are rare and treatment in advanced disease is limited. To evaluate the potential impact of anti-PD-1/L1 therapy in TMS, we examined the expression of PD-L1 in previously resected thymoma (TM) and thymic carcinoma (TC). Methods: We examined resected specimens from patients at Hartford Hospital with TM and TC between 2000 and 2014. Expression of PD-L1 was evaluated on formalin-fixed paraffin-embedded tissue. Immunohistochemical testing was done using four different clones of PD-L1 antibodies on the Leica Bond Max automated platform. The four clones include: E1L3N (Cell Signaling Technology), 28-8 (Epitomics) and SP142 (Spring Bioscience), and CAL10 (BioCare). PD-L1 expression was evaluated based on the percentage of tumor cells positive and their intensity graded as negative, weak (1+), moderate (2+), and strong (+3). The scoring was performed by three pathologists and was blinded for clinicopathologic data and antibody clones. Results: We evaluated a total of 29 patients, including 26 patients with TM and 3 with TC. Among the 29 available specimens, 12 had completed PD-L1 expression assessment at the time of submission. PD-L1 expression is present in 75-100% of the evaluated patients. All had positive PD-L1 staining by SP142 and CAL10. Three patients showed strong intensity by CAL10, and one by SP142. E1L3N and 28-8 had positive PD-L1 expression in 9 and 8 patients respectively with weak/moderate intensity. SP142 and CLA10 demonstrated the strongest concordance (R2 = 0.91) but there was significant variation between antibodies (R2 = 0.31-0.91). No correlation was detected between tumor grade and PD-L1 expression. There were focal areas that lacked expression in all of the evaluated specimens. Conclusions: There is increased expression of PD-L1 in TMS. The level of PD-L1 expression varies between the four PD-L1 antibodies. Increased PD-L1 expression provides evidence for the use of PD-L1 inhibitors in TMS. The variable staining highlights the heterogeneity of TMS and challenges in developing predictive biomarker in this cancer.
Noninvasive EGFR testing in plasma circulating free DNA (cfDNA) by a new diagnostic method to detect point mutations, deletions and insertions associated to non small cell lung cancer: CLART CMA EGFR LB.
Authors: Sanchez Marta , Sanz Maria Jesus , Aragon Ana , Manjon Nuria , Carrillo Jaime , Romero Atocha , Provencio Mariano , García-Barberán Vanesa , Caldes Trinidad , Rodriguez-Peralto Jose Luis , Hernandez-Losa Javier , Cospedal Rosario , Villahermosa Maria Luisa 
Published: September 2018

e20008 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) with activating EGFR gene mutations. Histological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible in advanced NSCLC patients. Moreover, a high percentage of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs such as T790M mutation. CLART CMA EGFR LB is a novel diagnostic assay able to detect 39 high-prevalence mutations associated with sensitivity or resistance to tyrosine kinase inhibitor treatment. Methods: A highly sensitive and specific method was developed for detection of EGFR mutations (G719X, T790M, L858R, L861Q, insertions in exon 20, and deletions in exon 19) in plasma samples (cfDNA). CLART CMA EGFR LB is based on a preamplification step with a multiplex ARMS-PCR and microarray detection system. Clinical testing was performed using 51 clinical plasma samples: 27 contained L858R, T790M, and deletions in exon 19; 24 contained wild type alleles. 20 samples were cross checked by next generation sequencing performed on the PGM platform (Ion Ampliseq™ Custom, deep-coverage 15000x). Results: Analytical sensitivity was assessed using recombinant plasmids, results ranged between 10-1000 copies/5µl for all mutations. cfDNA from cell lines with the mutations L858R, T790M and deletions in exon 19 at different frequencies (cfDNA Reference Standard, Horizon) were assessed. The system was able to detect the mutations present in a frequency of 2%. The analysis of 51 samples allowed establishing the diagnostic sensitivity and specificity in 93.33% and 100% respectively. CLART CMA EGFR LB showed similar analytical and diagnostic sensitivity than NGS for detecting L858R, T790M and deletions in exon 19. Conclusions: Our data support the use of CLART CMA EGFR LB for clinical testing prior to the selection of the appropriate treatment in NSCLC, monitoring the patient evolution and the emergence of resistance mutations such as T790M in plasma samples.
Novel prognostic markers for epithelioid malignant pleural mesothelioma.
Authors: Bruno Rossella , Poma Anello Marcello , Alì Greta , Giannini Riccardo , Puppo Gianfranco , Melfi Franca , Lucchi Marco , Mussi Alfredo , Falcone Alfredo , Chella Antonio , Fontanini Gabriella 
Published: September 2018

e20028 Background: Malignant pleural mesothelioma (MPM) is a deadly asbestos related tumour. The median survival is about 12 months and MPM patients are usually offered with a multimodality approach. With regard to chemotherapy the treatment of choice is the antifolate pemetrexed in combination with cisplatin or carboplatin. The high variability in the survival of patients with similar characteristics make it challenging to identify reliable prognostic markers. In this study we sought novel prognostic markers for epithelioid MPM, by investigating the expression levels of 117 genes involved in cancer. Methods: Gene expression analysis was evaluated on RNA from 15 epithelioid MPM patients undergoing pleurectomy (fomalin-fixed paraffin-embedded tissue) using a custom panel on nanoString platform. All patients were treated with cisplatin plus pemetrexed chemotherapy. Patients were divided in two groups for each gene (high and low expression level) on the basis of median. The correlation between gene expression, overall survival (OS) and progression free survival (PFS) was carried out by Log-rank test (Kaplan Meier). Results: A poorer OS was associated with a higher expression of 3 genes: MCM2 (p-value 0.005), PLK1 (p-value 0.005) and CCNB2 (p-value 0.01). These findings were in agreement with TCGA data ( PROGgeneV2: enhancements on the existing database. BMC Cancer 2014). Moreover, PLK1 showed a significant correlation also with PFS (p-value 0.01). Conclusions: Several biomarkers have been suggested as MPM prognostic factors, but sensitive and specific ones for the clinical practice are still missing. Despite the relatively small number of tissue samples, related to the rarity of this tumour, we identified 3 genes as potential prognostic markers. MCM2 is involved in the initiation of genome replication, PLK1 and CCNB2 regulate cell cycle by promoting mitosis. All these genes proved to be not only useful prognostic indicators but also promising therapeutic targets as reported in functional studies on different cancer models. The validation of these new markers, particularly of PLK1 which is correlated also with PFS, may improve the prognostic stratification at diagnosis, providing information valuable in the management of MPM patients.
Regional variation in high-resource utilization among lung cancer-related emergency department visits in the United States.
Authors: Ruban Cynthiya , Kowalkowski Marc , Blanchette Christopher Michael 
Published: September 2018

e20038 Background: Regional variation is common in oncology care but is not defined for emergency department (ED) care for cancer patients, particularly patients with lung cancer (LC) who regularly utilize EDs for management of acute cancer or treatment related illness. This study analyzed regional variation and other factors associated with high total episodic charge (≥75th percentile; HTC) among LC patients evaluated in the ED in relation to discharge or admission. Methods: A retrospective study of LC-related ED visits in the US was conducted using the 2013 Nationwide ED Sample. LC-related ED visits among adults were identified by LC-specific Clinical Classification Software codes (CCS = 19; mapping to ICD-9 = 162.x, 209.21, 231.2, V10.11). Multivariable logistic regression analyzed the association between patient and hospital factors and HTC, weighted to represent ED visits nationwide. Results: Among 373,761 LC-related ED visits, 134,838 (36%) were treated and discharged and 238,923 (64%) were admitted (ranging from 51% (West [W]) to 76% (South [S]). HTC was ≥$5,655 (median = $2,993) for ED discharges and ≥$54,760 (median = $29,590) for admissions. The proportion of visits with HTC differed by region and admission status (discharged: 7% [W] to 27% [S]; admitted: 20% [Midwest] to 39% [W]). After adjusting for clinical and hospital factors associated with increased HTC odds (metastases, common acute comorbid disorder [chest and abdominal pain, pneumonia, sepsis, respiratory failure], diagnostic radiology use, thoracic/other surgery, chemo/radiotherapy, length of stay, primary payer, and hospital ownership, location and teaching status), significant HTC variation remained by hospital region with opposing relative HTC odds among discharged and admitted patients (discharged: W v S OR = 0.3 95%CI = 0.2-0.6, Northeast v S OR = 0.5 95%CI = 0.3-0.7; admitted: W v S OR = 3.8 95%CI = 2.5-5.7). Conclusions: Regional variation in HTC suggest differences in ED use and management patterns for LC and may reflect quality of care concerns. Clinical outcome linkage (including ED revisit tracking) is needed to better define the impact of variation and develop strategies to improve care for patients with LC.
Survival prediction using time-evolving tumor load: An approach to rationally design treatment sequencing, staging, and dosing strategies for oncology combinations.
Authors: Dunyak James , Onishchenko Dmitry , Masson Eric , Helmlinger Gabriel , Tomkinson Helen , Abdallah Kald , Stanski Donald , Al-Huniti Nidal 
Published: September 2018

e20040 Background: Longitudinal tumor burden has long been used for the clinical diagnosis, staging, prognosis and treatment of non-small cell lung cancer (NSCLC). Tumor burden and growth rate correlate directly with survival and RECIST (measurement of tumor) is widely used as a surrogate endpoint. RECIST doesn’t take into account the impact of the therapy on the speed of growth over time, and poorly correlates with survival, especially in IO therapies. Surrogate endpoints such as progression-free survival (PFS) or dichotomous RECIST-based overall response rate (ORR) allow early assessment of efficacy based on reduced study population size. Unfortunately, ORR and PFS are poorly predictive of OS in NSCLC. This well-known loss of information during categorization emphasizes the potential benefits of continuous tumor load modeling. Methods: This research provides a statistically valid basis for modeling and interpretation of longitudinal response dynamics, in the context of time-to-event (survival) censoring, through development of a joint longitudinal/event model. Using clinical data from the Phase 3 IPASS study of Iressa (gefitinib), we build a generalizable model relating tumor load dynamics to a time-evolving hazard of progression. Results: Using longitudinal data from other smaller and shorter studies, we identify the time-progression of patient’s risk, including post-treatment time of minimum hazard of progression and the time when hazard rapidly increases. This is applied at both the population strata and individual patient level to assess different treatment paradigms. The model shows that EGFR-mutated patients on gefitinib have stable hazard of progression for about 8 months, as which point hazard increases rapidly. EGFR-mutated patients treated with carboplatin/paclitaxel started with a 72% higher initial progression hazard which then increased rapidly after 4 months. Conclusions: Because of their continuous-in-time nature, joint longitudinal/event models provide a basis for exploring the complex timing issues in oncology treatment sequencing, treatment staging strategies for combinations, and dosing regimes.
A new diagnostic method based on RT-PCR and CLART technology for non-small cell lung cancer (NSCLC) to detect major EML4-ALK and ROS.1 translocations: CLART CMA ALK and ROS.1.
Authors: Manjon Nuria , Martinez Jaime , Garcia Gonzalo , Aragon Ana , Carrillo Jaime , Rodriguez-Peralto Jose Luis , Antunez Lopez Jose Ramón , Hernandez-Losa Javier , Cospedal Rosario , Villahermosa Maria Luisa 
Published: September 2018

e20045 Background: EML4-ALK and ROS1 translocations represent 3-6% and 1-2% of NSCLC patients, respectively. These patients would benefit for a tyrosine kinase inhibitor therapies. Currently, the gold standard for ALK and ROS.1 detection are break-apart fluorescence in situ hybridization (FISH) or inmunodetection (IHC) of the chimeric fusion proteins. FISH has both high sensitivity and specificity, although often present technical interpretation problems due to signal instability and scoring. IHC is a rapid and low cost technique; however it presents several challenges regarding sensitivity and reproducibility. CLART CMA ALK & ROS.1 kit is based RT-PCR and detection of the amplified product was carried out by a low-density microarray platform: CLART (Clinical Arrays Technology) of major fusion transcripts of EML4-ALK and ROS.1 translocations ( V1: E13;A20 , V6: E13; ins69;A20 , V2: E20;A20 , V3a: E6:A20 , V3b: E6;ins33 A20 ,V5a: E2;A20 and V5b: E2;ins117A20 for EML4-ALK and SDC4-ROS1 S2;R32/ S2;R34, CD74-ROS1 C6;R34 and SLC34A2-ROS1 S4;R32/S4;R34). Methods: The translocations analysis was performed with CLART CMA ALK & ROS.1 kit. Clinical testing was performed using the RNA extracted from 115 samples of NSCLC patients being 34 patients with translocations detected in ALK or ROS.1 genes and 81 patients without any translocations. The results were cross-checked by comparison to Next GenerationS methodology performed on the PGM platform with the Ion Ampliseq Panel Oncomide Solid Tumor Fusion and the concordance was 95.6%. Results: Analytical sensitivity was assessed using fusion transcripts cloned in recombinant plasmids. Results ranged from 10 to 100 copies/5µl of recombinant plasmids. The analysis of 115 clinical samples allowed establishing the diagnostic sensitivity and specificity in 90.9-100% and 99-100% respectively. Conclusions: CLART CMA ALK & ROS.1 emerges as a suitable alternative of FISH/IHQ for diagnosis of the most common translocations in EML4-ALK and ROS.1 genes in NSCLC samples and therefore selecting patients that would best benefit from a target therapy.
Treatment outcome and lung toxicities of volumetric modulated arc therapy in the treatment of inoperable non-small-cell lung cancer patients.
Authors: Xie Congying , Lin Baochai , Jin Xiance 
Published: September 2018

e20046 Background: Volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time and less MU compared to conventional intensity-modulated fixed-field treatment (IMRT) in the treatment of inoperable non–small-cell lung cancer (NSCLC). However, published data on clinical outcome and lung toxicities of VMAT in the treatment of NSCLC are scarce. Methods: The clinical outcome, acute and late pulmonary toxicities of 134 consecutive inoperable NSCLC patients treated by VMAT with or without concurrent chemotherapy were retrospectively reviewed. Univariate and multivariate analysis on the dosimetric and characteristic factors associated with acute radiation pnuemonitis (RP) and pulmonary fibrosis were evaluated. Results: The average prescriptions dose to these patients were 5736.38±649.11 cGy (range from 5200 to 6400 cGy) with a median follow-up of 18.6 months (range, 2–45 months) for the enrolled 134 patients. The two-year progression-free survival (PFS) and overall survival (OS) for all patients was 18.2% and 38.4% with a median PFS and OS of 7.6 months and 18.6 months, respectively. There were 14 and 12 out of 134 patients experienced grade III/higher RP (10.45%) and pulmonary fibrosis (8.95%), respectively. Age, chemotherapy exposure, dose prescription, V10, V13, V20 and V30 were significantly associated with acute RP. Dose prescription was related to pulmonary fibrosis. Only V13 (p = 0.02) and age (p = 0.02) were independently associated with acute RP according to multivariate analysis. Based on regression analysis, the threshold for lung dosimetric metrics V10,V13,V20 andV30 were 50%,40%,28% and 18% in VMAT treatment of NSCLC to limit the RP rate < 10%. Conclusions: VMAT can be delivered safely with acceptable acute and late toxicities for NSCLC. Lung dosimetric metrics were valuable in predicting acute RP. A threshold of 40% of Lung V13 in VMAT treatment of NSCLC was helpful to limit the RP rate < 10%.