bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ribonucleotide reductase subunit-2 (RRM2) and thymidylate synthase (TS) to predict shorter survival in patients (pts) with resected stage I-III non-small cell lung cancer (NSCLC).
Authors: Grossi Francesco , Dal Bello Maria Giovanna , Savarino Graziana , Salvi Sandra , Puzone Roberto , Pfeffer Ulrich , Fontana Vincenzo , Rijavec Erika , Barletta Giulia , Genova Carlo , Sini Claudio , Ratto Giovanni Battista , Truini Mauro , Merlo Domenico Franco 
Published: March 2020

11063 Background: Tumor biomarkers can help to identify pts with early-stage NSCLC with high risk of relapse and poor prognosis. The aim of this study was to investigate the prognostic value of 7 biomarkers involved in DNA synthesis and repair. Methods: Tumour tissues from 82 radically resected, stage I-III NSCLC pts were consecutively collected to investigate the following biomarkers: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), ribonucleotide reductase subunit 2 (RRM2), subunit p53R2, thymidylate synthase (TS) and class III beta-tubulin (TUBB3) using immunohistochemistry (IHC) and quantitative real time-polymerase chain reaction (qRT-PCR). Expression levels of these genes were also investigated in a large publicly available NSCLC microarray dataset (Director Challenge Consortium, DCC). Results: RRM2 expression (p=0.031), TS expression (p=0.023), and pathologic stage (p<0.001) were found as independent prognostic factors for shorter survival. The expression of ERCC1, RRM1, p53R2, TUBB3, BRCA1, as well as other clinical characteristics, failed to show any statistically significant association with the survival. Despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤ 140) survived longer than pts with higher RRM2 levels (p=0.069). There was a trend towards longer survival for BRCA1-, ERCC1-, RRM1- and TS-negative pts and for p53R2- and TUBB3-positive pts. For all of the biomarkers except TUBB3, the OS trends relative to the protein expression levels were in agreement with those relative to the respective gene expression levels, although the differences were not statistically significant. In the larger DCC dataset, TS (p=0.005), and BRCA1 (p=0.021) were identified as prognostic markers for OS, independent of tumour stage. Conclusions: This study has shown that high RRM2 and TS protein levels are negative prognostic factors for resected, stage I-III NSCLC pts. The data obtained by qRT-PCR confirmed these results. Analysis of the DCC microarray dataset detected TS and BRCA1 as independent prognostic markers of OS.
Inflammatory phenotype of classical (CD14++CD16-) monocytes in patients with advanced non-small cell lung cancer.
Authors: McCarthy Fiona Margaret , Ghirelli Cristina , Zollinger Raphael , Phillips Melissa , Roshani Rozita , Candido Juliana , Trehy Roisin , Sheaff Michael , Steele Jeremy , Hagemann Thorsten 
Published: March 2020

11071 Background: Monocytes are intrinsic members of the innate immune system and play an important role in immunity and inflammation. Human monocytes are subdivided into three populations depending on cell surface CD14 and CD16 expression: Classical (CD14++ CD16-), intermediate (CD14+CD16- ) and non-classical (CD14- CD16++). These populations have diverse functions and have been postulated to play both anti and pro-inflammatory roles in a variety of diseases including atherosclerosis, sarcoidosis and other rheumatological conditions. However, the prevalent monocyte populations in cancer have not as yet been identified. We aim to define the prevalent monocyte populations in non-small cell lung cancer as well as further characterising them using flow cytometry and Affymetrix technology. Methods: Blood was obtained from 24 newly diagnosed patients with advanced non-small cell lung cancer and 12 age matched healthy donors. Monocyte subpopulations were sorted using flow cytometry. Gene expression profiling was performed using Affymetrix Human U133 Plus 2.0 array. Results: The classical (CD14++CD16-) monocyte population is significantly increased in non-small cell lung cancer patients when compared to healthy donors (p<0.01). The intermediate (CD14+CD16+) and non-classical (CD14- CD16++) populations are unchanged. Analysis of the gene expression profile of the classical monocyte subset identified 265 up-regulated and 261 down-regulated genes in cancer patients compared to healthy donors (p<0.05, fold change >2). These genes were assigned to biological processes with gene ontology annotation. Functional annotation reveals a strong association of regulated genes with the G.O term “inflammation” (p=0.009). Among these inflammatory genes are a cluster of chemokines including CXCL2 and CXCR4. Conclusions: By identifying the prevalent monocyte subsets as well as characterising their function in cancer, there is the potential to target detrimental effects and promote their beneficial functions. As such, monocytes subsets may be used as a possible therapeutic target.
Cancer-testis antigens in triple-negative and locally advanced breast cancer.
Authors: Harris Samuel John , Turner Natalie Heather , Chionh Fiona J.M. , Walkiewicz Marzena , Chakrabarti Anannya , Deb Siddhartha , Cebon Jonathan S. , White Shane , John Tom 
Published: March 2020

11072 Background: Cancer-Testis Antigens (CTAs) are immunogenic molecules that have increased expression in triple negative breast cancers (TNBC), a phenotype that whilst associated with poorer survival, is chemosensitive. We investigated expression of the CTAs MAGE-A, MAGE-C1, and NY-ESO-1 in women with Locally Advanced Breast Cancers (LABC) and TNBC to determine the association between CTA expression, survival and response to chemotherapy. Methods: We reviewed patient charts, treated for either TNBC or LABC between 1997 and 2011. Tissue samples were used for immunohistochemical (IHC) staining for MAGE-A, MAGE-C1 and NY-ESO-1 and compared using Fisher’s exact test. Positive expression was defined as any antigen staining above background.. Clinicopathological features were correlated with IHC results and survival estimated using the Kaplan Meier method. Results: A total of 106 cases were investigated (64 TNBC and 42 LABC). In the TNBC cohort the median age was 58 and TNM stages 1 to 3c. CTA expression occurred in 56, 51 and 43% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. CTA expression was not associated with overall survival (OS) or time to progression. In the LABC cohort the median age was 54 and consisted of stage IIIb tumors. All breast cancer subtypes were represented. CTA expression occurred in 26, 64 and 21% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. There was no association between CTA expression and response to chemotherapy. In a univariate analysis MAGE-A expression in the LABC group was associated with poorer OS (median 25 vs 76 months, HR 3.347 95% CI 1.44 to 21.68, p=0.015). However, there were more TN patients and Grade 3 tumors in the MAGE-A positive group. Across the two groups, MAGE-A (51 vs 14% p=0.002) and NY-ESO-1 (37 vs 2% p=0.006) but not MAGE-C1 had significantly higher expression in ER -ve tumors. There was higher expression of MAGE-A (51 vs 25% p=0.025) and NY-ESO-1 (43 vs 10% p=0.002) in Grade 3 tumors. Conclusions: MAGE-A, MAGE-C1 and NY-ESO-1 are highly expressed in TNBC and high-grade subsets of early breast cancer. CTA expression in TNBC was not predictive of survival nor response to chemotherapy in LABC. However, MAGE-A expression was found to be associated with poorer overall survival in LABC.
Clinical significance of programmed death ligand-1 expression in non-small cell lung cancer (NSCLC).
Authors: Velcheti Vamsidhar , Schalper Kurt , Carvajal Daniel , Chen Lieping , Sznol Mario , Gettinger Scott N. , Herbst Roy S. , Rimm David 
Published: March 2020

11075 Background: Programmed cell death ligand-1 (PDL1) is expressed on various human cancers and is a major mechanism for immune evasion. Preliminary evidence suggests that PDL1 expression on cancer cells predicts response to anti-PD-1 therapy. Here we report our findings using automated quantitative immunofluorescence (QIF) to determine the frequency and prognostic value of PDL1 in two independent NSCLC cohorts. Methods: Five antibodies against PDL1 were screened for sensitivity and specificity using PDL1 transfected cells, normal human placenta and tonsil. Only one monoclonal antibody (clone 5H1) met criteria for specificity. This antibody was used to assess two cohorts of NSCLC cases in TMAs. The cohorts represented 204 cases from Yale University and 340 cases from hospitals in Greece. PDL1 protein was measured using QIF analysis using AQUA method. In addition, in-situ PDL1 mRNA levels were measured in the Greek cohort using the RNAscope paired-primer assay with AQUA method. Results: PDL1 protein expression was detected in 25% and 36% of the studied cohorts, respectively. PDL1 positivity was significantly associated with the presence of tumor-infiltrating lymphocytes (TIL) in both series. Patients with PDL1 protein positivity had better outcome in both series (Log Rank: p=0.036 for Yale cohort, p=0.027 for Greek cohort). Multivariate analysis showed that PDL1 expression was associated with better outcome independent of histology, presence of TILs, and stage in the Greek cohort and marginally significant in the Yale cohort. These findings were further validated by the PDL1 in-situ mRNA measurement in the Greek cohort. PDL1 protein and mRNA levels showed a positive non-linear relationship (R2=0.14, P<0.001). Positive PDL1 mRNA was found in 53% of patients with NSCLC and was also associated with the presence of TILs and longer overall survival (31 vs. 43 months, p=0.017). Conclusions: Tumor PDL1 protein positivity is detected in 25-30% of NSCLCs and associates with increased TILs and better outcome. Elevated PDL1 mRNA occurs in a higher proportion of NSCLC cases and provides comparable prognostic information. Measurement of in situ PDL1 protein and mRNA could be of more clinical value than either method alone.
Intraoperative radiotherapy in early breast cancer: 400 consecutive patients in one institution.
Authors: Steiner Mariana , Leviov Michele , Biterman Arie , Shiloni Eitan , Goldman Jehudit 
Published: March 2020

1108 Background: From 2006 we offer intraoperative radiotherapy as the only post lumpectomy breast irradiation as an alternative to the standard post-operative WBRT in low risk early breast cancer patients (age > 60, invasive ductal carcinoma < 2 cm and clinically negative axilla). Younger patients (>50) or patients with tumors up to 3.5 cm or other histologies are treated too if they are not candidate for standard local therapy. In patients found to have high risk tumor characteristics at final pathology, additional local breast therapy is considered. Methods: Intrabeam System is used administering 20 Gy at the surface of surgical cavity. Results: 400 patients were treated. Their median age was 70 years (55-90). Median clinical tumor size was 12 mm (5-30). 14.5% had mild to moderate local complications: 6.5% wound infection, 5.8% complicated seromas, 1.7% bleeding or hematoma and 0.5% small skin necrosis. 6.2% experienced major complications: 2.5% required surgical intervention, 2% had late healing (> 90 days), 1% required IV antibiotics and 0.7% had grade III RTOG fibrosis. Median pathologic size was 14 mm (1-40). Pathologic free margins > 1mm were obtained in 98.8% of patients. 15.5 % were found to have axillary l-nodes involved (11% one node only), 12% of patients had adverse unexpected breast pathologic findings (7.5% EDCIS or LVI) and 11% had additional local therapy, most of them WBRT. Median follow up is 30 months (1-76) in the whole group and 43 months (3-76) in the first 200 patients treated. Seven ipsilateral breast failures (1.7%) and one axillary recurrence were observed, all had radical local therapy. Four patients developed systemic disease (1%), one of them with simultaneous breast recurrence and one had contralateral breast cancer. Conclusions: We conclude that intraoperative radiotherapy using the Intrabeam system is feasible and may offer an alternative to whole breast RT in low risk breast cancer patients. Clinically significant local morbidity rate is low and self limiting. Longer follow up is needed to evaluate final results and late toxicity.
Molecular tumor profiling (MTP) of poorly differentiated neoplasms (PDN) of unknown primary site.
Authors: Greco F Anthony , Spigel David R. , Hainsworth John D. 
Published: March 2020

11080 Background: The inability to definitively determine the lineage of neoplasms is less common with modern immunohistochemistry (IHC) and genetic profiling. Nonetheless some PDN defy lineage classification by extensive standard pathologic evaluation. The advent of MTP may provide a new method of improving the diagnosis of these challenging cancers. Methods: A total of 30 of 751 (4%) patients (pts) seen from 2000 – 2012 with cancer of unknown primary (CUP) had PDN without a definitive lineage determined by IHC (median 18 IHC stains, range 9 – 51). From 2008 – 2012 the 30 biopsies had MTP (RT-PCR mRNA CancerTYPE ID, bioTheranostics, Inc.). Additional IHC, genetic sequencing, fluorescent in situ hybridization for specific chromosomal changes and repeat biopsies were performed when feasible to support the MTP diagnosis, and clinical features correlated. Results: MTP lineage diagnoses were made in 25 of 30 (83%), including 10 carcinomas (3 germ cell, 2 neuroendocrine, 5 others), 5 melanomas, 8 sarcomas (3 peritoneal mesothelioma, 1 PNET) and 2 hematopoietic neoplasms (1 lymphoma, 1 chloroma). Additional IHC, genetic testing [BRAF, i(12)p] or repeat biopsies confirmed the MTP diagnoses in 11 of 15 tumors, and the clinical features were consistent with the MTP diagnoses in the majority of patients. Conclusions: This MTP assay can frequently provide a diagnosis for CUP pts and PDN without a definitive lineage defined by extensive IHC. The earlier application of MTP will likely provide an expedited diagnosis, and for some neoplasms is the only test capable of defining lineage and a more specific diagnosis. Appropriate therapy, particularly for pts with germ cell tumors, melanoma, and lymphoma depends on a specific tissue of origin diagnosis.
Diffusion-weighted imaging using ADC mapping as an imaging biomarker for breast cancer invasiveness.
Authors: Bickel Hubert , Bogner Wolfgang , Dubsky Peter Christian , Bartsch Rupert , Rudas Margaretha , Helbich Thomas , Pinker-Domenig Katja 
Published: March 2020

11093 Background: Recently, functional imaging techniques such as diffusion weighted imaging (DWI) have been added to routine MR and have shown great potential for improving breast cancer diagnosis. DWI depicts cellular diffusivity on a molecular level and can be quantified using the apparent diffusion coefficient (ADC). In malignant tumors diffusivity is restricted, leading to lower ADC values than benign tumors. The aim of this study was to proof, that DWI can be used to differentiate benign from malignant tumors and to elucidate if ADC can serve as an imaging biomarker for breast cancer invasiveness. Methods: In this IRB-approved study 250 patients with 267 suspicious breast lesions (BI-RADS IV-V) were included. All patients underwent routine MR at 3T. A DWI-sequence was added to a standard imaging protocol, increasing measurement time by 2:30 min. The lesions were identified in routine MR and DWI sequences and ADC values of the lesions were calculated. Histopathology was used as the standard of reference for all lesions. Appropriate statistical tests were used to compare the ADC values of benign and malignant tumors (cut-off value 1.25×10-3mm²/s), of invasive and non-invasive disease and between different invasive tumor subtypes. Results: There were 91 benign (mean ADC 1.58×10-3mm²/s) and 176 malignant (.94×10-3mm²/s) lesions, sensitivity and specificity were 94.3% (PPV 95.4%, CI 0.91-0.98) and 91.2% (NPV 89.2%, CI 0.81-0.94). 155 lesions were invasive cancers (median ADC .90×10-3mm²/s), while 21 were non-invasive ductal carcinoma in situ (1.22×10-3mm²/s). The invasive cancers were 130 invasive ductal (median ADC .91×10-3mm²/s) and 25 invasive lobular cancers (.83×10-3mm²/s). ADC was significantly different between benign and malignant lesions (p<.001) and between invasive and non-invasive cancers (p<.001), while no significant difference could be found between the invasive cancer subtypes (p=.163). Conclusions: Diffusion-weighted imaging reliably allows differentiation of benign and malignant breast tumors. The data suggest that ADC can be used as a non-invasive imaging biomarker for breast cancer invasiveness and may be of importance to treatment planning and outcome in breast cancer patients.
Clinical next generation sequencing (NGS) of fine needle aspiration (FNA) biopsies in non-small cell lung (NSCLC) and pancreatic cancers.
Authors: Hawryluk Matthew J. , Ross Jeffrey S. , Sheehan Christine E. , He Jie , Young Geneva , Otto Geoff , Yelensky Roman , Lipson Doron , Palmer Gary A. , Stephens Phil , Miller Vincent A. 
Published: March 2020

11100 Background: FNA is a common diagnostic procedure for the evaluation of pulmonary and pancreatic masses. We sought to determine whether NGS could be performed on these small specimens and to characterize heterogeneity across classes of genomic alterations (GA) in a subset of paired FNA and matched resected primary tumors. Methods: DNA was isolated from formalin fixed paraffin embedded (FFPE) sections of FNA cell blocks using 40µm total sections for NSCLC and 20µm total sections for pancreatic cancers in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries to a median depth of 931x for the NSCLC and 416x for the pancreatic FNAs. Results: Genomic profiles were successfully generated from 19/19 of the NSCLC and 22/23 of the pancreatic FNA cases. We found 97 GA in the 19 NSCLC FNAs (range 2-9, average 5.1 GA per patient). 68% of the patients had GA in TP53 and 21% in KRAS. Only 16% (3/19) patients did not exhibit an actionable alteration. We found 99 GA in the 23 pancreatic cancer FNAs (range 0-12, average 4.3 per patient). 74% of the patients had GA in KRAS. There was 94% concordance of GA found in 4 matched FNA and primary tumor pairs for the pancreatic cases. For the single discordance, manual inspection of the reads of the discordant allele indicated evidence of loss of heterozygosity. Conclusions: NGS can be reliably performed on small FNA samples processed into cell blocks, and the GA discovered significantly correlates with the GA found in matched primary tumors. This study demonstrates the feasibility of NGS in analyzing FNA samples and further broadens the spectrum of commonly encountered specimen types to which this approach can be successfully applied.
Comparison of in vivo skin and in vitro blood lymphocyte models for the prediction of late normal tissue responses in breast radiotherapy (RT) patients.
Authors: Chua Melvin , Somaiah Navita , Davies Sue , Gothard Lone , Rothkamm Kai , Yarnold John 
Published: March 2020

11116 Background: Critical opinions for the lack of success of DNA double-strand break (DSB) repair as a predictive marker of normal tissue radiosensitivity include the argument that in vitro cellular responses correlate poorly with in vivo responses due to the modifying influence of tissue environment. In this study, we test the hypothesis that a DNA damage assay based on in vivo irradiated skin tissues better predicts clinical responses in human skin, as opposed to the same assay performed in ex vivo irradiated lymphocytes. Methods: DSB levels (24 h post-4 Gy) were quantified using γH2AX/53BP1 immunostaining in irradiated skin tissues and G0 lymphocytes of 35 breast RT patients. Patients were selected on the basis of late RT effects in their breast and individuals with marked or minimal effects were classified as cases and controls, respectively. Risk factors of late effects established from multivariate analyses of outcomes of two breast RT trials were also considered in patient selection. They were 1) total RT dose, 2) RT dosimetry, 3) tumour bed boost, 4) breast size, 5) surgical cavity, and 6) axillary treatment. Results: Clinical parameters were balanced in both patient groups. Residual foci levels in skin epidermis and dermis were comparable between cases (n = 20) and controls (n = 15). Mean foci per cell were 3.29 in cases, 2.80 in controls for dermal fibroblasts (p = 0.07); 3.28 in cases, 2.60 in controls for endothelial cells (p = 0.08); 2.87 in cases, 2.41 in controls for superficial keratinocytes (p = 0.45); 2.32 in cases, 2.35 in controls for basal keratinocytes (p = 0.27). Residual foci levels in lymphocytes were however significantly higher among cases (foci per cell = 12.1) compared to controls (foci per cell = 10.3, p = 0.01). Of the different cell types, only residual foci levels of dermal fibroblasts and lymphocytes correlated with clinical severity (R = 0.722, p < 0.001; 0.593, p = 0.01, respectively). Interestingly, foci levels were not correlated between skin cells and lymphocytes of the same patients. Conclusions: DSB repair of ex vivo irradiated lymphocytes appears to be a better predictive marker of late effects to breast RT than DSB repair of in vivo irradiated skin.
Changes in the biologic markers between primary tumor and ipsilateral breast tumor recurrence after breast conserving surgery: Discordance and prognosis.
Authors: Okumura Yasuhiro , Nishimura Reiki , Nakatsukasa Katsuhiko , Yoshida Atsushi , Masuda Norikazu , Tanabe Masahiko , Shien Tadahiko , Arima Nobuyuki , Komoike Yoshifumi , Taguchi Tetsuya , Inaji Hideo , Ishitobi Makoto 
Published: March 2020

1116 Background: Changes in biological markers due to recurrence are clinically experienced in breast cancer. However, the clinical significance is still uncertain, especially after breast conserving surgery. The changes in biological markers between primary tumor and ipsilateral breast tumor recurrence (IBTR) and their correlations with prognosis were investigated, retrospectively. Methods: A total of 117 consecutive patients with IBTR without distant metastases were enrolled in this study. All patients were examined for ER, PgR, HER2 and Ki-67 in both the primary and recurrent tumors. The cases were categorized into 3 groups: patients with Ki-67 values <20%, <50% and ≥50%, and divided into 2 groups according to the IBTR site, same quadrant(SQ)and different quadrant(DQ) from the initial sites. The distant disease-free survival (DDFS) was calculated using the Kaplan-Meier method and evaluated by the log-rank test and multivariate analyses using Cox proportional hazards model. The median follow-up period was 4.8 years after IBTR. Results: The PgR positive rate from the primary tumor to IBTR decreased from 57% to 39% and the Ki-67 values increased significantly from a mean of 17% to 23%. The concordance rate of the subtype was 62%. In the SQ group, the PgR positive rate significantly decreased and the mean Ki-67 values significantly increased, whereas there was no significant difference in the DQ group. In terms of changes by category due to relapse, the discordance rate in Ki-67 was high in the SQ group, and HER2 was high in the DQ group. Regarding DDFS by a change in the categorization, the cases with discordance in Ki-67 values had significantly lower DDFS in the SQ group(5-year DDFS: 75% vs 52%, p=0.04). However, a clear difference was not found in the DQ group. Conclusions: The PgR positive rate decreased while the mean Ki-67 values increased due to IBTR in the SQ group. The categorical discordance in the Ki-67 values was significantly associated with lower DDFS, especially in the SQ group. These findings suggest that the recurrent site and change in the biological markers were clinical significant in the evaluation of the characteristics and treatment in cases with IBTR.