bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum metabolism during breast cancer treatment.
Authors: Giskeødegård Guro Fanneløb , Madssen Torfinn Støve , Vettukattil Riyas , Flote Vidar Gordon , Husøy Anders , Lofterød Trygve , Lundgren Steinar , Bertheussen Gro Falkener , Schlichting Ellen , Wist Erik Andreas , Thune Inger , Bathen Tone Frost 
Published: September 2018

e23043 Serum metabolism during breast cancer treatment Background: Breast cancer treatment may include surgery, systemic therapy and radiation, often involving side-effects. Many patients experience weight gain during treatment, which is associated with decreased survival rates1. The purpose of this study was to describe serum metabolic alterations in breast cancer patients undergoing treatment, and relate these alterations to weight gain during treatment. Methods: This pilot study includes 60 breast cancer patients, aged 35-75 years, with histologically verified stage I/II disease. All patients underwent tumor surgery, and were treated according to national guidelines. Samples were collected before and 6 months after surgery, and analyzed by MR spectroscopy (MRS) and mass spectrometry (MS). 170 metabolites and 105 lipoprotein subfractions were quantified by combined MRS and MS analyses. Results: Multilevel PLS-DA showed significant alterations in serum metabolite profiles post-treatment, both in patients receiving (n = 35) and not receiving (n = 25) chemotherapy (classification accuracy: 86.7% and 77.0%, resp., p < 0.001). Lipoprotein profiles were also significantly altered in both groups (p < 0.001). Chemotherapy recipients had decreased levels of citrate, ornithine, and methionine after treatment, while non-recipients had increased levels of glutamate, alanine, proline and two biogenic amines, and decreased levels of acylcarnitines. 17/52 patients (32.7%) gained weight (≥ 1.5 kg) during treatment. Weight gain was predicted from pre-treatment samples with accuracy 67.0% (p = 0.020). Weight gain patients had lower levels of three acylcarnitines and 20 phosphocholines, and higher levels of lysine and isoleucine, suggesting aberrant lipid and amino acid metabolism. Weight gain was also reflected in the post-treatment samples (accuracy 66.8%, p = 0.015), with weight gain patients having higher levels of five acylcarnitines, and lower levels of glycine, isoleucine and valine. Conclusions: This study indicates that treatment induces changes in serum metabolite levels. Patients gaining weight had significantly different metabolite profiles than those not gaining weight both before and after treatment. 1. Chan et al, Ann Oncol 25: 1901-14, 2014.
Baseline mutation profiling of circulating cell-free DNA from healthy individuals to improve the detection accuracy of circulating tumor DNA in cancers.
Authors: Tian Geng , Xia Ligang , Li Zhoufang , Li Xiaohua , Xu Feiyue , Liu Chaoyu , He Jiankui 
Published: September 2018

e23057 Background: Cell-free circulating tumor DNA (ctDNA) has emerged as an effective blood-based biomarker for clinical diagnostics in cancers, improving the accuracy and efficiency of cancer treatment for clinic. However, the somatic mutations originated from inheritance or normal biological metabolism in circulating cell-free DNA (cfDNA) in plasma can largely interfere with the detection of ctDNA. The baseline for ctDNA evaluation is urgently needed for accuracy identification of ctDNAs in patients. Methods: Averagely 20 ml blood samples were collected from more than 1200 individuals including healthy volunteers, lung cancer, colorectal cancer, pancreatic cancer, gastric cancer patients, etc. Genomic DNA from white blood cells and cfDNA from plasma were extracted and constructed as sequencing libraries using a panel contains 50 cancer-associated genes, respectively for each sample. Then they are subjected to ultra-deep sequencing with average depth > 40000 folds covering ~21K nucleotide regions. Results: The background somatic mutation frequencies were detected in genomic DNA and cfDNA in healthy controls. The results showed that most of mutations in cfDNA were consistent with those in genomic DNA. Using data from 1200 individuals, we generated the baseline mutation profiling of cfDNA, which was referred in the ctDNA determination in cancer samples, which significantly improved the accuracy of ctDNA detection compared with tissue biopsy. Conclusions: Our studies demonstrated the importance of sequencing both cfDNA and genomic DNA for ctDNA detection in cancers. We also determined the baseline mutation profiling of circulating cfDNA from more than 1200 healthy individuals and confirmed the value of it by comparing with DNA sequencing data in cancer tissue. Our work offers clue on how to improve the detection accuracy of circulating tumor DNA in early cancer diagnosis.
LKB1 and its importance for survival in EpCAM negative circulating tumor cells (CTC) in metastatic breast cancer.
Authors: Trapp Elisabeth Katharina , Andergassen Ulrich , Koch Julian Gregor , Majunke Leonie , Zill Beate , Kurt Ayse , Harbeck Nadia , Mahner Sven , Tzschaschel Marie Lena Johanna , Friedl Thomas W. P. , Janni Wolfgang , Rack Brigitte Kathrin , Alunni-Fabbroni Marianna 
Published: September 2018

e23061 Background: To reach distant sites, CTC overcome metabolic stress and acquire a mesenchymal phenotype. So we assessed the pro survival function of liver kinase B1 (LKB1) a cellular metabolic stress controller, in combination with the EMT transcription factor Zinc finger E-box binding homeobox factor 1 (ZEB1) and stem cell markers e.g. CD44 in EpCAM negative CTC. Tumor spheroids and targeted si-RNA knockdown of LKB1 were analyzed in two breast cancer cell lines to support transcriptomic data. Methods: CTC were isolated from whole blood of 27 metastatic breast cancer patients. 17 age matched healthy donors were negative control. All patients were analyzed with CellSearch system to detect EpCAM positive CTC, which were eliminated by immunodepletion (AdnaTest BreastCancerSelect Kit, TATAA Biocenter) together with CD45 positive white blood cells (Miltenyi Biotec). RNA transcripts were quantified by qPCR (TaqMan Gene Expression Assay, ThermoFischer Scientific) and the relative expression was calculated by the 2-DCtmethod. EpCAM negative CTC and spheroids were analyzed by immunofluorescence. Data were analyzed by non-parametric statistical tests. Results: According to the CellSearch system, most patients (74%, n = 20) were CTC negative. 20% of this sub-group showed enhanced levels of ZEB1, 15% of LKB1, and 40% of stem cell markers. ZEB1 and LKB1 were never co-expressed, while there was an almost significant association between enhanced ZEB1 and stem cell marker expression (p = 0.053). Immunofluorescence analysis on single CTC confirmed the transcriptomic result. MDA-MB 231 cell lines, normally negative for LKB1 and unable to grow in suspension, showed the ability to generate spheroids only if LKB1 expression was activated. Targeted knockdown of LKB1 confirmed these results. Conclusions: CellSearch system negative patients present a heterogeneous CTC population with enhanced levels of ZEB1, CD44, or LKB1. While ZEB1 and CD44 might be highly expressed in cells that already have entered EMT, LKB1 overexpression could represent the response to metabolic stress induced in the early phase of intravasation Hence, LKB1 might represent a novel therapeutic target to chase CTC and prevent metastasis.
Serial CTC/cfDNA assessment for the identification of pathogenic mutations in patients with breast cancer.
Authors: Irie Hanna , Schmidt Paul H. , Port Elisa R. , Kinoshita Yayoi , de la Iglesia Janis , Pisapati Kereeti , Couri Ronald , Kolodka Olivia , Arib Hanane , Sebra Robert P. , Donovan Michael Joseph 
Published: September 2018

e23070 Background: Serial liquid biopsy assessment provides a unique platform for detecting existing and / or emergent resistance mutations; it may be particularly beneficial when patients begin to progress on otherwise effective therapy. We aimed to determine the utility of such an approach for detection of tumor genetic alterations at multiple points during the clinical course of patients diagnosed with breast cancer. Methods: Twenty patients diagnosed with stage I-IV breast cancer (50% with triple negative disease) receiving treatment at the Dubin Center of Mount Sinai were consented for serial CTC/cfDNA collections between October 2015 and November 2016. Circulating tumor cell (CTC)/cell-free DNA (cfDNA) were isolated using Cynvenio’s Liquid Biopsy platform and sequenced utilizing the Hotspot/Oncomine panels. DNA from corresponding patient tumors, when available, was also sequenced. Results: 25% of patients had at least one known pathogenic mutation detected in either cfDNA or CTC DNA in at least one collection; all patients had stage IV disease at collection. Pathogenic mutations detected were in p53 (15%), PIK3CA (10%) and Smad4 (5%). For those patients with available tumor tissue, the same pathogenic mutation was detected in the primary tumor. Mutations were more often detected in cfDNA rather than CTC DNA. Finally, known pathogenic mutations were more consistently detected in serial collections with clinical disease progression and resistance to treatment. Conclusions: Pathogenic mutations were identified in 25% of patients, more frequently in cfDNA and not in every collected sample, supporting serial collection studies to monitor response. Presence of same pathogenic mutations in the patient’s primary tumor suggest a role for surveillance in early stage, as well as advanced disease.
Ultrastructural study of tumor-infiltrating СD4+ Т-lymphocytes in colon cancer.
Authors: Grankina Anastasia , Zlatnik Elena Yurievna , Novikova Inna Arnoldovna , Filippova Svetlana Yu. , Logvinov Aleksandr K. , Kolesnikov Vladimir 
Published: September 2018

e23074 Background: The purpose of the study was to assess stress-induced metabolic changes in СD4+ T-lymphocytes among tumor-infiltrating lymphocytes (TILs) according to ultrastructural morphometric parameters. Methods: Samples (n = 12) of colon adenocarcinoma, corresponding resection line tissues and blood of patients and healthy donors were studied. After grinding the samples and PBMC isolation using the density gradient, CD4+ T-lymphocytes separation with magnetic columns was performed using CD4 MicroBeads, human (MACS Miltenyi Biotech). The pellet obtained after centrifugation was embedded in agarose and prepared for transmission electron microscopy. Mitochondria images on ultrathin sections of Т-lymphocytes were randomly selected for the analysis. The total number of mitochondria studied were 71 (tumor), 78 (normal tissue), 78 (blood of patients), 80 (blood of healthy donors). For each image the unchanged cristae area was determined as a percentage of the total area of mitochondria cross section. Results: We found no differences in the structures of mitochondria of blood lymphocytes in patients and in healthy donors. Comparison of parameters of CD4+ Т-lymphocyte mitochondria in the colon unchanged tissues and in the blood of patients did not show significant differences indicating minimal damage during TILs` isolation from the tissues. Electron microscopy of TILs derived from tumor tissue showed more frequent apoptotic and necrotic death of lymphocytes, as well as some mitochondrial swelling with changes in the shape and the number of cristae compared to the norm. Statistical analysis revealed significant decrease in the relative area of unchanged cristae: 57% in tumor against 73% in the normal tissue (p < 0.0001, χ2Test). Conclusions: The results suggest that stress-induced changes are developed in tumor-infiltrating CD4+ T-lymphocytes, and these changes apparently enhance their death as demonstrated by ultrastructural characteristics of mitochondria.
Development of a unique anti-CD137 therapeutic antibody: Efficacy and safety profiles in mono and combination therapy.
Authors: Liu Guizhong , Cheung Peter , Chen Jun , She Xiaohong , Du Felix Fangyong , Luo Peter 
Published: September 2018

e23079 Background: Abstract: CD137 (4-1BB), a member of the TNFR super family, is expressed on several subsets of activated immune cells and acts as co-stimulatory receptor for T-cells to promote cellular proliferation, survival and cytokine production. Agonist antibodies against human CD137 in early clinical trials show strikingly different toxicology profiles, ranging from severe liver toxicity at low doses, to manageable adverse effects at modest doses. Whereas preclinical studies in mouse show intense liver T-cell infiltration and toxicity by surrogate agonist mAb. The preclinical efficacy and pharmacology of anti-CD137 were extensively tested and validated in various tumor models with intact immune system. Since none of the available anti-CD137 agonist antibodies display multiple species cross reactivity including rodent, the translational significance of these mAbs is limited concerning their efficacy and safety profile. Methods: Through our proprietary Dynamic Precision Library (DPL) technology, we have discovered multiple agonistic antibodies that exhibit high affinity and broad species cross-reactivity against a unique epitope shared among human, monkey and rodent CD137. Results: These mAbs, after crosslinking, strongly activate CD137 mediated cellular NFkB signaling, as well as stimulate T-cell proliferation and IFNg release in the presence of suboptimal concentrations of anti-CD3 antibodies. The broad species cross-reactivity by a single therapeutic agent enabled us to evaluate their potentiation of host immune responses that gives rise to the anti-tumor efficacy and potential toxicity in relevant rodent and monkey models. Our lead anti-CD137 agonist mAb has demonstrated robust anti-tumor activities in multiple mouse syngeneic tumor models, with durable antigen specific protective memory T-cell responses. Conclusions: In sharp contrast to surrogate anti-mouse CD137 mAbs, no toxicities including liver inflammation or other adverse effects were observed. These preclinical results warrant further clinical development of our lead as a novel immunotherapeutic anti-cancer agent.
Stratification of tumors based on mTOR-pathway biomarkers.
Authors: Laes Jean-Francois , Sauvage S Bastien , Ghitti Gregori 
Published: September 2018

e23097 Background: The mTOR pathway is often activated in human cancers. In this study, a total of 538 samples representing 40 different cancer types were analysed to evaluate the relationship between mTOR pathway activity and mutations in the upstream genes PIK3CA and PTEN. Methods: FFPE samples were analysed both by NGS (PIK3CA, PTEN, mTOR, TSC1, TSC2) and IHC (PTEN, 4pEBP1). Results: Overall, mTOR-pathway activation was identified in 83% of the samples, functional mutations were found in either or both PIK3CA and PTEN genes in 32% of the samples but there was no signification association between them. However when separating samples by cancer types, potential associations were identified. One example is the combination of PIK3CA activating mutation and PTEN loss of function which was associated with mTOR-pathway activation, most notably in the breast-cancer samples. Such combination has been associated with poor outcomes to some treatments (trastuzumab). Conclusions: In conclusion, our results show that stratification of tumors using the combination of mTOR-pathway biomarkers (and combined NGS and IHC technologies in their assessment) is potentially more informative than using a single biomarker to select the best treatment.
Secretary leukocyte peptide inhibitor (SLPI) in pleural fluid is useful as a diagnostic marker of malignant pleural mesothelioma.
Authors: Fujimoto Nobukazu , Kojima Yoko , Kishimoto Takumi 
Published: September 2018

e23098 Background: There is no established diagnostic marker for malignant pleural mesothelioma (MPM). In particular, the differentiation from benign asbestos pleural effusion (BAPE) is challenging. Secretary leukocyte peptide inhibitor (SLPI) is an enzyme encoded by SLPI gene. SLPI gene is reported to be overexpressed in MPM cells. Methods: SLPI in pleural fluid was determined using Quantikine ELISA Human SLPI kit (R&D Systems). Results: Exploratory research revealed that SLPI value in pleural fluid of patients with MPM (n = 52) were significantly higher than those in lung cancer (LC) (n = 69) and BAPE (n = 50) ( P= 0.000). Prospective validation study included 12 pts of MPM, 24 pts of LC, 26 pts of BAPE. Median values of SLPI in MPM, LC, and BAPE were 159 .6 ng/ml, 90.5 ng/ml, and 43.2 ng/ml, respectively. SLPI value in patients with MPM were significantly higher than those in other groups ( P= 0.000). Receiver operating characteristics ROC) analysis was performed to examine the usefulness of differentiation of MPM and other diseases, and demonstrated that area under the curve (AUC) value was 0.758. With the cut of value of 88.6 ng/ml, the sensitivity was 83.3% and the specificity was 59.8%. Concerning the differentiation between MPM and BAPE, AUC value was 0.904 and with the cut of value of 81.8 ng/ml, the sensitivity was 83.3% and the specificity was 92.3%. Conclusions: Pleural fluid SLPI is a useful biomarker for the diagnosis of MPM, in particular, for the differentiation from BAPE.
Ranolazine and TDM1 treatment: Cardioprotective effects in vitro and in vivo.
Authors: Maurea Nicola , Coppola Carmela , Piscopo Giovanna , Riccio Gennaro , Rea Domenica , De Vecchis Renato , Maurea Carlo , Sorrentino Giorgia , De Lorenzo Claudia , De Laurentiis Michele 
Published: September 2018

e23102 Background: Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate consisting of trastuzumab (TRAS) covalently linked to the highly potent microtubule inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2 positive breast cancer patients. Although, the potential cardiotoxic effects of TDM1 have not yet been fully elucidated, they can include changes in Ca2+ regulation related to blockade of ErbB2, PI3K-Akt and MAPK pathways. Here, we aim to elucidate whether Ranolazine (R), administered after TDM1 treatment, blunts or not cardiotoxicity in vivo and in vitro. Methods: In vitro, human fetal cardiomyocytes (HFC) were treated with TDM1 for 3 days and then treated in the absence or presence of R for 3 days. Cell viability was assessed by cell counting and MTT assay. To evaluate cardiac function in vivo, C57/BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured, by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using 2D speckle-stracking. These measurements were repeated after 5 days of R treatment (305 mg/Kg/day), started at the end of TDM1 treatment. Results: R reduces TDM1 toxicity in HFC, as evidenced by the higher percentage of viable cells treated with TDM1+ R with respect to the cells treated with TDM1 alone (p < 0.01). In in vivo studies: after 7 days with TDM1 administration, FS decreased to 53.6±0.9%, versus 61.0±0.8 % (sham), (p < 0.01), and EF decreased to 85.5±3.5 % versus 91.0±0.8% (sham), (p < 0.01). Moreover, RS decreased to 20.92±3.2 % versus 42.2±10.1% (sham) (p < 0.01), and LS decreased to -15.5±2.8 % versus -23.6±6.7% (sham), (p < 0.01).In mice treated with TDM1 and, successively treated with R for 5 days, the indices of cardiac function partially recovered: FS 58±2.4 % (p < 0.05), EF 88.8±1.7 %, (p < 0.05), RS (35.7±8.2 %, p > 0.05), whereas the alteration of LS persists even after treatment with R (-17.3±3.7 %, p > 0.05) Conclusions: Here we show that in vivo R post-treatment reduces cardiotoxic effects due to TDM1, as demonstrated by the recovery of FS, EF and RS values. As expected, R increases cell viability of HFC treated with TDM1.
Clinical and radiological features of advanced RET-rearranged lung cancer.
Authors: Saiki Masafumi , Ohyanagi Fumiyoshi , Ariyasu Ryo , Koyama Junji , Sonoda Tomoaki , Kawashima Yosuke , Takano Natsuki , Oguri Tomoyo , Nishikawa Shingo , Kitazono Satoru , Yanagitani Noriko , Horiike Atsushi , Ninomiya Hironori , Takeuchi Kengo , Ishikawa Yuichi , Oikado Katsunori , Nishio Makoto 
Published: September 2018

e23104 Background: RET fusion gene was found in 1–2% of non-small cell lung cancer (NSCLC). Most of the reports published so far investigated only surgical specimens, and details of advanced tumors were unknown. This study explored the clinical and radiological characteristics of RET-rearranged lung cancers in advanced stages. Methods: Among 1,074 advanced NSCLC patients who were treated at The Cancer Institute Hospital, Tokyo, from 2012 to 2016, 14 cases (14/1,074 = 1.3%) were treated as RET- rearranged lung cancer. The cases were identified by FISH and / or by RT-PCR (FISH 3, RT-PCR 2, FISH and RT-PCR 8, unknown 1). The fusion partner genes included KIF5B (n = 10), CCDC6 (n = 1). Three were unknown. The tumor size, location, and shape/margins of the primary tumor as well as lymphadenopathy and site of metastasis were recorded based on computed tomography (CT) images taken right before the initial chemotherapy. Results: The median age of the 14 patients was 64 years (range, 34–79), with 10 patients (71%) over 60 years old. Nine patients (64%) were women, whereas 10 patients (71%) were never smokers. Eight patients were classified as stage IV and 6 underwent recurrence after surgery. We successfully evaluated CT images at the initial chemotherapy of 12 patients. Of the 7 patients whose primary lesions were detectable, all were located peripherally and were of a solid tumor type without ground-glass, air bronchograms, or cavitation. The median size of the primary lesion was 3.0 cm (range, 1.2–6.8), and 3 lesions were less than 3.0 cm. Only 5 patients had lymphadenopathy (4 were of Stage IV, 1 was a recurrence), most of which were isolated with a median size of 1.5 cm (range, 1.2–3.5). The sites of distant metastases included 8 pleural disseminations, 5 lungs, 5 bones, 3 livers, 2 brains, and 0 adrenals. Conclusions: Advanced RET-rearranged lung cancer manifested as a relatively small and peripherally located solid primary lesion with isolated lymphadenopathy. Pleural dissemination was frequently observed, whereas brain metastasis was less frequent. These features differ from EGFR-mutated or ALK-fused lung cancers.
Next generation sequencing to reveal potentially actionable alterations in the majority of patients with hematologic malignancies.
Authors: Galanina Natalie , Goodman Aaron , Tran Lisa , Bejar Rafael , Choi Michael Y. , Kurzrock Razelle 
Published: September 2018

e23133 Background: Next generation sequencing (NGS) permits identification of genomic alterations that inform disease classification and prognosis and may also guide therapy selection. Methods: Using NGS (406 genes), we analyzed the clinical characteristics, genomic alterations, and potential actionability of 235 patients (pts) with diverse hematologic malignancies. Results: A total of 227 pts (96.5%) (59% men; median age 59 yrs) had adequate tissue for analysis. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), myeloproliferative neoplasm (9.2%), acute myeloid (11%) / lymphoid (8.8%) leukemia and multiple myeloma (7.5%). The majority of pts (N = 197/227 (86.8%)) harbored ≥1 genomic alteration(s); 164 pts (72%) had ≥1 potentially actionable alteration(s) targetable by an existing FDA-approved drug (mostly off label) or an investigational agent. A total of 551 distinct alteration s were seen with the most common involving TP53 (9.3%), TET2 (4.2%), DNMT3A (3.3%), ASXL1 (2.5%), MLL (2.5%), KRAS (2.2%). The vast majority of pts had unique molecular profile. Conclusions: About 96.5% of pts with hematologic malignancies have adequate tissue for NGS. Most pts had unique molecular signatures, and 72% had alterations that may be pharmacologically tractable. [Table: see text]