bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of personalized mRNA vaccine encoding neoantigen in patients with advanced digestive system neoplasms.
Authors: Zhan Xianbao , Wang Bin , Wang Yiran , Chen Longpei , Peng Xiaobo , Li Jie , Wu Meihong , Zhang Linli , Tang Shuhui 
Published: May 2020

e15269 Background: Cancer cells have characteristics of genetic instabilities and accumulate somatic mutations rapidly which could produce tumor specific antigens (TSAs) called as neoantigens. As the cancer vaccine based on TSAs has potential to treat the disease, personalized neoantigen-based immunotherapies are emerging. We report for the first time that vaccines are used to treat advanced digestive system neoplasms. Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03468244) to investigate the feasibility, safety, immunogenicity and clinical activity of personalized mRNA vaccine. Patients with advanced digestive system neoplasms received up to 20 stimulatory synthetic long peptides vaccine at a dose of 0.2 mg on days 1 and 0.8mg on days 2, administered subcutaneously of every 3 weeks(Q3W) for 12 weeks. Patients was treated with standard treatments according to NCCN guideline simultaneously. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Immune factors and ELISPOT assay were examined every 3 weeks after vaccination. Results: As of February 1st, 2020, three patients (52yrs, 47yrs and 52yrs; ECOG PS: 0) with advanced rectal, colon and gastric cancer completed the vaccine therapy for 3-4 cycles. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. The most common treatment-emergent adverse event (TEAE) was erythema at injection sites in three patients. Vaccine combined standard treatments treatment was associated with G3/4 hematological side effects: leucopenia (18%); neutropenia (9%); anemia (0); thrombocytopenia (18%). Blood samples for immune monitoring (ELISPOT and intracellular cytokine staining [ICS]) were collected pre-dose and at weeks 3 and 12. The level of IL-1β, IL-2 receptor, IL-6, IL-8, IL-10, and TNF-α increased for all patients. Especially, IL-8 and IL-2R increased significantly for more than 800 times in the patient with rectal cancer and more than 4 times in the patient with gastric cancer after injection, respectively. The PFS were 3.2, 3.0 and 3.0 months and the OS were 9.1, 6.0 and 7.8 months, respectively. Best response was 2 SD and 1 PD. Conclusions: This clinical study indicated that personalized mRNA vaccine may be safe and could activate immune response in vivo which is convinced by ELISPOT assay in vitro. Further studies are indicated to explore the personalized mRNA vaccine in gastrointestinal cancer. Clinical trial information: NCT03468244 .
Alterations of Raman profiles of nasopharyngeal carcinoma cells after treated with chemodrugs detected by laser tweezer Raman spectroscopy.
Authors: Li Miaomiao , Chen Xiaochuan , Lin Ting , Huang Zongwei , Wu Shihong , Liu Wei , Lin Duo , Zhang Lurong , Qiu Sufang 
Published: May 2020

e15513 Background: To explore the metabolic alterations of nasopharyngeal carcinoma (NPC) cells after treated with chemodrugs, the Raman profiles were characterized with laser tweezer Raman spectroscopy. Methods: Two NPC cell lines (CNE2 and C666-1) were treated with gemcitabine, cisplatin, and paclitaxel, respectively. The high-quality Raman spectra of cells without or with treatments were recorded at the single-cell level with label-free laser tweezers Raman spectroscopy (LTRS) and analyzed for the differences of alterations of Raman profiles. Results: Tentative assignments of Raman peaks indicated that the cellular specific biomolecular changes associated with drug treatment, including changes in protein structure (e.g. 1655 cm−1), changes in DNA content and structure (e.g. 830 cm−1), destruction of DNA base pairs (e.g. 785 cm−1), and reduction in lipids (e.g. 970 cm−1). Besides, both principal components analysis (PCA) combined with linear discriminant analysis (LDA) and the classification and regression trees (CRT) algorithms were employed to further analyze and classify the spectral data between control group and treated group, with the best discriminant accuracy of 96.7% and 90.0% for CNE2 and C666-1 group treated with paclitaxel, respectively. Conclusions: This exploratory work demonstrated that LTRS technology combined with multivariate statistical analysis has promising potential to be a novel analytical strategy at the single-cell level for the evaluation of NPC-related chemotherapeutic drugs.
A retrospective analysis of venous thromboembolism trends in chemotherapy-induced anemia.
Authors: Bryer Emily Jane , Kallan Michael J. , Chiu Ting-Shan , Scheuba Katharina M. , Henry David H. 
Published: May 2020

e15515 Background: Anemia is a common and unfortunate consequence of chemotherapy. Patients receiving a variety of chemotherapy regimens often develop chemotherapy–induced anemia (CIA), which contributes to poor outcomes, including increased mortality. Prompt and effective treatment of CIA is essential to prevent fewer chemotherapy dose delays and reductions. Despite the baseline coagulopathies present in patients with malignancy, administration of RBC transfusions is associated with venous thromboembolism (VTE). It remains unknown whether the risk of VTE in patients with CIA is greater among patients who receive single or multiple RBC transfusions. Methods: A retrospective study analyzed 10,269 University of Pennsylvania Health System patients with malignancies of various type, stage, and histopathology who developed CIA between 5/1/08-12/31/17. We analyzed rates of VTE development after adjusting for RBC intervention with a 95% confidence interval during the 90 days following CIA diagnosis. Results: Among the 10,269 patients with CIA, 2,008 patients (19.6%) received only RBC transfusion as anemia treatment; of that group, 545 (27.1%) developed a VTE. Transfusion of 2+ units RBC compared with 1 unit of RBC was associated with an increase in VTE development (RR = 1.37, 95% CI 1.09-1.72). The relationship of higher VTE development with increasing number of transfusions is displayed below. Conclusions: While RBC transfusion in patients with CIA is independently associated with VTE, our data further suggests an exponential risk of VTE development with increasing numbers of RBC transfusions. [Table: see text] [Table: see text]
Effect of different dox concentration with hapten and dose selection intratumoral injection on the survival time of tumor bearing mice.
Authors: Fu Qiang , Han Yan , Yu Baofa ,   Shandong Baofa Cancer Therapeutics, Inc,
Published: May 2020

e15517 Background: To explore the effect of chemotherapeutic drug (Dox) with the concentration on the survival of tumor-bearing mice after intratumoral injection plus hapten. It is important to observe whether there is any difference in survival rate between the different dose of drug-administered group with hapten and the positive control group. Methods: The H22 liver tumor-bearing mice with the longest path length of tumors of 5-8 mm were selected and administered according to the tumor volume. The second dose was administered at intervals of 7 days. The death of the mice was observed daily and the time of death was recorded in order to evaluate the survival of the mice. Results: The effect on body weight, except for the negative control group, decreased in weight after the first administration, and the effect was reversible. The effect on tumor volume was significantly slower than that of the negative control group after administration. In the life extension rate study, the sustained-release drug group was compared with the corresponding positive control group, the sustained-release drug group II and the positive control group II, the sustained-release drug group IV group and the positive control group IV group, and the sustained-release drug group V and The positive control group V had significant significance (P < 0.01). Therefore, the survival time of the group IV of the sustained-release drug was better than that of the positive control group IV, and the dose of the group IV of the sustained-release drug was the optimal dose. Conclusions: The reduction of doxorubicin hydrochloride concentration can prolong the survival time of mice and the survival rate of the sustained-release drug group with hapten is generally higher than that of the positive control group. By comparing the tumor inhibition rate and survival test results of the slow release drug group with hapten and the positive control group, the concentration of doxorubicin hydrochloride was initially screened at 1.0 mg/ml which is best concentration for this therapy.
Can tumor cells be distinguished from blood cells by mechanical parameters? A label-free CTC detection approach.
Authors: Nel Ivonne , Morawetz Erik W , Kaes Josef A , Aktas Bahriye 
Published: May 2020

e15526 Background: Even years after successful treatment of the primary tumor about 30% of breast cancer patients are suffering from metastatic relapse. One reason might be hematogenous spread. Therefore circulating tumor cells (CTC) in the blood might be interesting and easy accessible surrogate markers for disease monitoring. Due to phenotypical, mechanical and functional changes during cancer progression and treatment response, isolation of CTC subpopulations remains very challenging. Here we focused on the characterization of CTC mechanics to evaluate the utility of mechanical parameters for CTC separation from blood. Methods: For the first time, we investigated the active and passive mechanical CTC properties such as elasticity, viscosity and contractile force exertion using a dual beam trap. For proof of premise we used peripheral blood mononuclear cells (PBMC) from a healthy donor and human GFP-expressing MDA-MB 231 breast cancer cells to mimic a CTC model system and to measure cell type specific mechanical deformation profiles using an optical rheometer. For translational experiments blood samples were collected from patients with mamma or vulvar carcinoma. Hematopoietic cells were depleted using CD45. The remaining cell suspensions were applied to the optical stretcher and rheological parameters were measured in the same manner. Results: We were able to reveal distinct mechanical profiles from hematopoietic cells and breast cancer cells, respectively. The optical deformability was significantly different in both the model and the translational, systems comparing healthy PPMC to MDA-MB 231 cells, respective possible CTC candidates from breast and vulvar carcinoma patients. Evaluation of secondary parameters like viscosity and activity using a machine learning algorithm allowed for a clear distinction between hematopoietic and cancer cells in the model system. CD45-positive and -negative cells from patients with mamma or vulvar carcinoma (n = 7) showed distinct differences in the rheological behavior of both cell populations. Surprisingly, the mechanical profiles of CD45-negative cells from mamma carcinoma samples were severely different from vulvar carcinoma. Conclusions: Together with morphology and cell size, the cellular deformation pattern might be a proper tool for marker-free CTC detection in the peripheral blood of breast cancer patients.
Clinical utility of circulating genetically abnormal cells within low-dose computed tomography lung cancer screening: A correlative MCPND trial study.
Authors: Feng Mingxiang , Lin Miao , Zhou Haining , Zhu Yunhe , Chen Baishen , Ye Xin , Huang Chuoji , Zhang Juncheng , Bai Chunxue 
Published: May 2020

e15536 Background: Recent screening trial results using low-dose computed tomography (LDCT) have been shown to reduce lung cancer mortality in high-risk patients. However, high false-positive rates, inter-grader variability, and radiation injuries are challenging, and therefor highlight the necessity for complementary biomarkers. The diagnostic performance of circulating genetically abnormal cells (CACs) was respectively evaluated in samples collected from patients with pulmonary nodules before and after lung lobectomy within the Multicenter Chinese Pulmonary Nodule Detection (MCPND) trial. We also propose a deep learning that detects related genetically abnormal cells in excisions of symptomatic lesions to identify the source of CACs. Methods: 269 plasma samples (n = 179, before surgery; n = 90, after surgery) from 179 participants, including 125 patients with lung cancer and 54 donors with benign nodular lesions, were analyzed by using a FISH–based assay for 3p22.1, 3q29, 10q22_3 and CEP10. Diagnostic performance of CAC was evaluated in a blinded validation group. 109 paraffin-embedded specimens (45 benign nodular lesions, 64 malignancies) obtained from participants were tested in the same way to identify the genetically abnormal cells. Results: The diagnostic performance of CACs for lung cancer detection was 91% for sensitivity and 81% for specificity. For all participants, CACs had a positive predictive value of 92% and 80% for negative predictive value, respectively. Area under the ROC curve was 0.89 (P < 0.01; 95%CI (0.82, 0.96)). 90 plasma samples were drawn from patients within 10 days after surgery. Of these samples, 58 participants’ CACs level reduced and 25 of them remained stable. Moreover, of 64 malignant specimens, genetically abnormal cells were detected in 60 specimens. However, only 4 specimens were detected having genetically abnormal cells in 45 benign nodular lesions. Conclusions: This validation study indicated that the number of genetically abnormal cells in circulation decreased after surgical resection, which suggested CACs could be released from lung cancer. CACs have diagnostic and prognostic value and could assist to improve the diagnostic accuracy in early stage lung cancer after low-dose computed tomography. Clinical trial information: ChiCTR1900026233.
Potentially targetable alterations identified in circulating tumor DNA (ctDNA) from patients (pts) with advanced rare cancers.
Authors: Okuma Hitomi Sumiyoshi , Yonemori Kan , Kojima Yuki , Tanioka Maki , Sudo Kazuki , Noguchi Emi , Hijioka Susumu , Wakakuwa Keiko , Kato Ken , Ichikawa Hitoshi , Hirakawa Akihiro , Kuchiba Aya , Shibata Taro , Sukigara Tamie , Nakamura Kenichi , Yamamoto Noboru 
Published: May 2020

e15540 Background: People with rare cancers have limited treatment options. In April 2017, the MASTER KEY Project, a prospective registry study with multiple clinical trials embedded, was established to promote treatment development for rare cancers. ctDNA analysis by next-generation sequencing (NGS) has provided new insight into personalized medicine; however, reports are focused on common cancers. Using our platform, we examined the feasibility of ctDNA NGS analysis for rare solid cancers. Methods: Prospectively consented pts with advanced rare cancers enrolled in MASTER KEY had ctDNA NGS testing (Guardant360, Guardant Health). Alterations were assessed for incidence according to cancer type, functional impact, and therapeutic implications. Results: From Nov 2018 to Jan 2019, 98 samples from 100 consented pts were analyzed. Diseases included soft tissue sarcoma (39); cancers of the ovary (12) and salivary gland (9); neuroendocrine tumors (8); carcinoma of unknown primary (6); carcinosarcoma (5); mesothelioma (4); gastrointenstinal stromal tumor (3); and olfactory neuroblastoma (2). All pts were Japanese, male/female = 40/58, median age 53, ECOG performance status 0/1/2/3 = 56/41/0/1, prior pharmacotherapy yes/no = 77/21. 76% of pts (75/98) had at least 1 alteration detected (median 2.8/pt; range: 0-9), with variant allelic frequency of 0.1-73.3%; 61%(60/98) of pts had a likely pathogenic variant, most commonly TP53 (43), KRAS (11), and NRAS (6); 36% (36/98) had a potentially actionable variant, such as BRCA1/2 (6), EGFR (6), PIK3CA (6), ARID1A (5), FGFR1/2/3 (4), and other homologous recombination deficiency genes. Known resistant mutations such as ROS1 G2032R and RAS mutations were detected in patients on a ROS inhibitor and a BRAF inhibitor, respectively, which suggested drug resistance prior to clinical diagnostic imaging. Mean turn-around-time from blood collection was 9.5 days. Conclusions: ctDNA testing is capable of rapidly identifying alterations that lead to clinical decision making in pts with advanced rare cancers, who have a crucial lack of treatment options compared to common cancer pts. Clinical trial information: UMIN000034394.
Monitoring of therapeutic efficacy to CDK4/6 inhibitors and early detection of metastatic relapse in breast cancer by ultra-deep sequencing of plasma cell-free DNA.
Authors: Chin Yoon Ming , Shibayama Tomoko , Otaki Masumi , Chan Hiu Ting , Ono Makiko , Ito Yoshinori , Takahashi Shunji , Ohno Shinji , Ueno Takayuki , Nakamura Yusuke , Low Siew-Kee Kee 
Published: May 2020

e15544 Background: CDK4/6 inhibition substantially improves progression-free survival for women with advanced estrogen receptor-positive breast cancer. Despite this, most patients experience acquired resistance. The analyses of cancer specific genomic aberrations in plasma cell free DNA, or commonly referred to as ‘liquid biopsy’, has generated immense interest. The role of liquid biopsy enables monitoring of therapeutic efficacy to detect relapse in a minimally invasive manner. It would drastically impact risk stratification, treatment selection and patient clinical outcome in advanced stage breast cancer. Methods: We have recruited consecutive patients with metastatic breast cancer who received CDK4/6 inhibitor treatment in combination with endocrine therapy between April 2018 and December 2019. Somatic mutations identified by the Oncomine Pan-Cancer cell free assay were used to assess the mutation profiles of circulating tumor DNA (ctDNA) by ultra-deep sequencing (~56,000 depth) of the plasma DNA. Plasma samples (N = 146) were collected before and during treatment (2 years) or until disease progression. Paired white blood cells (WBC) were also sequenced to exclude clonal hematopoiesis-derived mutations. Results: Twenty-eight patients were enrolled. Based on RECIST criteria, 1 patient showed complete response (CR) within 18 months of treatment, 5 patients showed partial response (PR) 6-18 months from start of treatment, 9 patients showed stable disease (SD) condition within 3-18 months and 13 patients developed progressive disease (PD) within 1-12 months. In 22 of 28 patients (79%), ctDNA was detected prior to start of treatment (12 responders; 10 PD) and used as a monitoring marker. Majority of mutations detected in pre-treatment samples were TP53, PIK3CA and ESR1. Among the 12 ctDNA positive responders, ctDNA levels of 9 patients were undetectable within 2 weeks to 6 months from start of treatment (median 3 months). ctDNA profiles were more reflective of clinical response compared to the tumor markers CEA and CA15-3. In 7 of the 10 PD patients with ctDNA monitoring markers, ctDNA showed higher sensitivity to predict disease progression compared to tumor markers that remained stagnant or below normal threshold. ctDNA also predicted PD earlier than radiological images with a median lead time of 3 months. Conclusions: ctDNA assessment for therapy monitoring and early relapse detection in advanced breast cancer is feasible and provides a basis to evaluate early therapeutic interventions.
Urinary cell-free DNA analysis for tumor mutation detection in patients with oligometastatic colorectal cancer.
Authors: Pellini Bruna , Pejovic Nadja , Harris Peter , Feng Wenjia , Usmani Abul , Qaium Faridi , Fields Ryan , Chaudhuri Aadel 
Published: May 2020

e15545 Background: Cell-free DNA (cfDNA) analysis from blood is a useful liquid biopsy strategy. However, it requires phlebotomy and moderate volumes of plasma. Here, we explored the feasibility of urinary cfDNA (ucfDNA) analysis in patients with oligometastatic colorectal cancer (CRC). Methods: We applied error-corrected targeted next-generation sequencing (NGS) (AVENIO ctDNA surveillance assay) to 10 patients with oligometastatic CRC to the liver who underwent curative-intent surgery. 40 paired samples (tumor, plasma, urine supernatant, peripheral blood mononuclear cells (PBMCs)) were collected, from which DNA was extracted. Plasma and urine cfDNA samples (acquired preoperatively) were sequenced to a median de-duplicated depth of 8,065X with on-target rate of 71%. Similarly high depth targeted NGS was applied to tumor and PBMC samples. Variants were called from plasma cfDNA and tumoral DNA and queried in ucfDNA using methods derived from CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) with integrated digital error suppression (iDES). Clonal hematopoiesis was accounted for by removing mutations also present in PBMCs. Results: Patients had a median of 2 tumors resected (range 1-7) with average sum of longest diameters of 8.7 cm (range 0.6-11). We used an average of 10 ml of blood and 37 ml of urine for cfDNA extraction. Circulating tumor DNA (ctDNA) was detected in all preoperative plasma samples (n = 10) at a mean mutant allele fraction (MAF) of 2.35% (range 0.09-11.78). Plasma ctDNA MAFs correlated significantly with tumor SLD (Pearson r = 0.81, P = 0.03). The average number of single nucleotide variants detected in plasma cfDNA, tumor and ucfDNA was 8 (range 1-42), 4 (range 1-7) and 2 (range 0-11), respectively. Indicative of concordance, 79% of the mutations called in tumor were detected in plasma. Tumor-derived DNA was detected in the preoperative urine of 6 patients (60%) with a MAF of 0.05% (range 0.03-0.12), ~35-fold less than in plasma (MAF of 1.78%, range 0.09-7.94) (P = 0.004). 38% of mutations identified in tumor and 26% from plasma were detected in ucfDNA for these 6 patients. In two patients, targetable mutations (BRAF p.Asp594Gly and PIK3CA p.Glu545Lys) present in tumor were also detected in ucfDNA, with the latter not detected in plasma. Conclusions: Our results indicate that ucfDNA analysis in patients with oligometastatic CRC is feasible; however, the mutational levels and detection sensitivity were much lower than from plasma. Yet, there may be situations where actionable mutations are missed in plasma but detected in urine.