bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of microRNAs that target PD-L1 in mismatch repair-deficient colorectal cancer.
Authors: Ashizawa Mai , Okayama Hirokazu , Ishigame Teruhide , Mimura Kousaku , Kono Koji 
Published: February 2018

85 Background: Programmed cell death 1 (PD-1) / PD-ligand 1 (PD-L1) immune checkpoint blockade has emerged as a promising therapeutic strategy in various types of cancer. Here we report that certain microRNAs (miRNAs) are involved in immunosuppressive microenvironment by directly targeting PD-L1 in mismatch repair deficient (dMMR) colorectal cancer (CRC). Methods: We identified candidate miRNAs by using RNA-sequence analyses for mRNA and miRNA expression obtained from The Cancer Genome Atlas (TCGA) Colon Adenocarcinoma combined with miRNA target prediction programs. HCT116 and SW837 CRC cell lines were transfected with miRNA mimics and inhibitors, and PD-L1 expression was examined by qRT-PCR, western blotting and flow cytometry. The CRC cell lines were co-cultured with activated T cells and then cytotoxicity for T cells were evaluated. Results: Using miRNA expression profiles of 260 tumors obtained through TCGA Colon Adenocarcinoma, 47 miRNA probes were found to be inversely correlated with PD-L1 expression. Among them, 19 mature miRNAs were down-regulated in dMMR tumors. Furthermore, eight in silico miRNA-target prediction programs were utilized to identify candidate miRNAs that target the 3’UTR of PD-L1 mRNA. We found that forced miRNA expression decreased PD-L1 expression in protein (total and surface) and mRNA levels, and they also dramatically decreased IFN-induced cell surface PD-L1 expression by 32% in CRC cell lines. Furthermore, we found that forced miRNA expression decreased PD-L1 associated apoptotic cell death in co-cultured activated T cells. Conclusions: Our findings suggest that PD-L1 expression is at least in part regulated by miRNAs and may also suggest potential miRNAs to serve as biomarkers and therapeutic targets for cancer immunotherapy.
Aspartyl (Asparaginyl) β-Hydroxylase AABH as a serum biomarker for colorectal cancer.
Authors: Moshiri Mahmood , Moshiri Kiarash , Farbod Yasamin , Moshiri Arsha , Sekhavati Mohammad Hadi 
Published: February 2018

86 Background: Colorectal Cancer (CRC) is the third most common type of cancer diagnosed in the US and Canada. WHO, Canadian Cancer Society (CCS), the National Comprehensive Cancer Network (NCCN) and American Cancer Society (ACS) recommend that men and women begin CRC screening at age 50 or younger if at high risk. Recommended screening procedures: Annual occult fecal blood test (OFBT), a colonoscopy every 5 years, OFBT and colonoscopy every 5 years, or a colonoscopy every 10 years. According to The Surveillance, Epidemiology, and End Results (SEER) Program, only 39% of CRC are diagnosed in stage I, 36% are diagnosed in Stage II, 19% are diagnosed with metastasis. The corresponding 5-year survival rates are 89.8%, 67.7%, and 10.3%. Neither the CCS nor the ACS recommends a blood test be done as part of screening. This is due to the fact that, until now, there has not been a blood test with adequate sensitivity or specificity for screening. Methods: In this study we discovered that Aspartyl (Asparaginyl) β-Hydroxylase (AABH) measurement in serum can be used as an screening test for CRC. AABH has been detected by immunohistochemical staining (IHC) on the cell surface of different cancers including CRC. It has been detected by IHC in > 97% of tumor specimens tested (n > 200) but has not been found in tissue samples from normal individuals. Results: This observation and the observation that AABH is found in the serum of patients with cancer, but not in n0n cancer patients, led us to develop a Sandwich ELISA Assay to measure AABH in serum. In the current study we have quantified AABH levels in CRC patients and compared it with normal individual. Increased levels of AABH were found in the serum of 91.5% of patients with CRC in all different stages of Cancer (n = 60). In normal individuals, AABH was essentially undetectable in serum (n = 30). AABH was identified in serum from patients with CRC irrespective of cancer stage. All serum AABH levels for stages I, II, III and IV were more than 3.3 ng/mL. Conclusions: Thus, our data indicate that by measuring AABH in the serum, we should be able to detect CC at an earlier stage than it is currently detected, resulting to a much better 5-year survival for CC.
Autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: An analysis of immunological responses.
Authors: Sato Yasuyoshi , Yagi Koichi , Mori Kazuhiko , Matsushita Hirokazu , Kakimi Kazuhiro , Seto Yasuyuki 
Published: February 2018

96 Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. We already reported the clinical results for enrolled 11 patients. All patients completed the protocol therapy and no treatment-related adverse events more than grade 3 was observed (primary endpoint), and recurrence rate within 2 years was 18% (n = 2). In this study, we further analyzed the immune responses in vaccinated patients. Methods: Patients with stage IIA (T2N0 or T3N0, UICC TNM classification 6th edition) esophageal cancer after curative (R0) resection were eligible. Tumor lysate we used for DC vaccines potentially contains mutated proteins (neoantigens) derived from somatic mutations. Patients received DC vaccines (more than 5.0×106 cells) 6 times every 2 weeks. We evaluated neutrophil-to-lymphocyte ratio (NLR) in each patient from CRF data. We identified candidate neoantigens by next generation sequencing and MHC class I binding prediction algorism. We screened the immune responses against those neoantigens using HLA transgenic mice and healthy human PBMCs. Results: Absolute lymphocyte counts, absolute neutrophil counts and NLR were not specifically different between patients with or without recurrence. For specific immune responses, we observed the reactivity in 6 out of 59 candidate neoepitopes identified from two patients in HLA transgenic mouse system. Two out of 6 peptides displayed reactivity in human healthy PBMCs. Conclusions: We analyzed immune responses to predicted candidate neoantigens. We are now investigating immune landscape in the tumor using RNA sequencing data and its relevance to the antigen responses. Clinical trial information: UMIN000002837.
A phase 1b investigation of safety/efficacy of nivolumab and ABI-009 (nab-rapamycin) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS) and Ewing sarcoma.
Authors: Gordon Erlinda Maria , Chua-Alcala Victoria S. , Kim Katherine , Quon Doris M , Chawla Sant P 
Published: February 2018

TPS45 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. Objectives: (1) To investigate the maximum tolerated dose of ABI-009, an mTOR inhibitor, when given sequentially with nivolumab, a PD-1 inhibitor, in advanced UPS, LPS, CS, OS and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression free survival (PFS), recurrence-free survival (RFS) and overall survival using nivolumab/ABI-009 combination therapy in advanced UPS, LPS, CS, OS and Ewing sarcoma; (3) To correlate disease control rate (DCR) based on Immune-related Response Criteria (irRECIST) with that based on RECIST v1.1, and to correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty to fifty previously treated patients with UPS, LPS, CS, OS or Ewing sarcoma will be enrolled. This is a phase 1b study using a defined dose of nivolumab 240 mg and escalating doses of ABI-009 56,75,100 mg/m2 given i.v. I. Dose Escalation Phase 1 Part of Study: The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 1b Part of Study: An additional 22-28 patients will receive ABI-009 at the MTD and defined doses of nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. Clinical trial information: NCT03190174.
Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC.
Authors: Blumenschein George R. , Bourgogne Agathe , Reinhardt Carsten , Ma Hong , Walter Steffen , Weinschenk Toni , Kebriaei Partow , Hwu Patrick , Singh Harpreet 
Published: February 2018

TPS78 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy. T-cell receptor (TCR) engineered ACT approach has contributed to success in solid tumors. ACTengine IMA201 is a product based on autologous T cells engineered to express a naturally occurring TCR specific to a cancer-germline peptide. The target peptide has been characterized in depth by Immatics’ proprietary antigen discovery platform, XPRESIDENT showing exceptional specificity, copy number and expression homogeneity. XPRESIDENT has applied two independent methodologies to confirm the selectivity of tumor target: i) ultra-sensitive quantitative immunopeptidome analyses by mass spectrometry and ii) quantitative mRNA expression analyses by RNASeq. Immatics´ TCR discovery platform is optimized to identify TCRs with low micromolar affinity, specific recognition of tumor cell lines and lack of recognition of healthy normal cells. Methods: This study is an open-label first-in-human dose-escalating phase I trial investigating safety, tolerability and clinical activity in end-stage solid tumor patients. Key eligibility criteria include: recurrent or refractory squamous non-small cell lung cancer or head and neck squamous cell cancer, HLA-A*02:01 phenotype, qPCR biomarker positive from a tumor biopsy, prior established lines of therapy, RECIST v1.1 measurable lesions and ECOG score 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells (PBMC). The activated PBMC will be transduced with a lentiviral vector for manufacturing of IMA201. IMA201 is infused after a pre-conditioning (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objectives include: i) the persistence and functionality of IMA201 in vivo, ii) correlative biomarkers for clinical success, and iii) target expression levels in the tumor. Enrollment to the study is currently ongoing. Clinical trial information: NCT03247309 .
Aspartyl (Asparaginyl) ß hydroxylase (AABH) as a serum bio-marker for prostate cancer to identify prostate cancer, regardless of PSA level.
Authors: Moshiri Mahmood , Moshiri Kiarash , Moshiri Arsha , Monhemi Hassan , Sekhavati Mohammad Hadi 
Published: February 2018

10 Background: Background: Prostate Specific Antigen (PSA) is a molecular marker of prostate cancer (PC). I most countries, standard of care suggests annual PSA testing in all men over 50 years of age; and for men at high risk, the test is recommended from 40 years of age. Due to low Specificity and low sensitivity of the PSA test, a large number of unnecessary biopsies occur every year. This low specificity can be due to the fact that PSA is found in both benign and malignant lesions of Prostate tissue. To date measurement of the percentage of free PSA, have resulted an small improvements in specificity of PSA testing. Thus, the development of a simple blood test to detect prostate cancer that exhibits higher specificity compared to PSA could have the potential of reducing biopsies performed due to false positive screening results and improve the quality of medical care. Methods: We have investigated the utility of aspartyl (asparaginyl) β-hydroxylase (AABH) as a prostate cancer biomarker. AABH has been detected by immunohistochemical staining (IHC) in a broad range of cancers including Prostate Adenocarcinoma through out the world. AABH have been detected by IHC in more than 97% of tumor specimens tested (n > 200) while absent in normal and non cancer tissue. We have developed a sandwich ELISA test for the detection of AABH in serum samples. Preliminary results showed an accuracy of 91- 94% for detecting cancer patients from non-cancer patients in different types of Cancer. Here we have utilized this assay to detect AABH levels in the sera of patients diagnosed with Prostate cancer (biopsy proven, pre-treatment samples), compared to non-cancer individuals. Results: AABH was detected above a threshold level of 1.2 ng/mL in 91% of the sera of PC patients (n = 60), in all different stages and grades of Prostate Cancer. All non-cancer individuals (n = 30) had AABH values below the threshold. Further study of direct comparison of AABH to PSA levels (n = 4,000) is underway. Conclusions: Our data suggest that measurement of serum AABH levels may help to detect Prostate Cancer in early stage and potentially reduce the number of prostate biopsies performed due to increased high serum PSA.
Prostate 8 study: A pilot randomized controlled trial (RCT) of a web-based lifestyle intervention versus control group among men with prostate cancer.
Authors: Kenfield Stacey A. , Van Blarigan Erin , Ameli Niloufar , Lavaki Emil , Monroy Cynthia , Tantum Lucy K. , Newton Robert Usher , Zhang Li , Cooperberg Matthew R. , Carroll Peter , Chan June M. 
Published: February 2018

105 Background: Lifestyle behaviors may reduce risk of prostate cancer progression. Guidelines and tools to support lifestyle modification are needed to improve prostate cancer care. Methods: We conducted a 12-week RCT among 73 men with clinical stage T1-T3a prostate cancer to determine if a lifestyle intervention that included a responsive website, Fitbits, and text messaging helps men adopt 8 healthy lifestyle behaviors (vigorous activity, not smoking, and 6 diet factors) compared to a control group. Eligible men had no contra-indications to aerobic exercise, Internet access, and engaged in ≤4 of the targeted 8 habits at baseline. We explored the efficacy of the intervention (n = 32) vs. control (n = 32) on behavior change via a lifestyle survey, 7 days of ActiGraph GT3X+ accelerometer data, and the Prostate 8 (P8) score (8 self-reported behaviors assigned 0 or 1 point, range 0-8). Results: Baseline characteristics were similar between arms. The median baseline P8 score was 3 in each arm. 12-week assessments were 88% complete (intervention, 94%; control, 82%). Intervention arm participants’ wore their Fitbits a median of 82 days (98%, IQR: 72-83), replied to a median of 71% of texts (N = 60, IQR: 57-89%), and visited the website a median of 3 days [IQR: 2-5] and over 3 visits [IQR: 2-5]. Baseline moderate and vigorous activity were self-reported as 3.7 hrs/wk and 12 min/wk (intervention) and 5.3 hrs/wk and 18 min/wk (control). 1 person was a smoker at baseline. Median [IQR] absolute change in the P8 score from baseline to 12 wks was 2.0 [1.0, 3.0] (intervention) and 0.0 [-1.0, 1.0] (control) (p = 0.0005); and the change between groups was statistically significant for cooked tomatoes, cruciferous vegetables, fish, processed meat, but not significant for healthy sources of vegetable fat (high at baseline) or vigorous activity. Accelerometer data indicated no significant differences in change in physical activity between arms. Conclusions: This novel intervention was feasible and acceptable. These data suggest that the intervention was effective for promoting healthier dietary changes; further research is warranted to examine how to facilitate improvements in physical activity. Clinical trial information: NCT02470936.
Stereotactic body radiotherapy (SBRT) versus high dose rate (HDR) brachytherapy (BT) boost for high-risk (HR) prostate cancer.
Authors: Gonzalez-Motta Alejandro , Roach Mack 
Published: February 2018

12 Background: Declining use of BT has prompted questions regarding the use of SBRT in HR patients. A systematic literature review was conducted to assess toxicity, and biochemical outcomes following SBRT or HDR BT boost in HR patients. Methods: A search was carried out on the PubMed and Embase databases, for studies published between 2007 and 2017, including HR patients treated with SBRT or HDR boost. Results: We identified 11250 articles, with 6 SBRT and 41 HDR boost studies eligible. The median follow-up was 3.5-5.5 and 2.6-10.3 years in SBRT and HDR boost studies, respectively. The five-year bDFS was 41%–96% in HDR and 69%–98% in SBRT boost studies. Toxicity was reported using the Radiation Therapy Oncology Group (RTOG) scale or the Common Terminology Criteria for Adverse Events (CTCAE) scale and/or validated patient reported Quality of Life (QoL) outcomes. Single SBRT and HDR studies reported 1 year IPSS scores < 7, with 2 SBRT reports of excellent outcomes by the EPIC scale. Acute grade 2 (G2) genitourinary (GU) toxicity ranged from 24-46% and 0.4-33% in SBRT and HDR boost studies, respectively. Late G2 GU toxicity occurred in 2.3-25% and 0-22% following SBRT and the HDR boost, respectively. Late grade 3 (G3) GU toxicity was reported in 0-2.3% and 0-10% with SBRT and HDR boost, respectively. Late G3 GU was reported in 0.8% (2/226) and 4% (114/2763) following SBRT and HDR boost, respectively. Acute G2 gastrointestinal (GI) was noted in 8-19% and 0-19% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 0-10% and 0-4.6% of SBRT and HDR boost studies, respectively. Late G3 GI was reported in 2% (5/226) and 0.6% (18/2829) of SBRT and HDR boost studies, respectively. Conclusions: SBRT boost may be associated with higher acute G2 but lower late G3 GU toxicity but was not shown by QoL reports, and could be due to selection bias, learning curves or other factors. Randomized trials and validated QoL instruments are needed to accurately compare SBRT to HDR boost.
Is expanded radiographic criteria for clinically positive lymph nodes associated with outcome in pathologically node positive prostate cancer?
Authors: Reichard Chad A. , Gregg Justin , Bathala Tharakeswara , Achim Mary F. , Davis John W. , Chapin Brian Francis 
Published: February 2018

126 Background: Patients with pN1 prostate cancer (PCa) have heterogeneous outcomes largely dependent on variables only known post-treatment. Traditionally, the size criteria for clinically positive pelvic adenopathy is axial diameter of 10mm. We employed expanded radiographic criteria (ERC) to evaluate for association with differences in outcome differences. Methods: 187 men treated with RP BPLND for PCa from 2001-2013 were identified as pN1. Imaging studies were re-reviewed by a single radiologist (TB) for nodes that were considered positive if they were 8mm or greater in size OR if they were 6mm or greater in size AND either rounded, asymmetrical OR heterogeneously enhancing. This yielded a group of 34 cN1 patients by ERC. Time to biochemical recurrence (BCR) was compared between cN0 and cN1 patients by K-M method. Cox proportional hazards modeling was used to determine association of baseline PSA, node status, adjuvant therapy, Gleason score, positive margins, and ECR with time to BCR and overall survival (OS). Results: Median age (61 v 59 p = 0.3), baseline PSA (8.7 v 11.1 p = 0.2), and positive margin rate (33% vs 32% p = 0.9) did not differ between cN0 and cN1 patients. Median number of positive LNs was higher in the cN1 group (2.7 v 1.8) p = 0.03. Median biochemical recurrence free survival did not differ between groups (3.3 vs 1.8 years p = 0.3) (Fig1). Only Gleason score was associated with shorter BCR free survival HR 1.3 (95%CI 1.0-1.62, p = 0.047). cN1 disease with expanded radiographic criteria did not predict BCR (HR 1.03, 95CI 0.62-171, p = 0.9) or ACM (HR 0.46, 95CI, 0.1-2.12, p = 0.3). Conclusions: Expanded radiographic criteria for clinically positive lymph nodes was not associated with BCR-free survival or OS in a group of pN1 PCa patients. Further study is required to determine if cN1 status based on expanded clinical criteria or more sensitive imaging methods is associated with outcome differences.
Secondary malignancies following low-dose-rate brachytherapy for prostate cancer in a single institution.
Authors: Obayashi Kotaro , Kimura Go , Kuribayashi Shigehiko , Shibayama Keita , Sano Masayuki , Tanabe Kuniaki , Akatsuka Jun , Hayashi Tatsuro , Toyama Yuka , Hamasaki Tsutomu , Maebayashi Katsuya , Kumita Shinichiro , Kondo Yukihiro 
Published: February 2018

142 Background: Low-dose-rate brachytherapy (BT) is the internal radiation therapy for non-metastatic prostate cancer by implanting radioactive isotope Iodine 125 into the prostate. The carcinogenetic effect of radiation for the treatment of cancer has been proven during the last decades. However, few studies have been reported about brachytherapy-induced secondary malignancies. In this study, we assessed the BT-induced secondary malignancies in our institution. Methods: We reviewed 487 patients treated with low-dose-rate BT from 2006 to 2016 in our hospital. We checked the occurrence of metachronous malignancies (MM) in all the patients and examined the features of MM including the number, organ sites, histology, period from BT to the occurrence, and analyzed whether the features meet the criteria of radiation-induced malignancies. We also examined the relationship between the BT-related radiation doses and the occurrence of MM. We adopted the criteria of radiation-induced cancer proposed by Sakai et al in 1981; different pathological feature from the organ of origin, the follow-up duration after radiation therapy (over 5 years), and whether the lesion is located in the irradiated field. Results: After a median follow-up period of 57 months (range 10-125 months), 23 MM occurred, which were bladder cancer in 4 cases (0.8%), esophageal in 2 (0.4%), gastric in 5 (1.0%), colon in 4 (0.8%), rectal in 3 (0.6%), pancreatic in 1 (0.2%), lung in 3 (0.6%), and brain in 1 (0.2%). Time from initial treatment to MM was 36 months (range 1-85 months). None of the cases had experienced biochemical recurrence. Average radiation dose to the urethra and the rectum including UD90, UD5, U200, R100, R150 showed no significant difference compared to the patients without occurrence of MM. According to the Sakai’s criteria, one bladder and one rectal cancer were judged as radiation-induced secondary malignancies (0.2%). Conclusions: The risk of secondary malignancies in patients undergoing BT was very low. Further studies with longer follow-up are required because it has been only about 10 years since low-dose-rate brachytherapy started in Japan.