bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of Tfh-like cells in breast cancer.
Authors: Ma Linxiaoxi , Guo Liang , Goswami Shyamal , Zhang Xiaoming , Wu Jiong 
Published: May 2019

e14285 Background: The treatment of breast cancer, one of the most common malignant tumors for female, focuses on the combined treatments based on subtypes including Luminal A, Luminal B, HER2 overexpression and triple negative. Given that none of those subtypes takes into consideration of immunological parameters, it is valuable to explore the biological characteristics and prognostic value of immune cells in breast caner. T follicular helper cells (Tfh cells) have been identified in different types of tumors with rare datas in breast cancer. One of them indicated the positive prognostic value of 8-gene Tfh signature. Exploration of Tfh cells may provide new clues to the potential immunotherapies in breast cancer. Methods: Freshly resected invasive breast cancer tissue from Fudan University Shanghai Cancer Center were collected during 06/2015 to 05/2017. Patients were divided into Luminal A (N = 61), Luminal B (HER2-) (N = 138), Luminal B (HER2+) (N = 72), HER2+ (non-luminal) (N = 57) and triple negative (N = 58) based on St Gallen International Expert Consensus. Results: A subpopulation of PD1hiCD4+ T cells in the tumor tissues of breast cancer was identified as Tfh-like cells, with the specific expression of Bcl-6 and CXCL13, confirmed by IHC. Phenotypes of those cells were checked by flow cytometry. Tfh-like cells were of a high level of ICOS but negative for CXCR5, suggesting that they were atypical Tfh cells. Data showed that high grade (N = 166; mean±SEM, 17.62±0.87) compared with low grade (N = 220; mean±SEM, 12.41±0.46) or high Ki-67 level (N = 300; mean±SEM, 15.38±0.58) with low Ki-67 level (N = 86; mean±SEM, 12.10±0.67), and negative ER expression (N = 115; mean±SEM, 17.47±1.05) compared with positive ER expression (N = 271; mean±SEM, 13.46±0.50) or negative PR expression (N = 177; mean±SEM, 16.87±0.83) compared with positive PR expression (N = 209; mean±SEM, 12.77±0.50) was associated with higher frequency of Tfh-like cells (P < 0.01 to all). Patients with triple negative had higher frequency of Tfh-like cells than those with Luminal A (difference, 6.83; P = 0.0006) and Luminal B (HER2-) (difference, 4.61; P = 0.0124). Patients with HER2+ (non-luminal) had higher frequency of Tfh-like cells than those with Luminal A (difference, 5.34; P = 0.0146). These results indicate that higher frequency of Tfh-like cells could have negative prognostic influence. Conclusions: Our study defined a PD1hiBcl6+CXCL13+CD4+ T cell subpopulation, which specifically secretes cytokine IL-21 as Tfh-like cells. Higher frequency of Tfh-like cells is more likely to be seen in patients with poor prognosis.
Prediction the clinical outcomes of cancer patients after peptide vaccination.
Authors: Toke Eniko Rita , Megyesi Mónika , Molnar Levente , Tóth József , Lőrincz Orsolya , van der Burg Sjoerd H. , Welters Marij , Melief Cornelis Joseph , Schönharting Wolfgang , Urban Sybille , Roehnisch Tim , Heine Uwe , Somogyi Eszter , Csiszovszki Zsolt , Pántya Katalin , Páles Péter , Miklós István , Lori Franco , Lisziewicz Julianna 
Published: May 2019

e14295 Background: Neoantigen vaccines can activate T-cells that specifically kill tumor cells. However, most vaccine peptides, selected either as HLA-binders or as HLA-presented epitopes, do not induce T-cell responses in HLA allele-matched individuals. We hypothesized that personal-epitopes (PEPIs) binding to multiple autologous HLA-alleles induce potent T-cell responses. Methods: Epitopes binding to single HLA and PEPIs binding to 3 autologous HLA-alleles were identified with our novel and validated PEPI Test (CE Marked) and correlated with CD8+ and CD4+ T-cell responses of (pre)malignant patients vaccinated with Synthetic Long Peptides (SLPs) in 2 clinical trials. A Model Population of 433 HLA-genotyped individuals was used to determine the percentage of subjects with PEPIs from SLPs (PEPI-Score). As a proof of principle, a personal vaccine was developed matching with 14 HLA-alleles of a cancer patient with PEPIs from 12 tumor-antigens. T-cell reactivities were tested by interferon-γ ELISPOT. Results: There was no correlation between single HLA-binding epitopes and HPV-specific T-cell responses of patients. In contrast, there was 90% and 69% agreement between HLA-class-I PEPIs and CD8+ T-cell responses (p < 0.001) and HLA-class-II PEPIs and CD4+ T-cell responses (p = 0.005), respectively. PEPI-Score predicted the T-cell response rate of SLP vaccine clinical trials. As predicted by the PEPI Test, personal vaccine treatment activated tumor-specific T-cells: 91% and 100% of the vaccine peptides elicited CD8+ and CD4+ T-cell responses, respectively. Conclusions: A patient’s HLA genotype is a major determinant of vaccine responses and PEPIs are genetic biomarkers of T-cell responses. PEPI Test prediction of vaccine responses can be utilized by clinicians for selecting the vaccine treatment and for the development of highly immunogenic personal vaccines matched to a patient’s complete HLA genotype (NCT03391232).
Analysis of Chinese acral and mucosal melanoma patient genomic and neoantigen profiles in cancer vaccine development: A pilot study.
Authors: Guo Xianling , Gao Song , Yang Li , Fang Juemin , Wei Guochao , Ma Xiaochun , Zhao Zhikun , Weeraratne S Dilhan , Snowdon Jane , Wang Sheng , Qing Xu 
Published: May 2019

e14300 Background: Acral and mucosal melanoma are rare subtypes accounting for about 3% of all melanoma cases. The cutaneous melanoma genomic landscape is well defined; however, little is known about the acral and mucosal melanoma mutational spectrum. In this pilot study, we evaluated the genomic and neo-antigen profiles and tumor mutational burden (TMB) from acral and mucosal melanoma patients with the aim of designing personalized vaccines and longitudinally tracking patients’ clinical courses. Methods: Tumor whole exome sequencing and neo-antigen profiling of 5 acral and 3 mucosal melanoma patients at Shanghai Tenth Peoples Hospital, Tongji University, China between April 2018 and January 2019 was performed using YuceBio’s proprietary analytics platform. Watsonä for Genomics, an artificial intelligence decision-support system, was used for variant interpretation and annotation. A comparative analysis was performed on Chinese acral melanoma data with the published Caucasian acral cohort from the Translational Genomics Research Institute (TGen) and The Cancer Genome Atlas (TCGA) predominantly Caucasian cutaneous melanoma data set. Results: TMB in our acral/mucosal melanoma cohort was 2.26/Megabase (Mb) compared to over 20/Mb in published cutaneous melanoma studies. Tumor neo-antigen burden (TNAB) in our group was 1.03 neo-epitopes/Mb. Low TNAB levels were associated with low TMB levels in all tumors. Incidence of BRAF and NRAS mutant cases in our cohort was 0% (0/8) and 13% (1/8) respectively compared to 19% (5/27) and 7% (2/27) of the Caucasian acral population in the TGen dataset. Incidence of BRAF and NRAS mutations in the TCGA cutaneous melanoma dataset was 54% (237/440) and 28% (125/440), respectively. Conclusions: TMB was significantly lower in acral/mucosal than in cutaneous melanoma and may be a surrogate for TNAB. Detection of BRAF and NRAS mutations, the two most prevalent driver mutations in cutaneous melanoma, were significantly lower frequencies in both Chinese and Caucasian acral melanoma patients in this study, suggesting alternate cancer drivers may exist in this subtype. Strategies to address challenges of low TNAB in vaccine development are being explored.
Effect of ligand binding domain activating mutations of ESR1 on cellular metabolism, liver tropism, and chemotherapy resistance.
Authors: Wolf Ido , Zinger Lotem , Merenbakh-Lamin Keren , Klein Goldberg Anat , Elazar Adi , Journo Shani , Boldes Tomer , Taya Marwa , Pasmanik-Chor Metsada , Spitzer Avishay , Rubinek Tami 
Published: May 2019

e14506 Background: Mutations in the ligand binding domain (LBD) of estrogen receptor α (ER) confer constitutive transcriptional activity and resistance to endocrine therapies in breast cancer patients. Accumulating clinical data suggest adverse outcome for patients harboring tumors expressing these mutations. We aimed to elucidate mechanisms conferring this aggressive phenotype. Methods: Cells constitutively expressing physiologic levels of ER harboring activating LBD mutations were generated and characterized for viability, invasiveness and tumor formation in vivo. Gene expression profile was studied using RNAseq. Metabolic properties were assessed using global metabolite screen and direct measurement of metabolic activity. Response to chemotherapies was assessed using viability assays. Results: Cells expressing mutated ER showed increased proliferation, migration and in vivo tumorogenicity compared to cells expressing the WT-ER, even in the presence of estrogen. Experiments in mice revealed a more aggressive phenotype of the Y537S mutant compared to D538G as well as unique tissue predilection. Thus, 538G-ER cells exhibited liver tropism while Y537-ER cells mainly metastasized to the lungs and lymph nodes. Importantly, both mutations conferred resistance to paclitaxel and doxorubicin. Further studies indicated association of the mutated ER with upregulation of genes involved in tumor cell metabolism. Indeed, a global metabolic screen revealed distinct metabolic profile for cells harboring activating mutations, including the ability to utilize glutamine as an alternative carbon source. Moreover, we observed unique metabolic activities enabling cells to thrive in urea-reach environment of the liver, and overcome doxorubicin-induced stress responses. Conclusions: Taken together, these data indicate estrogen-independent rewiring of breast cancer cell metabolism by LBD-activating mutations, enabling aggressivene clinical behavior and chemotherapy resistance. Importantly, These unique metabolic activities may serve as a potential vulnerability and aid in the development of novel treatment strategies to overcome endocrine resistance.
Assessing the risk of chemotherapy toxicity and hospital admission due to toxicity.
Authors: Malton Samuel Robert 
Published: May 2019

e14508 Background: Acute chemotherapy toxicity can have negative effects for the patient and the health economy. Finding overall toxicity incidence for a typical teaching hospital population proved difficult, although the 2008 report in to deaths within 30 days of chemotherapy found that 43% of patients who died reported a grade 3 or 4 toxicity1. At Nottingham University Hospitals (NUH) a Cancer Admissions and Triage Team was established, who undertake a proactive telephone toxicity assessment 24 hours following the administration of a first cycle of chemotherapy. This had the aim of reducing hospital admission due to toxicity through timely advice and intervention and allowed the accrual of data regarding reported toxicity. Methods: Data was obtained from the telephone assessment of acute toxicity 24 hours after administration of a first cycle of chemotherapy, once the service had been in use for 1 year. Descriptive statistics were produced to establish toxicity incidence and severity and hospital admission rates as well as length of stay. Regression modelling was used to identify predictors of the four outcome measures. The commonest toxicities were explored as secondary outcome measures. Results: 1539 patients were studied and the overall incidence of toxicity was 35.6%. Disease site and number of chemotherapy agents given were shown to predict toxicity, with breast and upper gastrointestinal cancers having a higher likelihood of toxicity. The more anticancer agents used, the higher the risk of toxicity. Disease was predictive of toxicity grade, with urology, gynaecology and lung patients experiencing higher grades of toxicity than other tumour sites. The rate of hospital admission due to toxicity was 13.1% and median length of stay 3 days. The risk of admission had some risk factors in common with toxicity. Disease and the number of drugs in the regimen affected the risk of admission, with gynaecology, head and neck and lung patients and patients who received 3 drugs having a higher likelihood of admission. No predictors could be reliably identified for length of stay. Predictors in the sub-groups of breast, lower gastrointestinal and lung cancers did not differ greatly from the whole population and the number of drugs was shown to be a predictor of nausea, vomiting and fatigue when explored as secondary outcomes. Conclusions: Predictors were identified for occurrence of toxicity, severity of toxicity, risk of hospital admission but not for length of stay. Sub-group analyses were undertaken. The overall burden of acute chemotherapy toxicity of a heterogeneous population was elucidated.
Rationale and preclinical development of LEAF-1401 and LEAF-1701: A novel class of potent next generation antifolates.
Authors: Moyo Victor M. , Xu Zhenghong , Khalifa Kaniz , Gandhi Nishant , Geng Bolin , Dhindsa Navreet , Niyikiza Clet 
Published: May 2019

e14515 Background: Polyglutamation of antifolates by folylpolyglutamate synthase (FPGS) greatly enhances their activity, e.g. pentaglutamated pemetrexed is 80-fold more potent at inhibiting thymidylate synthase than pemetrexed. Polyglutamated antifolates however, do not readily cross the cell membrane, due to high negative charge and molecular mass. The resulting poor intracellular bioavailability greatly limits their therapeutic potential. Gamma glutamyl hydrolase (GGH) enzyme removes the glutamate residues from polyglutamates, which then are subject to efflux pumps. Resistance to pemetrexed has been linked to downregulation of both FPGS and folate transporters and upregulation of both GGH and the efflux pumps. We have been developing a novel class of nanoliposomal polyglutamated-antifolates including: LEAF-1401; nanoliposomal gamma-L pentaglutamated antifolate LEAF-1701; nanoliposomal alpha-L pentaglutamated antifolate These were designed to address key challenges of currently used antifolates namely: Bypassing the need for intracellular endogenous FPGS Direct delivery of the much more active polyglutamates through nanoliposome technology Minimizing toxicity to normal cells Mitigating against key antifolate resistance mechanisms such as downregulation of FPGS and folate transporters, and upregulation of GGH and efflux pumps Methods: In vitro testing in cell lines and in vivo testing in mice were performed using LEAF-1701 and LEAF-1401 in various tumor types. Results: Compared to pemetrexed: In vitro, LEAF-1701 and LEAF-1401 were more potent, in various cell lines while sparing normal neutrophils, colon and liver cells. In vivo, in H292 lung cancer xenografts, treatment with LEAF-1701 improved survival to 59 days vs 39 days for pemetrexed. In A549 lung cancer mouse orthotopic models, treatment with LEAF-1401 reduced metastatic tumor burden and prevented new metastases. In vivo, in mice doses of up to 80 mg/kg IV weekly were tolerated with little impact on blood counts and chemistry. Conclusions: LEAF-1701 and LEAF-1401 are innovative new chemical entities with promising preclinical activity and improved safety profiles and are now advancing to the clinic.
Integrin β5 in plasma-derived exosomal protein predicting liver-specific metastasis in advanced gastric cancer patients.
Authors: Li Qian , Xu Xiaojing , Yu Yiyi , Li Wei , Liang Li , Song Jia , Li Bin , Li Fu-Gen , Cai Shangli , Liu Tianshu 
Published: May 2019

e14521 Background: Gastric cancer (GC) is the second leading cause of cancer death in China. Liver metastasis (LM) is a highly frequent event of the advanced GC, and the patients with LM always present dismal prognosis. A predicted factor of LM is urgently established to screen out the population in high risk of LM. Tumor-derived exosomes play critical roles in cancer metastasis process. Exosomes integrin (ITG) αvβ5 is uptake by liver resident cells and linked to LM in cell lines. This study is designed to evaluate the association between exosomes ITG αvβ5 and liver metastasis, especially in HER2 positive gastric cancer. Methods: 74 untreated advanced GC patients with matched blood and tumor tissue samples and clinical features were collected in the study. Exosomal HER2, ITG αv and β5 expression were measured by enzyme-linked immunosorbent assay (ELISA) after the exosomes isolated from plasma. HER2 status of tumor tissue was determined by IHC and/or FISH. Results: Based on HER2 status of tumor tissue, we initially proved the feasibility of detecting HER2 expression from exosome. ROC curves showed the optimum exosomal HER2 expression diagnostic cutoff for HER2 positive patients was 266.38 pg/ml (sensitivity 71.4% and specificity 72.6%). In total, 27 patients were LM and the rest (n = 47) was non-LM. The median expression value of ITG αv and β5 were 57.55 pg/ml and 836.00 pg/ml, respectively. And these two median value were identified as the cutoff value for subsequent analysis, respectively. HER2 expression was merely linked to ITG β5 expression (P = 0.019), not ITG αv (P > 0.050). There was no relationship between ITG αv and LM (P = 0.629), however, ITG β5 expression presented significant association with LM (P = 0.016). We further probed the relationship between ITG and other metastasis. Results showed no correlation between any ITG and other non-liver organic metastases, like lung, bone, ovarian, lymph, and peritoneal metastasis. Besides, ITG β5 expression was also associated with LM in the HER2-positive GC patients. Conclusions: Exosomes might serve as a potential non-invasive diagnostic and screening tool. In clinical samples, ITG β5, not αv, was linked to LM, and might be a valuable biomarker in the use of predicting LM of GC, even in the HER2-positive patients.
Imaging features of genomic instability in circulating tumor cells (CTCs) from metastatic triple-negative breast cancer (metTNBC) patients (pts) who received PIKTOR.
Authors: Ontiveros Priscilla , Levin Maren K. , Wang Yipeng , Hom Beverly , Dittamore Ryan , O'Shaughnessy Joyce 
Published: May 2019

e14527 Background: A subset of TNBCs have homologous recombination deficiency (HRD) with upregulation of compensatory DNA repair pathways. A combination of TAK-228 and TAK-117 (PIKTOR), investigational oral TORC1/2 and PI3Kα selective inhibitors, respectively, is hypothesized to increase genomic instability (GI) and decrease double strand DNA repair. CTCs from metTNBC pts are being characterized for imaging features that may correlate GI in blood obtained at baseline (BL) prior to beginning PIKTOR, and at disease progression (PD) on PIKTOR. Pts are treated with a cisplatin-based regimen after PD on PIKTOR. Methods: Following IRB-approved informed consent, metTNBC pts received 4 mg PO TAK-228 and 200 mg PO TAK-117 QDx3d QW until PD. Blood samples collected at BL and at PD were sent to Epic Sciences for CTC analyses including enumeration, cell morphology, phenotypic heterogeneity, and GI analysis via a previously developed GI prediction algorithm based on cell phenotypes (Jendrisak et al AACR 2018). Results: The 9 pts treated with PIKTOR to date had mets in lymph nodes (n = 8), lung (n = 5), chest wall (n = 2), and bone (n = 2). Median number of prior regimens for metTNBC was 2; median duration of PIKTOR treatment was 8 wks (range, 5-15). CTCs were detected in 62.5% (5/8) BL and 100% (9/9) PD samples. 2 pts had high phenotypic CTC heterogeneity at both BL and PD (pt#36: 0.69 to 0.64; pt#80: 0.93 to 1.41), 1 pt had increased heterogeneity (pt#75: 0 to 1.68) and 1 pt had decreased heterogeneity (pt#67: 1.26 to 0) post-PIKTOR. 1 pt had predicted phenotypic GI (pGI+) CTCs detected at both BL and PD (pt#80), 1 pt had pGI+ CTCs at BL only (pt#36) and 1 pt at PD only (pt#75). Higher expression of the epithelial marker, cytokeratin (CK), and larger cell size were observed in the PD samples. Conclusions: Following treatment with and PD on PIKTOR, higher CK expression, higher phenotypic heterogeneity, and more pGI+ CTCs were observed in a subset of pts, suggesting that these TN CTCs may have developed epithelial transition and greater GI with PIKTOR treatment. Accrual continues and CTC GI biomarkers will be correlated with pts’ response to subsequent cisplatin-based therapy.
Modeling of pharmacodynamic (PD) biomarkers (BM) related to CDK4/6 inhibition and exploratory BM-response (progression free survival [PFS]) analyses in patients with advanced breast cancer.
Authors: Yu Yanke , Liu Yuan , Wang Diane Dan 
Published: May 2019

e14528 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinase 4 and 6 (CDK4/6) approved for advanced breast cancer (ABC). In a clinical trial, the expression levels of PD BMs related to PAL effect, including thymidine kinase (TK) in serum and phosphor-Rb (pRb) and Ki67 in skin tissues, were measured at both baseline and post-treatment in patients with ABC treated with PAL plus letrozole (LET). Pharmacokinetic (PK)/PD modeling was conducted previously to characterize the longitudinal change of pRb and Ki67. The PK/PD was further evaluated for TK and exploratory analyses were conducted to evaluate the relationship between PFS and all three BMs. Methods: The present analyses used data from a Phase 1 study evaluating the PK, PD, safety and efficacy of PAL plus LET in 26 Chinese women with ABC. A 2 compartment model was used to describe the PK of PAL. A precursor-dependent indirect response model was developed to describe the TK time course after PAL treatment. PAL effect was modeled as Imax inhibitory model. Cox proportional hazard model was used to assess the correlation of PFS with three BM metrics (baseline BM, simulated lowest BM and maximum BM change in Cycle 1). Results: The BM data included 194 TK observations from 26 patients. The PK/PD models adequately described the longitudinal change of TK, and showed PAL caused TK reduction. The estimated IC50 value was 49.5 ng/mL, similar to those for pRb and Ki67. The BM-response analyses for PFS showed that correlation was found for TK. There was a significant correlation between PFS and baseline TK (BTK) and minimum TK (MTK) in Cycle 1. A longer PFS was associated with lower BTK and lower MTK. A trend for longer PFS with higher maximum TK change in Cycle 1 was observed although the relationship was not statistically significant. Conclusions: PAL exposure had significant correlation with the reduction of all three BMs. Longer PFS was associated with lower BTK and MTK. Due to the small sample size (N = 26), this analyses result need to be confirmed in a larger study.