bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation of tumor-specific cytotoxic T-lymphocytes from peripheral blood of colorectal cancer patients for adoptive immunotherapy.
Authors: Bregni Marco , Del Bue Serena , Galli Andrea , della Valle Alberto , Ferrante Pasquale , Carluccio Silvia 
Published: March 2020

3056 Background: Adoptive T-cell transfer (ACT) using autologous TIL, grown ex vivo and then infused into the cancer patient after lymphoablative chemotherapy, has emerged as an effective treatment for patients with metastatic melanoma. However, this approach has been hampered by the difficulty of isolating TILs from tumors other than melanoma, and of amplifying a sufficient quantity of autologous tumor-reactive T cells. So we decided to adopt a recently described procedure for generating in vitro large numbers of anti-tumor HLA-restricted CTLs, by stimulating patient’s CD8-enriched peripheral blood mononuclear cells (PBMCs) with DCs pulsed with apoptotic solid tumor cells (TCs) as a source of tumor antigens. Methods: 61 patients affected by CRC were enrolled. Tumor biopsies were obtained at surgery, together with 100 ml of heparinized peripheral blood. Tumors were dissociated to a single-cell suspension and cultured in order to obtain tumor cell line from each patient. Dendritic cells (DCs) were generated from previously separated PBMCs, using a magnetic positive selection of CD14+ monocytes, cultured in presence of Interleukin-4 and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Anti-tumor cytotoxic T lymphocytes (CTLs) were elicited using DCs as antigen-presenting cells, autologous apoptotic tumor cells as source of antigens and T CD-8 lymphocytes enriched effectors, with weekly stimulation. To evaluate the cytotoxic activity of CTLs, interferon-γ (IFN-γ) secretion was assessed by ELISPOT. Results: Tumor cell lines and DCs were obtained from 19 out of 61 patients. ELISPOT was performed so far for 6 patients: strong IFN-γ secretion was detected at the third, fourth and fifth stimulations for one patient and at the second for another patient, whereas for three patients a weak secretion was detected during the second and the third stimulations. CTLs from one patient did not react to the stimulations. Conclusions: Generation of CTLs suitable for ACT immunotherapy is feasible from peripheral blood in patients with CRC.
A phase I study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors.
Authors: Soliman Hatem Hussein , Minton Susan E. , Han Hyo S. , Ismail-Khan Roohi , Mahipal Amit , Janssen William , Streicher Howard , Vahanian Nicholas N. , Link Charles J. , Ramsey William Jay , Antonia Scott J. , Sullivan Daniel 
Published: March 2020

3069 Background: Indeolamine 2,3 dioxygenase (IDO) is an inducible tryptophan-catabolizing enzyme that downregulates the immune system. Many tumor cell types overexpress IDO to avoid elimination by infiltrating cytotoxic T cells. 1-methyl-D-tryptophan (1-MT, indoximod) is an IDO pathway modulator. Published preclinical data suggested that blockade of IDO with indoximod enhances the immunologic response to dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used for generating DC vaccines directed against p53 epitopes. Ad.p53 when given to previously treated SCLC patients significantly increased their response rate to subsequent chemotherapy. The primary goal in phase I is the MTD of indoximod +Ad.p53. Methods: This phase 1 study used a 3+3 design with 7 indoximod dose levels (DL) (100 mg, 200 mg, 400 mg, 800 mg QD then 800 mg, 1,200 mg, and 1,600 mg PO BID)+up to 6 fixed dose Ad.p53 DC vaccinations q2wks. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilimumab. Treatment will continue until disease progression or unacceptable toxicity. DLT rules are 1st cycle ≥G3 AE related to treatment. Results: Total patients accrued to phase I=32. Types treated were 22 breast, 3 colon, 2 gastric, 1 ovarian, 1 NSCLC, 1 oropharynx, 1 sarcoma. No. of patients treated at DL 1-7 were 3, 3, 4, 6, 6, 3, 6, respectively. Toxicities possibly related to therapy were G1-2 fatigue, nausea, constipation, diarrhea, photosensitivity, hyponatremia, hyperglycemia, AST elevation. The MAD was 1,600 mg BID of indoximod with no DLTs noted. All discontinuations were due to progression of disease. No objective responses to study therapy were noted, but 6/10 breast patients treated with carboplatin/gemcitabine or gemcitabine alone responded to salvage therapy. Conclusions: The combination of indoximod+Ad.p53DC vaccine was well tolerated.The RP2D of indoximod is 1,600 mg BID + Ad.p53DC vaccine. There may be a chemosensitizing effect of Ad.p53DC+indoximod with chemo. The phase II trial in metastatic breast is looking at the response rate of indoximod+Ad.p53DC vaccine followed by salvage carboplatin/gemcitabine in previously treated patients. NCT01042535 Clinical trial information: NCT01042535.
Effect of therapeutic targeting of EMP2 on breast and endometrial cancer stem cells.
Authors: Wadehra Madhuri , Kiyohara Meagan , Ashki Negin , Chan Ann 
Published: March 2020

3080 Background: There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast and endometrial cancers, metastatic CSCs are defined as CD44+/CD24- and ALDH+, and in this study, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple-negative breast, ovarian, and endometrial tumors. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels alter the number and expression of CSC markers. To translate this work, EMP2 and ALDH expression were correlated in primary human endometrial and breast cancers. To determine the therapeutic efficacy of our fully-human EMP2 IgG1 antibody, xenografts from breast or uterine cancer were treated, removed, and then reinjected into secondary mice. Results: In this study, we show new evidence that EMP2 is highly expressed in CSCs. High levels of EMP2 increase the tumor forming potential of both endometrial and breast cancer lines. In tumors created from these cells, high levels of ALDH+ expression were also observed. In contrast, reduction in EMP2 decreased CD44 expression and ALDH activity both in vitro and in vivo, with the net consequence of poorly vascularized and slow growing tumors. We have recently developed a novel monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1a, CD44, and ALDH levels, ultimately leading to caspase mediated apoptosis. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load in both subcutaneous and metastatic models of breast and endometrial cancer resulting in a significant improvement in survival. Reinjection of these cells post treatment into secondary mice failed to efficiently form, and histological examination of the tumors revealed significant necrosis and elimination of ALDH+ CSCs. Conclusions: These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development.
Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma.
Authors: Klein Oliver , Davis Ian D. , McArthur Grant A. , Haydon Andrew Mark , Parente Phillip , Dimopoulos Nektaria , Jackson Heather , Maraskovsky Eugene , Hopkins Wendie , Stan Rodica , Chen Weisan , Cebon Jonathan S. 
Published: March 2020

3093^ Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p=0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.
Use of genetic variants in pericyte-driven tumor vessel maturation genes to predict treatment efficacy in mCRC patients treated with FOLFIRI/bevacizumab.
Authors: Volz Nico Benjamin , Zhang Wu , Yang Dongyun , Ning Yan , Stintzing Sebastian , Wakatsuki Takeru , El-Khoueiry Rita Elie , Li Joseph Ethan , Kardosh Adel , Loupakis Fotios , Marmorino Federica , Antoniotti Carlotta , Lenz Heinz-Josef 
Published: March 2020

3566 Background: Angiogenesis is maintained by the presence of PDGFB (platelet derived growth factor beta) which binds to the receptor, PDGFRB on pericytes, signaling them to stabilize stalk cells adjacent to tip cells. PDGFB signaling by endothelial tip cells promotes proliferation, migration, and stabilization of pericytes which are closely associated with endothelial cells. VEGF driven angiogenesis in response to tumor hypoxia relies on several genes. Previously, studies showed RALBP1, RGS5, and CSPG4 greatly impact the structure of blood vessels during angiogenesis. Recognizing these genes are important in angiogenesis through pericytes, we investigated the correlation between polymorphisms in these genes and clinical outcomes in patients with mCRC treated with FOLFIRI/bevacizumab (BV). Methods: Genomic DNA was extracted from 455 patients’ blood or tissue treated with first-line BV + FOLFIRI and prospectively enrolled in a prospective pharmacogenomic translational study. Median follow up is 24 months and median PFS and OS were 10.5 and 29.9 months, respectively. Eight functionally significant SNPs; RGS5 (rs1056515, rs2661280), PDGFRB (rs2229562, rs2302271), CSPG4 (rs8023621, rs1127648), and RALBP1 (rs10989, rs329007) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with tumor response rate (RR), progression free survival (PFS), and overall survival (OS). Results: Four SNPs showed significant results in the univariate analysis of either OS or PFS. PDGFRB rs2302273 remained significant upon multivariate analysis. Univariate analysis of PDGFRB rs2302273 concluded patients with any T (CT/TT) allele were significantly associated with longer PFS compared to those with CC genotypes (median 10.2 vs 11.6 months, HR=0.78 [95%CI: 0.63-.98], p=0.031, log-rank test) which remained significant upon multivariate analysis (HR=0.73 [95% CI: 0.57-0.92], p=0.008, log-rank test). Conclusions: Our results show that the PDGFRB polymorphism rs2302273 may serve as a prognostic marker for the efficacy of FOLFIRI + BV treatment in patients with mCRC. Studies to confirm and update these preliminary findings are ongoing.
Primary tumor location and expression of mir-664 as a combined biomarker for bevacizumab effectiveness in metastatic colorectal cancer.
Authors: Boisen Mogens Karsboel , Dehlendorff Christian , Linnemann Dorte , Larsen Jim S. , Oesterlind Kell , Hansen Joergen , Nielsen Svend Erik , Pfeiffer Per , Tarpgaard Line Schmidt , Hollander Niels Henrik , Keldsen Nina , Hansen Torben , Jensen Brita Bjerregaard , Hoegdall Estrid Vilma Solyom , Jensen Benny Vittrup , Johansen Julia S. 
Published: March 2020

3572 Background: We aimed to identify tissue microRNAs (miRs) that could predict outcome for patients with metastatic colorectal cancer (mCRC) treated with first line bevacizumab (BEV) and chemotherapy (CT) but not for patients treated with CT alone. Methods: Patients with mCRC treated with first line capecitabine and oxaliplatin (CT) with or without BEV at ten hospitals were identified and data was extracted retrospectively. Formalin-fixed paraffin-embedded tissue samples from primary tumors were collected and RNA was purified from 3 x 10 µm sections, without micro-dissection. miR expression was measured using Applied Biosystems TaqMan Custom LDA cards profiling 22 selected miRs in duplicate. The 22 miRs were selected from a previous discovery study profiling 754 miRs. miR expression was related to time to disease progression (TTP) and overall survival (OS) in multivariate analyses using Cox proportional hazards models with adjustment for age, prior adjuvant treatment, and no. of metastatic sites. We have previously found that patients with primary tumors originating in the sigmoid colon and rectum (S+R) experienced a better outcome than patients with other primary tumor locations (caecum to descending colon) when treated with BEV, so our analyses were stratified by primary tumor location. Results: miR expression was measured in samples from 399 patients: 155 samples from the original CT+BEV discovery study, 119 samples from a new CT+BEV cohort, and 125 samples from a CT alone cohort. Expression of miR-664 showed a significant positive association with increasing TTP, OS, and response rate (RR), but only in the cohort of patients with sigmoid colon- and rectal primary tumors treated with CT+BEV (n=183). Conclusions: We have identified a subgroup of patients with mCRC that are likely to benefit from BEV addition to first line CT using the combined information of location of the primary tumor and expression level of miR-664. [Table: see text]
Correlation of hypertension and proteinuria with outcomes in elderly bevacizumab (BEV)-treated patients with metastatic colorectal cancer (mCRC): Analysis of the BECOX and BECA studies.
Authors: Salud Salvia Antonieta , Feliu Jaime , Safont Maria Jose , García-Girón Carlos , Aparicio Jorge , Losa Ferran , Bosch Carlos , Escudero Pilar , Casado Enrique , Jorge Fernández Mónica , Bohn Sarmiento Uriel , Pérez-Carrión Ramon , Carmona Bayonas Alberto , Custodio Ana B. , Maurel Juan 
Published: March 2020

3589 Background: Studies suggest a relationship between hypertension, which is common in older patients, and outcome in BEV-treated patients with mCRC. We performed a retrospective analysis of two studies – BECA [Feliu et al BJC 2010; EudraCT 2005-002808-42] and BECOX [NCT01067053] – to determine if hypertension and proteinuria predict outcome in elderly BEV-treated patients. Methods: Patients ≥70 years received capecitabine 1250 mg/m2 bid po on days 1–14 + BEV 7.5 mg/kg on day 1 every 21 days in the BECA study; BECOX patients received capecitabine 1000 mg/m2 bid po on days 1–14 with BEV 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 (oxaliplatin discontinued after cycle 6). Primary endpoints were overall response rate (ORR) in BECA and time to progression (TTP) in BECOX. Correlations were investigated for hypertension and proteinuria with ORR, disease control rate (DCR), overall survival (OS) and TTP. Logistic regression was performed to identify factors associated with hypertension and proteinuria. Results: 127 patients were included (BECA n=59; BECOX n=68; 61% male, median age 76 years; ECOG PS 0/1/2 45%/52%/2%). During the study 16% of patients had hypertension and 61% had proteinuria as an adverse event. Hypertension correlated with DCR, OS and TTP but not ORR; proteinuria correlated with ORR and DCR (Table). Development of proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors associated with development of hypertension were female gender (odds ratio [OR] 0.241; p=0.011) and greater no. of BEV cycles (OR 1.112; p=0.002); factors associated with proteinuria were diabetes (OR 3.869; p=0.006) and greater no. of BEV cycles (OR 1.181; p<0.0001). Conclusions: This analysis of the BECOX and BECA studies suggests that hypertension and proteinuria are associated with outcome in BEV-treated elderly patients with mCRC. Clinical trial information: NCT01067053. [Table: see text]
Natural history and outcomes of synchronous and metachronous colorectal cancers (CRC): A population-based analysis.
Authors: Chu Jackson , Goktepe Ozge , Cheung Winson Y. 
Published: March 2020

3593 Background: Early data suggest that synchronous and metachronous CRC portend a worse prognosis when compared to solitary CRC. Our aims were to 1) characterize the clinical features and treatment patterns of synchronous and metachronous CRC and 2) compare their survival outcomes with those of solitary CRC. Methods: All patients diagnosed with non-metastatic CRC between 1999 and 2008 and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were reviewed. Synchronous and metachronous CRC were defined as multiple (2 or more) distinct tumors that were diagnosed within and beyond 6 months of the date of index CRC diagnosis, respectively, during the study period. Patients with liver metastases at initial diagnosis were excluded. Kaplan-Meier and Cox regression analyses were used to estimate survival among the different CRC groups. Results: A total of 6360 patients were identified: 6147 (96%) solitary, 178 (3%) synchronous and 35 (1%) metachronous tumors; median age was 68 years (IQR 59-76); 57% were men; and 75% were ECOG 0/1 at the time of index cancer diagnosis. Baseline demographic characteristics were comparable across patients (all p>0.05). Compared with solitary CRC, synchronous and metachronous CRC more commonly affected the colon rather than the rectum (84 vs 85 vs 59%, respectively, p<0.001), but presenting symptoms, treatment approaches, and use of chemotherapy, radiation and surgery were similar among the different tumor groups (all p>0.05). In terms of survival, no differences were observed in 3-year relapse free survival (66 vs 66 vs 56%, p=0.20), 5-year cancer specific survival (69 vs 69 vs 53%, p=0.34) and 5-year overall survival (62 vs 59 vs 49%, p=0.74) for solitary, synchronous and metachronous CRC, respectively. These findings persisted after controlling for known prognostic factors, such as age and ECOG. Conclusions: In this large population-based cohort, there were no differences in survival outcomes among solitary, synchronous and metachronous CRC. Patients who present with multiple tumors in the colon or the rectum should be managed similarly to those who present with an isolated tumor.
Discovering new targeted therapies for BRAF mutant-like colorectal cancers.
Authors: San Lucas F. Anthony , Kopetz Scott , Scheet Paul A. , Vilar Sanchez Eduardo 
Published: March 2020

3623 Background: Approximately 10% of colorectal cancers (CRCs) harbor a BRAF mutation (BRAFm). Patients with BRAFm tumors have poor prognosis and are a therapeutic challenge. A BRAFm gene expression signature has been communicated (Popovici et al, JCO 2012), which can identify BRAFm tumors as well as BRAF wild-type tumors that display a similar expression pattern. Collectively, these tumors are termed BRAFm-like. Our goal was to validate this signature using next-generation sequencing and to discover novel therapies for BRAFm-like CRCs using a systems biology approach. Methods: We developed a semi-automated workflow that integrates publicly available tools named the Cancer In-silico Drug Discovery (CIDD). To validate the BRAFm-like signature, we used CIDD to analyze the CRC dataset from the The Cancer Genome Atlas Network (TCGA). Samples were stratified on BRAFm status using exome-sequencing, and expression profiles were inferred from RNA-sequencing. We matched expression profiles with drug-induced signatures inferred from the Connectivity Map (CMap) – a systems biology tool that contains expression data of cell lines treated with 1,500 compounds. CIDD statistically ranks candidate compounds and annotates them to pathways using public databases. Results: When applied to TCGA RNA-sequencing data, a classifier based on the BRAFm-like signature resulted in 93.3% sensitivity and 83.5% specificity for detecting BRAFm samples. When applied to Agilent gene expression data, this resulted in 80% sensitivity and 91.1% specificity. 41% of KRAS-mutated samples and 14% of double wild-type samples were predicted to be BRAFm-like. 100% of MSI-high and 18% of MSS samples were predicted to be BRAFm-like. Compounds near the top of our drug rankings include Gefitinib and MG-262 a proteasome inhibitor. Conclusions: We have validated the BRAFm-like signature using RNA-sequencing and Agilent expression data from the TCGA, and showed a high degree of robustness across technologies. We have identified EGFR and proteasome inhibitors as potential compounds to target BRAFm-like CRCs.
Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial.
Authors: Brose Marcia S. , Nutting Christopher , Jarzab Barbara , Elisei Rossella , Siena Salvatore , Bastholt Lars , de la Fouchardiere Christelle , Pacini Furio , Paschke Ralf , Shong Young Kee , Sherman Steven I. , Smit Johannes WA , Chung John Woojune , Siedentop Harald , Molnar Istvan , Schlumberger Martin 
Published: March 2020

4 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.