bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4295: INT230-6, a novel intratumoral anticancer agent, is able to eradicate large established tumors and stimulate potent anti tumor immunity
Authors: Walters Ian B. , Bender Lewis H. , Terabe Masaki , Berzofsky Jay A. 
Published: August 2015

Abstract
Historically, intratumoral (IT) administered chemotherapy has not been shown to provide better efficacy than the same drugs delivered intravenously. This is postulated to be due to poor drug diffusion and dispersion throughout the tumor. Intensity has developed a novel formulation of cytotoxic chemotherapy plus a penetration enhancer which improves drug diffusion and uptake into the cancer cell. INT230-6 is a combination of low dose cisplatin, vinblastine and a cell penetration excipient. This technology enables more rapid and improved penetration throughout the tumor including hypoxic and un-vascularized areas. Cohorts of 10 BALB/c mice were inoculated with 1×106 CT26 cells subcutaneously (SC). Tumors were grown to a mean of 325mm3 and then treatment with INT230-6 was administered IT daily for a single cycle of 5 days. Control arms using comparable size tumors pre-dose included no treatment, IV cisplatin and vinblastine, and IT injection of these drugs without the enhancer. INT230-6 treatment resulted in regression from baseline in all animals with a complete regression of the large tumors in 20%. Many tumors continued to shrink in size well beyond multiple half-lives of the chemotherapy and excipient implying an anti-tumor effect not due to direct cytotoxicity from the drugs. INT230-6 administration resulted in a significant extension of overall survival compared to all controls. Notably complete responders with this treatment were resistant to 3 separate attempts at re-inoculation with 1×106 CT26 cells by SC or IV administration without retreatment of drug, while control animals rapidly developed metastatic tumors and died. This apparent tumor immunity persisted for &gt; 440 days suggesting permanent immunity. In a follow-on study, tumors of some animals receiving INT230-6 were shown to be 75% necrotic on day 3 of treatment with an observed increase in the density of CD4 positive cells and CD11c positive cells in the treated tumors on day 10 versus controls. These changes might be involved in the induction of immunity. These results suggest that intratumoral administration of INT230-6 creates the proper tumor cell apoptosis kinetics and antigen presentation to enable a personalized adaptive immune response to develop. Further work is being done to look at repeat dosing and combinations with other immunomodulating agents.
Citation Format: Ian B. Walters, Lewis H. Bender, Masaki Terabe, Jay A. Berzofsky. INT230-6, a novel intratumoral anticancer agent, is able to eradicate large established tumors and stimulate potent anti tumor immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4295. doi:10.1158/1538-7445.AM2015-4295
Abstract 4296: Dextran sodium sulfate-induced colitis in dendritic cell deletion mice
Authors: Masuda Junko , Kitani Atsuhi , Fuss Ivan , Seno Masaharu , Strober Warren 
Published: August 2015

Abstract
Dendritic cells (DC) located in lamina propria are critical for converting to CD4+Foxp3+ regulatory T (Treg) cells from CD4+Foxp3- in the presence of retinoic acid and TGF-beta. However, role of DC and Treg in immunological tolerance with commensal bacteria is still controversial. To address this question, we bred constitutively CD11c+ DC-depleted mice on C57BL/6 background. Although CD4+ T cells isolated from splenocytes showed normal in vitro differentiation into Th1 and Th17 cells, these DC-depleted mice were more protective than that of control against dextran sodium sulfate (DSS) -induced colitis. Treg expression level of DC-depleted mice was lower than that of control and not changed even after colitis. These results suggest that other cell populations regulate gastrointestinal system in both static and chronic inflammatory state in DC-depleted mice.
Citation Format: Junko Masuda, Atsuhi Kitani, Ivan Fuss, Masaharu Seno, Warren Strober. Dextran sodium sulfate-induced colitis in dendritic cell deletion mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4296. doi:10.1158/1538-7445.AM2015-4296
Abstract 4309: Description of a scientific treatment approach of mast cell leukemia, an aggressive orphan hematologic disorder: strategy based on next-generation sequencing data
Authors: Youk Jeonghwan , Koh Youngil , Kim Ji-Won , Kim Dae-Yoon , Jung Woo June , Ahn Kwang-Sung , Yoon Sung-Soo , Jung Hye Lim 
Published: August 2015

Abstract
Background
Mast cell leukemia (MCL) is the most aggressive form of disorder among systemic mastocytosis. Due to its rarity, neither pathogenesis nor standard treatment is not established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing result of the patient's own DNA and RNA.
Brief Case History and Results
In October 2013, an 18-year-old Korean female were diagnosed as MCL after visiting our hospital due to left knee, ankle pain and inguinal lymphadenopathy. C-KIT overexpression was observed by immunohistochemistry. Whole exome sequencing result failed to demonstrate either noticeable single nucleotide variant (SNV) or copy number change. Interestingly, whole transcriptome sequencing (WTS) revealed mutation of KIT S476I, functionality of which is not known. Fusion analysis was performed using WTS data, possibility of RARα-B2M fusion has been arised. However, it was not validated by PCR sequencing. When RNA expression analysis was performed using WTS data, upregulation of PIK3/AKT pathway, which is a downstream of KIT (BAD phosphorylation) and mTOR has been observed.
For the treatment perspective, she failed to achieve complete remission after cytarabine and idarubicin chemotherapy. Based on our WES and WTS result, we first tried all-trans retinoic acid targeting RARα, which failed to demonstrate efficacy. Then, she received dasatinib targeting KIT, which showed transient response for 2 weeks. Now she is under everolimus targeting mTOR pathway and, further treatment with PI3K inhibitor is planned in case of disease progression.
Conclusions
We are demonstrating a case of orphan disease, where we used targeted approach using WES and WTS data of the patient. Final results of our treatment outcome will be uncovered shortly, and utility of this kind of approach is to be validated.
Citation Format: Jeonghwan Youk, Youngil Koh, Ji-Won Kim, Dae-Yoon Kim, Woo June Jung, Kwang-Sung Ahn, Sung-Soo Yoon, Hye Lim Jung. Description of a scientific treatment approach of mast cell leukemia, an aggressive orphan hematologic disorder: strategy based on next-generation sequencing data. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4309. doi:10.1158/1538-7445.AM2015-4309
Abstract 4322: Kinase activity profiles distinguish papillary thyroid cancers with and without BRAF V600E mutations
Authors: Hilhorst Maria H. , van den Berg Adrienne , van Wezel Tom , Kievits Tim , Boender Piet J. , de Wijn Rik , Ruijtenbeek Rob , Corver Wim , Morreau Hans 
Published: August 2015

Abstract
Background: Most differentiated non medullary thyroid cancers (DTC) are curatively treated by surgery and radio-active iodine ablation therapy. A subset of patients shows recurrence due to a loss of iodine transport. Two main subgroups of recurrent DTC are seen: papillary thyroid cancers (PTC) with somatic BRAF mutations (V600E) and oncocytic follicular cancer. Recurrent DTC are clinically treated by multi-kinase inhibitors such as sorafenib, with a low affinity for BRAF V600E. Vemurafenib and dabrafenib were specifically designed against this mutant.
The aim of this study was twofold:
- Can benign and malign DTC be classified based on kinase activity profiles?
- Do sorafenib (and regorafenib) show different inhibition profiles than dabrafenib?
Methods: Tissue cryosections from fresh frozen thyroid tumors were lysed. All tumor specimens were analyzed for BRAF mutations. Serine/threonine kinase (STK) activity profiles of the lysates (0.5 μg protein per array) were generated on PamChip® peptide microarrays, comprising peptide sequences from known human phosphorylation sites. The ex vivo effect of BRAF inhibitors sorafenib, regorafenib and dabrafenib on kinase activity profiles of 14 PTC's was determined as well. Data were analysed with Bionavigator software.
Results: A classifier built on the STK kinase activity profiles of 57 thyroid cancer samples was able to classify malignant and benign tumors with a limited error rate. Leave One Out Cross Validation classified 26/35 of malignant and 17/22 of benign samples correctly. Kinase inhibition profiles of PTC's with sorafenib and regorafenib did not discrimate V600E mutants from wild type tumors whereas with dabrafenib 34/144 peptides were identified that potentially differentiated the groups.
Conclusions: Serine/threonine kinase activity profiling appears to be able to differentiate benign and malignant thyroid tumors. Ex vivo spiking in of kinase inhibitors shows differential inhibition in tumors with a somatic BRAF mutation. Potentially, an industrial prediction platform can be envisioned for testing of novel drugs in tumor tissue. Whether individual patient responses against registered kinase inhibitors can be predicted must be investigated.
Citation Format: Maria H. Hilhorst, Adrienne van den Berg, Tom van Wezel, Tim Kievits, Piet J. Boender, Rik de Wijn, Rob Ruijtenbeek, Wim Corver, Hans Morreau. Kinase activity profiles distinguish papillary thyroid cancers with and without BRAF V600E mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4322. doi:10.1158/1538-7445.AM2015-4322
Abstract 4332: Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung cancer
Authors: Su Yinghao , Zhang Ming-Zhi , Wen Wanqing , Zheng Wei , Eisenberg Rosana , Massion Pierre P. , Cai Qiuyin 
Published: August 2015

Abstract
Background: Arachidonic acid (ARA) is a polyunsaturated fatty acid present in the phospholipids of cell membranes. ARA is metabolized through two major pathways, cyclooxygenase (COX) and lipoxygenase (LOX), resulting in various biologically active eicosanoids, such as prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids. Cumulative evidence from both in vitro and animal studies suggests that COX and LOX pathways may be involved in the development and progression of lung cancer by regulating multiple biological processes. However, no direct evidence exists to connect key enzymes of COX and LOX pathways with prognosis of non-small cell lung cancer (NSCLC). We conducted a study to evaluate the association of protein expression of major enzymes in the COX and LOX pathways with prognosis of NSCLC. Materials and Methods: Included in the study are 98 patients with surgically resected NSCLC. The archived paraffin-embedded tumor tissue blocks were retrieved, and tissue microarray were constructed with at least two cores for most cases. Clinical data were obtained from medical records. Expression levels of COX-2, 12-LOX, 15-LOX-1, 15-LOX-2, 5-LOX activating protein (FLAP), and 11β-hydroxysteroid dehydrogenase type I (11βHSD1) and type II (11βHSD2) were evaluated immunohistochemically. Odds ratios (OR) of death were estimated using logistic regression models with adjustment for age at diagnosis, BMI, smoking status, and tumor stage. Results: All seven assayed markers were significantly correlated with one another (r = 0.299 - 0.658, P &lt; 0.01). We observed that a higher level of COX-2 protein expression was associated with advanced tumor stage (P = 0.026). A higher level of 15-LOX-1 protein expression was associated with significantly increased risk of death (OR = 3.27, 95% CI 1.01 - 10.5, P = 0.048) and a higher level of 11βHSD1 protein expression was associated with a marginally significant increased risk of death (OR = 2.67, 95% CI 0.86 - 8.31, P = 0.089). No association of other markers with lung cancer death was found. Conclusions: 15-LOX-1 and 11βHSD1 may be prognostic markers for NSCLC. Validation of the findings in an independent patient cohort is warranted.
Citation Format: Yinghao Su, Ming-Zhi Zhang, Wanqing Wen, Wei Zheng, Rosana Eisenberg, Pierre P. Massion, Qiuyin Cai. Evaluation of arachidonic acid pathways with prognosis in patients with surgically resected non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4332. doi:10.1158/1538-7445.AM2015-4332
Abstract 4338: Clinical significance of soluble CD26 in malignant pleural mesothelioma
Authors: Fujimoto Nobukazu , Ohnuma Kei , Aoe Keisuke , Hosono Osamu , Yamada Taketo , Kishimoto Takumi , Morimoto Chikao 
Published: August 2015

Abstract
There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.
Citation Format: Nobukazu Fujimoto, Kei Ohnuma, Keisuke Aoe, Osamu Hosono, Taketo Yamada, Takumi Kishimoto, Chikao Morimoto. Clinical significance of soluble CD26 in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4338. doi:10.1158/1538-7445.AM2015-4338
Abstract 4340: Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis
Authors: Wang Liangzhe , Xu Yingjie , Wu Shulin , Fergus Mary , Wu Chin-Lee , Zetter Bruce 
Published: August 2015

Abstract
Novel molecular markers that are associated with prostate cancer progression are needed to provide more useful information for the diagnosis and treatment of this disease. The antizyme inhibitor (AZI), a non-enzymatic homologue of ornithine decarboxylase (ODC), is upregulated in many cancer types, including: prostate cancer, breast cancer, hepatocellular carcinoma and non-small cell lung cancer. In this study, we examined the distribution of AZI in benign prostate tissues and in prostate cancers at differing stages. We were interested specifically in the possible correlation between AZI expression and patient survival. We found that AZI can reside in the cytoplasm and/or nuclear space in prostate cancer tissue. Nuclear AZI was observed in nearly all of the prostate cancer specimens but not in benign prostate tissue. Cytoplasmic AZI was found both in tumor cells and in adjacent benign prostate tissue. Nuclear AZI was associated significantly with prostate-specific antigen recurrence-free survival but not with overall survival. Further, we found that the presence of nuclear AZI could distinguish poor survival in lower grade patients (Gleason score ≤ 7), especially in samples with non-cribriform tumors. Our results demonstrate a potential role for nuclear AZI as an independent marker of patient outcome in prostate cancer patients.
Citation Format: Liangzhe Wang, Yingjie Xu, Shulin Wu, Mary Fergus, Chin-Lee Wu, Bruce Zetter. Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2015-4340
Abstract 4344: Olfactomedin 4 plays a tumor-suppressor role and is a novel candidate biomarker in the prostate cancer progression and independent of PSA
Authors: Li Hongzhen , Chen Ye , Liu Wenli , Zhu Jianqiong , Kay Chin , Wang Xujing , Rodgers Griffin P. 
Published: August 2015

Abstract
Prostate cancer is the most commonly diagnosed solid tumor and the second leading cause of cancer-related death in the American male population. The olfactomedin 4 gene (OLFM4) plays critical tumor suppressor roles in human and murine prostate cancer. We have previously reported that loss or reduce of OLFM4 expression is associated with the progression of human prostate cancer. We further found that loss of Olfm4 leads to prostate neoplastic progression in the Olfm4-knockout mouse model.
To study the clinical impacts of OLFM4 gene in the prostate cancer, we have performed bioinformatics analysis from the published datasets, GSE35988, GSE21032 and TCGA as well as immunohistochemical analysis with prostate cancer tissue arrays by using OLFM4 antibody. The copy number variations (CNV) of OLFM4 gene were significantly associated with Gleason scores of prostate cancer. The pattern of OLFM4 CNV is similar with other tumor suppressor genes, RB1, PTEN and P53. We have observed consist reduce or loss of mRNA expression in the castrate resistant and metastatic prostate cancer patient samples. To study the relationship between OLFM4 expression and prostate cancer recurrence, we performed Kaplan-Meier Plots and Log-rank statistic analysis for GSE21032 and TCGA data sets. Overall, there was no significant relationship between OLFM4 expression and prostate cancer recurrence. However, when analysis was restricted to the lower quartile of OLFM4 expression, we obtained a highly significant inverse relationship (p = 0.02) between OLFM4 expression and recurrence. We also observed that alteration of CNV and expression of OLFM4 gene has no relationship with the level of (patient) serum prostate specific antigen (PSA).
We performed immunohistochemical analysis with prostate cancer tissue arrays by using OLFM4, PSA and E-cadherin antibodies. Lower or loss of expression of OLFM4 protein is associated with advanced Gleason scores of prostate cancer specimens. The pattern of OLFM4 protein expression in prostate cancer patient samples is similar to that of E-cadherin, but not PSA.
Taken together, these results suggest that OLFM4 plays a tumor-suppressor role, and therefore is a likely therapeutic target for prostate cancer interdiction.
Citation Format: Hongzhen Li, Ye Chen, Wenli Liu, Jianqiong Zhu, Chin Kay, Xujing Wang, Griffin P. Rodgers. Olfactomedin 4 plays a tumor-suppressor role and is a novel candidate biomarker in the prostate cancer progression and independent of PSA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4344. doi:10.1158/1538-7445.AM2015-4344
Abstract 4346: Prognostic gene signature for intermediate risk prostate cancer
Authors: Li Brian , Hallet Robin , Wu Ying , Pong Greg , Hassell John , Hotte Sebastien , Levine Mark , Lukka Himansu , Bane Anita 
Published: August 2015

Abstract
The over treatment of prostate cancer patients is a significant concern, as recent clinical trials suggest that many patients are over treated which can lead to significant patient morbidity. Although the Gleason score is a powerful predictor of lethal or indolent disease, a significant proportion (∼40%) of men present with early stage Gleason score (GS) 7 tumors, for whom prognosis is variable. The goal of this study is to develop and optimize a robust prognostic gene signature that can be utilized on formalin fixed paraffin embedded (FFPE) core biopsy tumor material to better classify patients with intermediate risk, GS 7 tumors into good and poor outcome groups.
Three gene signatures were derived from publicly available gene expression profiles of the Swedish Watchful Waiting cohort. The Genomic Grade Index consisted of the top 25 molecular signatures discriminating between high (8, 9 & 10) and low (≤ 6) GS tumors. The Lethal Gene Score consisted of the top 25 molecular signatures discriminating between lethal and indolent disease within GS 7 tumors only. A network-based gene signature consisted of 88 genes which accurately stratified GS 7 patients into high risk and low risk groups, resembling the survival curves of high GS and low GS patients. The prognostic capacity of the combined gene signature was tested in silico on the gene expression profiles of the Mayo cohort. Results demonstrated the gene signature's highly robust capacity for differentiating low risk and high risk patients within GS 7 patients.
The NanoString nCounter System will be used to quantify mRNA from prostate FFPE blocks to assess the expression of the 138 prognostic genes. 156 archived prostate tumor blocks will be collected from intermediate risk, GS 7 patients enrolled in the 2005 PR5 prostate trial, which also collected 12 years of clinical follow-up information. Results will be correlated with biochemical (PSA) failure rates and overall survival.
In short, our findings provide proof-of-principle that through the use of gene signatures it is possible to separate prostate cancer patients of intermediate risk into good and poor outcome groups. Furthermore, they also identify multiple gene candidates whose expression could likely be formulated into a clinically applicable assay, the implementation of which could serve to stratify prostate cancer patients with tumors of intermediate risk into more accurate high and low risk groups.
Citation Format: Brian Li, Robin Hallet, Ying Wu, Greg Pong, John Hassell, Sebastien Hotte, Mark Levine, Himansu Lukka, Anita Bane. Prognostic gene signature for intermediate risk prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4346. doi:10.1158/1538-7445.AM2015-4346