bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 659: Multiplex cocktails for immunotherapy targets: PD-L1 with tumor specific transcription factors
Authors: Altree-Tacha David , Yuan Wei , Yang George 
Published: July 2017

Abstract
Introduction
Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to generate impressive antitumor responses. Therapeutics targeting PD-L1 in several cancers are currently in clinical trials, and the U.S. FDA has granted accelerated approval for Keytruda (pembrolizumab) to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC). Various pathology scoring and interpretation methods have been put forth to assay PD-L1 expression, and variability of non-PD-L1 staining across tumors may have important prognostic aspects. PD-L1 expression on tumor cells can be upregulated via activation of CD8+ cytotoxic T lymphocytes. PD-L1 expression is also associated with certain subtypes of tumor-associated lymphocytes, macrophages and dendritic cells. In certain cancers, the cross reactivity of PD-L1 can make interpretation and scoring difficult. Thus, a strategy using IHC multiplex stains could help resolve challenging cases by cocktailing PD-L1 with target tissue transcription factor antibodies along with other potential markers.
Method and Materials
Formalin-fixed paraffin-embedded tissues and tissue microarrays for various tumor types including lung, bladder and melanoma were processed and cut at 4-5 microns. PD-L1 rabbit monoclonal antibody was cocktailed with the following antibodies: TTF-1 (lung cancer); CD163 (lung cancer); p40 + GATA3 (bladder cancer); and SOX10 (melanoma). Cocktails were detected with double stain detection systems using brown, red and blue chromogens for visualization. Sections were counterstained with a standard hematoxylin or Wiegert’s iron hematoxylin.
Results
PD-L1 and TTF-1 with or without CD163 (macrophage) and PD-L1 + CD163 were used in lung cancers. The nuclear staining of TTF-1 in lung adenocarcinoma (blue chromogen) helped define tumor positive PD-L1 (DAB) positive cells and CD163 (Fast Red) marked macrophages. PD-L1 combined with p40 and GATA3 was deployed for bladder cancers. PD-L1 membranous expression in tumor cells and co-expression of p40 and GATA3 gave robust nuclear staining in bladder tumor cells. Finally, SOX10 nuclear staining was observed in most melanoma cells and could be easily separated from PD-L1 membrane staining.
Conclusion
PD-L1 cocktailed with strategic nuclear or cytoplasmic antibodies can help discriminate tumor cells from non-tumor cells, and may facilitate quantitation or scoring methods for more accurate assessment of this key immunotherapy marker.
Citation Format: David Altree-Tacha, Wei Yuan, George Yang. Multiplex cocktails for immunotherapy targets: PD-L1 with tumor specific transcription factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 659. doi:10.1158/1538-7445.AM2017-659
Abstract 674: HPV16 was the preponderant type of HPV infection in cutaneous squamous cell carcinoma
Authors: Shi Gang , Fischer Anne C. , Zenilman Jonathan M. , Gravitt Patti E. , Fischer Max , Sander Inbal B. , Cuda Jonathan D. , Taube Janis M. , Lilo Mohammed , Lee W P Andrew , Tufaro Anthony P. 
Published: July 2017

Abstract
Purpose: Human papillomavirus (HPV) has been well established as a causative factor in mucosal oropharyngeal cancer and anogenital surface malignancies. However, its etiological role in cutaneous squamous cell carcinoma (cSCC) is still debated. The aim of this study is to identify the presence of HPV types in cSCC and identify their associations with cSCC.
Methods: 77 cSCC blocks from 54 patients underwent DNA isolation and a broad spectrum of HPV PCR tests to detect the presence of HPV genotypes by the use of a universal primer pair GP5+/GP6+. The resultant PCR products were cloned to T Vectors and subsequently underwent DNA sequencing and Nucleotide BLAST search to identify the HPV types in cSCC. To ensure the accuracy of the HPV PCR test, 16 blocks from 10 head and neck SCC (oropharyngeal) patients were also included in the HPV presence and type analyses. Cutaneous SCC patients’ demographics, pathology and clinical parameters were compared and analyzed statistically in conjunction with the HPV test results.
Results: HPV DNA was found in 37 of 77 (48.1%) blocks representing 32 of 54 (59.3%) cSCC patients. HPV16 was the preponderant type of HPV Infection, accounting for 28 of 32 (87.5%) and 30 of 37 (81.08%) HPV positive patients and blocks. Other HPV genotypes found included HPV18, 57, 10, 2, accounting for 4 of 32 (12.5%), 2 of 32 (6.25%), 2 of 32 (6.25%), 2 of 32 (6.25%) of the HPV positive patients and 4 of 37 (10.81%), 2 of 37 (5.41%), 2 of 37 (5.41%), 2 of 37 (5.41%) of the HPV positive blocks, respectively. HPV infection was significantly associated with the cSCC tumor size in this cohort of patients. Tumors with a size of ≤20mm were more frequently associated with HPV. Moreover, the average tumor size of the HPV positive group was also significantly smaller than that of the HPV negative group.
Conclusions: HPV infection is very commonly found in cSCC patients and HPV16 is the major type of HPV involved in cSCC oncogenesis, accounting for &gt;80% of HPV infections. HPV is a contributing factor, which appears to be contributing to a smaller size of cSCC, which may improve the prognostic classification of patients to provide a new insight into tumorigenesis.
Citation Format: Gang Shi, Anne C. Fischer, Jonathan M. Zenilman, Patti E. Gravitt, Max Fischer, Inbal B. Sander, Jonathan D. Cuda, Janis M. Taube, Mohammed Lilo, W P Andrew Lee, Anthony P. Tufaro. HPV16 was the preponderant type of HPV infection in cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 674. doi:10.1158/1538-7445.AM2017-674
Abstract 675: The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication
Authors: An Ho Jung , Kim Tae-Jung , Sa Young Jo , Kang Chang Suk 
Published: July 2017

Abstract
Introduction: The Hedgehog (Hh) signaling plays essential role in transcription regulation and embryonic development. In many cancers including lung cancer, it is related to carcinogenesis and poor prognosis. This signaling also mediates epithelial to mesenchymal transition (EMT) by paracrine mechanism in various diseases. We aim to study the interaction between Hedgehog and EMT pathway and its clinical implication in non-small cell lung cancer (NSCLC).
Method: Total 271 cases of NSCLC who received surgical resection in Yeouido St. Mary’s Hospital between 1997 and 2011 were included. For immunohistochemical analysis of Hh and EMT related proteins, 4um sections were sliced from tissue microarray. Hh signaling proteins including Sonig hedgehog (Shh), Patched (Ptch), Smoothened (Smo), Glioma-associated oncogene (Gli-1) and Suppressor of fused (Sufu), and EMT associated molecules including E-cadherin and vimentin were analyzed. Staining intensity (IS) was estimated as follows 0 (no staining), +1 (weak), +2 (distinct), +3 (strong). Intensity score (IS) ≥1 was defined as positive. Medical record was retrospectively reviewed. The study was approved by the institutional review board the hospital.
Result: The median age was 63 (18-84) years, and 65.3% were male. Squamous cell carcinoma was diagnosed in 113 (41.7%), adenocarcinoma in 153 (56.5%), and mixed type in 153 (56.5%). Stage 1 and 2 were 46.9% and 30.6%, respectively, and 8 cases had distant metastasis. The Hh proteins showed positive correlation each other. For EMT, the expressions of Hh protein was significantly correlated with tumoral and stromal positivity of vimentin, and inversely with positivity of E-cadherin (P = 0.002 and P = 0.028, respectively). The expression of Hh proteins were significantly associated with lymph node metastasis along with large tumor size (P = 0.021 and P = 0.035, respectively). In survival analysis, expressions of Shh and Gli1 were independent predictor of disease free survival and cancer-specific survival (P = 0.007 and P = 0.025, respectively).
Conclusion: Expression of Hh protein is associated with epithelial-mesenchymal transition and associated with poor prognosis in NSCLC.
Citation Format: Ho Jung An, Tae-Jung Kim, Young Jo Sa, Chang Suk Kang. The interaction between hedgehog and EMT pathway in non-small cell lung cancer and its prognostic implication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 675. doi:10.1158/1538-7445.AM2017-675
Abstract 676: Nuclear expression of insulin receptor (InsR) adds prognostic information in primary breast cancer patients with high BMI
Authors: Björner Sofie , Rosendahl Ann H. , Simonsson Maria , Markkula Andrea , Jirström Karin , Borgquist Signe , Rose Carsten , Ingvar Christian , Jernström Helena 
Published: July 2017

Abstract
Aim and introduction The aim of this study was to elucidate the prognostic importance of nuclear expression of the insulin receptor (nucInsR) in primary breast cancer. The InsR is important for the metabolism, for the insulin-like growth factor (IGF) signaling network and is implicated in breast cancer. Insulin and InsR are interlinked with obesity and body mass index (BMI), which are also associated with breast cancer. The InsR is present both in the membrane and cytoplasm and can additionally translocate to the nucleus. The role of nucInsR is not well understood and the prognostic importance is unclear.
Methods The tumor-specific expression of nucInsR was evaluated by immunohistochemistry on invasive breast cancer tissue microarrays from 984 primary breast cancer patients included in a population-based cohort in Sweden. Patients were followed for up to 11 years, the median follow-up for patients still at risk was five years. nucInsR in relation to prognosis was analyzed using Cox regression, adjusted for age, invasive tumor size, axillary lymph node involvement, histological grade, estrogen receptor (ER) status, BMI, tumor storage time, and treatment.
Results Status for nucInsR was available for 900 patients (91.5%). nucInsRpos staining was present in 214 patients (23.8%) and was associated with lower age (P=0.004), and lower waist-to-hip ratio (P=0.006), but not with BMI, ER or PR status. During follow-up, 107 patients had a first breast cancer event. nucInsR had no prognostic significant impact among all patients. However, there was a significant effect modification of BMI on nucInsR regarding event-free survival (Pinteraction=0.006). Patients with nucInsRpos-expressing tumors and higher BMI (≥25 kg/m2) had lower risk for any breast cancer event, adjusted HR (0.49; 95% CI 0.26-0.93), while patients with nucInsRpos-expressing tumors and normal BMI (&lt;25 kg/m2) were associated with a non-significant higher risk of events, adjusted HR (1.72; 95% CI 0.93-3.17).
Conclusions These results indicate that nucInsR status may add prognostic information in primary breast cancer depending on BMI.
Citation Format: Sofie Björner, Ann H. Rosendahl, Maria Simonsson, Andrea Markkula, Karin Jirström, Signe Borgquist, Carsten Rose, Christian Ingvar, Helena Jernström. Nuclear expression of insulin receptor (InsR) adds prognostic information in primary breast cancer patients with high BMI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 676. doi:10.1158/1538-7445.AM2017-676
Abstract 677: Progranulin/GP88 tumor tissue expression further stratifies survival outcomes of patients classified by their Nottingham Prognostic Index
Authors: Serrero Ginette , Hawkins Douglas , Ioffe Olga , Bejarano Pablo , Yue Binbin 
Published: July 2017

Abstract
Background: The Nottingham Prognostic Index (NPI) combines nodal status, tumor size and histological grade and is used to provide predictive value information on survival for patients with primary breast cancer. Attempts to improve the performance of NPI have been carried out by inclusion of other factors, such as biomarker expression as well as addition of other structural features such as vascular invasion. In the present study, we investigated whether expression of the survival factor GP88 (progranulin), known to be overexpressed in breast cancer, would improve NPI’s predictive value. GP88/Progranulin is an 88 kDa autocrine growth and survival factor that is overexpressed in estrogen receptor positive (ER+) invasive ductal carcinoma (IDC) in association with resistance to anti-estrogens and aromatase inhibitor while the cells remain ER+. Previous training and validation pathological studies totaling 600 cases of ER+ IDC had demonstrated that GP88/Progranulin tissue expression was an independent prognostic marker od recurrence and mortality for early stage ER+ IDC.
Methods: We examined by immunohistochemistry the GP88 tumor tissue expression of 508 formalin fixed paraffin embedded cases of ER+ IDC with known clinical outcomes and for which NPI had been determined. GP88 IHC expression was scored by two board certified pathologists and classified into two score groups of GP88 &lt; 3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) and overall survival outcomes (OS) was then examined by Kaplan Meier analysis, Cox proportional Hazard ratio and Pearson’s X2 test.
Results: Patients were categorized into three NPI groups (&lt; 3.4, 3.4-5.4, &gt;5.4). Kaplan-Meier survival graphs of cases categorized by their NPI scores and GP88 expression showed that for each NPI subgroup, patients having tumors with a high GP88 expression (GP88 IHC score of 3+) had a worse DFS than patients within the same NPI subgroup with low GP88 expression (GP88 IHC score &lt; 3+). When adjusted for NPI, high GP88 score was highly significantly associated with recurrence. Its hazard ratio is 3.30 (95% CI 2.12 to 5.14).
Conclusions: These data suggest that the determination GP88 tumor expression at time of diagnosis for early stage breast cancer patients could provide additional survival information than the ones provided by NPI alone that maybe useful for improving the risk management of patients.
Citation Format: Ginette Serrero, Douglas Hawkins, Olga Ioffe, Pablo Bejarano, Binbin Yue. Progranulin/GP88 tumor tissue expression further stratifies survival outcomes of patients classified by their Nottingham Prognostic Index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 677. doi:10.1158/1538-7445.AM2017-677
Abstract 678: A strategy to overcome the interfering problem of tissue embedding OCT compound in activity based multiplex profiling of tyrosine kinase substrates
Authors: Arni Stephan , Caviezel Claudio , Weder Walter , Hillinger Sven 
Published: July 2017

Abstract
Introduction: The analysis of clinically relevant human tissue preserved in optimal cutting temperature (OCT) medium with activity based proteomic approaches are promising for the discovery of novel druggable disease biomarkers for the diagnosis, prognosis and prediction of response to therapeutic interventions. Nonetheless, and for many different proteomic approaches, there are important signal interferences observed in the presence of the OCT compound.
Methods: We tested activity based multiplex profiling tyrosine kinase substrates in a large batch of neoplastic and non-neoplastic lung resection specimen embedded with or without OCT. We observed significant differences in overall phosphorylation levels and searched for reasons explaining such a large effect.
Results: We ruled out the implication of either short versus long storage time after sample extraction or of nonhomogeneous batch processing of samples. We documented that the clear downward shift in overall phosphorylation levels coincided with the introduction of OCT as an improved embedding medium for resection specimen. For all the kinomes extracted, we developed a corrective procedure where a median centering was performed on the values of each peptide, separately for the with or without OCT samples.
Conclusions: We applied corrective filtering of data to the multiplex profiling approach of well characterised tyrosine kinase substrates obtained in lung resection specimen embedded with or without OCT. With the OCT correction parameters applied, the quantitation of molecular prognosis signature based on tyrosine kinase activity differences found in lung adenocarcinoma resection specimens may result in the identification of novel targets for future anti-lung cancer therapies.
Citation Format: Stephan Arni, Claudio Caviezel, Walter Weder, Sven Hillinger. A strategy to overcome the interfering problem of tissue embedding OCT compound in activity based multiplex profiling of tyrosine kinase substrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 678. doi:10.1158/1538-7445.AM2017-678
Abstract 689: Immune checkpoint targeting to improve immunotherapy in neuroblastoma
Authors: Ortiz-Ruiz Myrna L. 
Published: July 2017

Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Current treatments accounts only for at the most 40% of survival rate in high-risk NB patients. Hence, there is a need to develop new strategies that disrupt immunosuppressive signals in the tumor microenvironment in order to achieve robust anti-tumor immune responses. Co-inhibitory signals through receptors such as PD-1 can lead to the inactivation of T cells. On the other hand, co-stimulatory signals through receptors such as 41BB can enhance T cell activity against tumors. These receptors can serve as tools to develop strategies to optimize and enhance T cell anti-tumor functions. In this study, we used 9464D NB tumor mouse model to evaluate antibody treatment as a possible immunotherapy strategy. We further examine the infiltration and function of T cells after targeting checkpoints in 9464D NB tumor bearing mice. Blockade of various receptors in mice bearing 9464D tumor showed that anti-PD1 and anti-41BB delayed tumor growth. Combination therapy with anti-PD1 and anti-41BB antibodies significantly delayed tumor growth compared to single antibody treatment. This combination therapy led to a higher infiltration of CD8+ cells within the tumor. Splenocytes from 9464D tumor bearing mice treated with anti-PD1 and anti-41BB are tumor specific. In conclusion, our findings intend to design the best complement therapy to improve survival of patients with advanced NB. Our data demonstrates that tumor reactive T cells in NB tumors may express different checkpoint receptors including PD1 and 41BB. 9464D tumor bearing mice that received a combination of anti-PD1 and anti-41BB antibodies have smaller tumor size compared to single antibody therapy. Future direction includes examine T cells activation after combination therapy of BMT and immunecheckpoint targeting. Also we want to test adoptive transfer of T cells in tumor bearing mice after BMT. Further we want to measure the infiltration of other immune cells, such as myeloid cells and Tregs, in the tumor environment and possible target immune suppressive populations to see the effects in tumor growth.
Citation Format: Myrna L. Ortiz-Ruiz. Immune checkpoint targeting to improve immunotherapy in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 689. doi:10.1158/1538-7445.AM2017-689
Abstract 692: Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma in vivo and in vitro
Authors: Thiel Uwe , Kirschner Andreas , Thiede Melanie , Grünewald Thomas GP , Rubio Rebeca Alba , Richter Günther , Kirchner Thomas , Busch Dirk , Sorensen Poul , Burdach Stefan 
Published: July 2017

Abstract
Pregnancy-associated plasma protein-A (PAPPA), also known as pappalysin, is a member of the insulin like growth factor (IGF) family. PAPPA acts as a protease, cleaving IGF inhibitors, i.e. IGF binding proteins (IGFBPs), thereby releasing IGFs from IGFBPs. The insulin/IGF-axis is involved in cancer in general and in Ewing sarcoma (ES) in particular. ES is a highly malignant bone tumor characterized by early metastatic spread. PAPPA stimulates normal bone growth, and is also associated with various cancers. In particular, PAPPA is overexpressed and required for proliferation in ES. We isolated HLA-A*02:01+/peptide restricted T cells from A*02:01- healthy donors directed against PAPPA, generated by priming with A*02:01+ PAPPA peptide-loaded dendritic cells. After T cell receptor (TCR) identification, retrovirally TCR transduced CD8+ T cells were assessed for their in vitro specificity and in vivo efficacy in human ES bearing Rag2-/-γc-/- mice. Engraftment in mice and tumor infiltration of TCR transgenic T cells in the mice was evaluated. The TCR transgenic T cell clone PAPPA-2G6 demonstrated specific reactivity towards HLA-A*02:01+/PAPPA+ ES cell lines. We furthermore detected circulating TCR transgenic T cells in the blood in Rag2-/-γc-/- mice and in vivo engraftment of the in bone marrow. Tumor growth in mice with xenografted ES was significantly reduced after treatment with PAPPA-2G6 TCR transgenic T cells compared to controls, and tumors from treated mice revealed tumor infiltrating PAPPA-2G6 TCR transgenic T cells. In summary, we demonstrate that PAPPA is a promising target for TCR based immunotherapy of ES. We demonstrate that TCR transgenic T cells recognize this target, home to the tumor, and causes tumor regression in a preclinical mouse model.
Citation Format: Uwe Thiel, Andreas Kirschner, Melanie Thiede, Thomas GP Grünewald, Rebeca Alba Rubio, Günther Richter, Thomas Kirchner, Dirk Busch, Poul Sorensen, Stefan Burdach. Pappalysin-1 is a suitable target for T cell receptor transgenic T cells to kill Ewing sarcoma in vivo and in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 692. doi:10.1158/1538-7445.AM2017-692