bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2245: FDG PET quantification for prediction of early recurrence in patients with stage I and II non small cell lung cancer
Authors: Burger Irene A. , Arvanitakis Michael , Steiger Seraina , Weder Walter , Hillinger Sven 
Published: July 2016

Abstract
Background: Although surgical resection remains the optimal treatment for early-stage NSCLC, up to 50% of patients with stage I and II relapse and die within 5 years after curative resection. Therefore prognostic markers are important as these patients might benefit from adjuvant therapy. The goal of this study was to evaluate established PET quantification metrics including: maximal standard uptake volume (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) as prognostic markers for early recurrence and overall survival in resected early stage lung cancer.
Methods: Between January 2003 and December 2010 182 surgically resected patients with stage I-II NSCLC who underwent 18 F FDG PET/CT less than one month prior to surgery have been evaluated. All patients had at least 5 years of follow-up. Cox proportional hazard model was used to determine the association between variables and survival respectively time to recurrence. For the multivariate analysis the following variables have been included: tumor size on CT, age tumor stage, histology, SUVmax, TLG (for TLG42% (threshold at 42% SUVmax) and TLG2.5 (cut-off at SUV 2.5) and MTV42% and MTV2.5).
Results: 133 patients were included, 71 with adeno carcinoma, 62 with squamous cell carcinoma. TLG2.5 and MTV2.5 values have been a significant prognostic factor for recurrence (P&lt;0.0001). Patients with a MTV2.5 above 42 cm3 had a mean recurrence time of 0.8±0.9 years, while patients with MTV2.5 ≤ 42 cm3 recurred within 2.8±1.3 years. TLG2.5 and MTV2.5 PET volume metrics have not been predictable for overall survival in adenocarcinoma patients, recurrence or overall survival in squamous cell cancer. SUVmax, TLG42% and MTV42 were not predictable for early recurrence or survival for both histologies.
Conclusions: TLG2.5 and MTV2.5 may be useful prognostic variables in stage I-II NSCLC depending on the tumor type. Using a cut-off at 42 cm3 for early stage adenocarcinoma patients a high risk of recurrence within one year might be identified and adjuvant therapy following surgical resection could improve outcome for those patients.
Citation Format: Irene A. Burger, Michael Arvanitakis, Seraina Steiger, Walter Weder, Sven Hillinger. FDG PET quantification for prediction of early recurrence in patients with stage I and II non small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2245.
Abstract 2247: A multicenter clinical trial of lung cancer circulating tumor cell assay with the largest sample size (1210 cases) in China
Authors: Lou Jiatao , Zhou Caicun , Wu Jing , Qiao Lihua , Liang Xiaohui , Wang Xiaoqian , Chen Xiaoxia , Li Xuefei , Zhao Chao 
Published: July 2016

Abstract
Background: As a novel biomarker of primary tumors, circulating tumor cells (CTCs) are well known to play an important role in cancer diagnosis, recurrence and metastasis, and disease monitoring. This study investigated the application of CTCs in lung cancer therapy by quantitative determination of folate receptor-positive CTCs.
Methods: This study enrolled 1210 subjects (including 560 lung cancer patients, 350 patients with benign lung diseases, 150 healthy subjects and 150 non-lung cancer malignant tumor patients) and quantified the tiny amounts of CTCs in peripheral blood by negative enrichment using immunomagnetic beads in combination with folate receptor-directed polymerase chain reaction (PCR).
Results: Following ROC curve analyses of CTC levels in the patients with benign lung diseases or benign lung diseases and the healthy subjects, the cut-off of CTCs was 8.70 CTC Units/3mL with a specificity of 88.2% (441/500) and a sensitivity of 79.6% (446/560) as determined by the method mentioned above. The ROC area under
curve of more than 0.8 (AUC = 0.8797, P&lt;0.0001) suggested the excellence of ligand-directed PCR to diagnose lung cancer. For stage II-IV lung cancer patients, the sensitivities were 70.8%(34/48), 79.6% (125/157), and 90.2% (185/205) respectively, and the sensitivity in stage I patients can reach up to 68.0% (102/150) as well. CTC levels appeared to have greater accuracy to diagnose lung cancer (AUC: 0.8833, P&lt;0.0001) than the combination of the other four lung cancer-specific serum tumor markers (CEA, NSE, CYFRA21-1 and SCC)(AUC: 0.8557, P&lt;0.0001). CTCs were related to tumor stage and tumor size other than pathological type. By quantitative determination of folate receptor-positive cells in 150 different types of cancers, the CTC level in lung cancer was found to be higher than those in gastric, breast, colorectal, liver, and esophageal cancers.
Conclusions: LT-PCR achieves quantitative determination of folate receptor-positive CTCs to diagnose lung cancer with high sensitivity and specificity, and significantly greater diagnosis accuracy than the model of combined lung cancer-specific serum tumor markers.
Citation Format: Jiatao Lou, Caicun Zhou, Jing Wu, Lihua Qiao, Xiaohui Liang, Xiaoqian Wang, Xiaoxia Chen, Xuefei Li, Chao Zhao. A multicenter clinical trial of lung cancer circulating tumor cell assay with the largest sample size (1210 cases) in China. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2247.
Abstract 2287: Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors
Authors: Wicki Andreas , Prêtre Vincent , Ritschard Reto , Brown Nicholas , Bize Vincent , Fabbro Thomas , Cmiljanovic Natasa , Dimitrijevic Sasa , Schmitz Deborah , Stumm Michael , Kristeleit Rebecca 
Published: July 2016

Abstract
Background: PQR309 is a novel, oral, balanced pan-class 1 PI3K, mTORC1 and mTORC2 inhibitor. PQR309-001 was a first-in-man dose escalation study evaluating PQR309 in patients with advanced solid tumours.
The primary objective of the study was to establish the maximum tolerated dose (MTD) of PQR309, its safety and tolerability. Secondary objectives included characterization of PQR309 pharmacokinetics (PK) and pharmacodynamics (PD).
Methods: We investigated PQR309 treatment-induced PD, including changes of 16 PI3K-mTOR and MAPK associated phospho-proteins, and 84 mRNAs in serial tumor biopsies obtained from patients enrolled in study PQR309-001. 13 patients were eligible for PD analysis after histologic evaluation of fresh-frozen tissue. A solid-phase assay with phospho-specific antibodies was used for the investigation of PI3K/mTOR and MAPK signalling. RNA analysis was performed with an RTK/PI3K-specific RNA array.
Results: Under treatment with PQR309, phospho-Akt (p_T308 and p_S473), phospho-mTOR and phospho-S6 were significantly downregulated compared to baseline (p&lt;0.05, Wilcoxon signed-rank test). Moreover, patients with radiographic tumor shrinkage (n = 7) had significantly stronger phospho-Akt (p_T308), phospho-mTOR and phospho-S6 reduction than patients whose tumor was growing (n = 6) (p&lt;0.05, Mann-Whitney test). Importantly, ERK1/2 phosphorylation, as the readout of MAPK activity, was decreased overall with no statistically significant difference between shrinking and growing tumors. The analysis of mRNAs showed a trend towards upregulation of PDGFRA (3.2 times, not statistically significant) after 21 days of therapy with PQR309. Intriguingly, no consistent changes of other PI3K-related RNAs was observed.
Conclusion: PD assessments in tumour tissue samples from patients treated with PQR309 demonstrated a reduction of phosphorylation of direct targets for PQR309 (PI3K and mTOR) as well as downstream effectors of mTOR. Furthermore, the data indicate that downregulation of phospho-Akt (p_T308) and mTORC1 activity may be predictive of tumor shrinkage while upregulation of PDGFRA may represent a mechanism of resistance against PI3K/mTOR inhibition.
Citation Format: Andreas Wicki, Vincent Prêtre, Reto Ritschard, Nicholas Brown, Vincent Bize, Thomas Fabbro, Natasa Cmiljanovic, Sasa Dimitrijevic, Deborah Schmitz, Michael Stumm, Rebecca Kristeleit. Final results of the pharmacodynamic (PD) data of PQR309-001, a first-in-human trial of a combined PI3K/mTOR inhibitor in advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2287.
Abstract 2288: Targeting mTOR pathway in rare and recalcitrant tumors
Authors: Rojas Veronica , Ganesan Shridar , Hirshfield Kim M. , Dipaola Robert S. , Rodriguez-Rodriguez Lorna 
Published: July 2016

Abstract
INTRODUCTION: Genomic alterations affecting the PI3K/AKT/mTOR pathway are commonly seen among various cancer types [Kandoth 2013]. The objective of this study is to determine the clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify genomic alterations affecting the PI3K/AKT/mTOR pathway in patients with either rare or refractory cancers.
METHODS: CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an institutional molecular tumor board (MTB). Consensus recommendations on genomically targeted, clinically relevant FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician for their consideration as treatment alternatives. Ninety-seven tumors with alterations in the PI3K/AKT/mTOR pathway were analyzed.
RESULTS: Thirty-three patients with cancers that were either rare or refractory to standard therapy received drug targeting the PI3K/AKT/mTOR pathway. Age range was 18-78 years old. Thirteen patients were non-Hispanic White, three non-Hispanic Black, two Hispanic and one Asian. Tumors tested included 6 gynecologic, 5 renal, 2 sarcomas and one each of pancreatic, melanoma, T cell lymphoma, bladder, adrenal, and skin-not melanoma. Treatment outcomes were available for 19/33 patients (one patient died soon after presentation at the MTB and could not be treated). Seven (37%) patients derived clinical benefit from a drug targeting the PI3K/AKT/mTOR pathway; the duration of clinical benefit ranged from 90-245 days. The clinical benefit was not tumor type specific and included two endometrial tumors, 2 renal tumors, one sarcoma, one adrenal paraganglioma and one micropapillary urothelial carcinoma. Eight patients have not been started on PI3K/AKT/mTOR targeted therapy yet.
CONCLUSION: These data suggest that tumors with alterations in the PI3K/AKT/mTOR pathway may respond to targeted therapy regardless of tumor of origin.
Citation Format: Veronica Rojas, Shridar Ganesan, Kim M. Hirshfield, Robert S. Dipaola, Lorna Rodriguez-Rodriguez. Targeting mTOR pathway in rare and recalcitrant tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2288.
Abstract 2292: Reconstitution of myeloid derived suppressor cells after the induction of lymphopenia and TIL therapy
Authors: Kodumudi Krithika N. , Wiener Doris , Weber Amy , Royster Erica , Kelley Linda , Sarnaik Amod , Pilon-Thomas Shari 
Published: July 2016

Abstract
Factors such as T regulatory (Treg) cells and myeloid derived suppressor cells (MDSC) limit the effectiveness of current immunotherapy protocols. Several reports have shown that administration of chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells reduces or eliminates the immunosuppressive populations such as Tregs and MDSC. A previous study in our lab has shown that MDSC that reconstitute after lymphodepletion are highly suppressive compared to the endogenous MDSC in a B16 melanoma model. Blockade of MDSC expansion in combination with adoptive T cell transfer delayed tumor growth and improved survival rate. However, there is very little known about the MDSC reconstitution after the adoptive transfer of tumor infiltrating lymphocytes (TIL) in melanoma patients. Melanoma patients were treated with non- myeloablative therapy that included cyclophosphamide and fludarabine. At the time of TIL transfer, no circulating lymphoid or myeloid cells were detected in the PBMC. One day after completion of chemotherapy, up to 100 billion TIL were transferred followed by high dose bolus IL-2. At weeks 1-4 after TIL transfer, PBMC were collected and we investigated the reconstitution and the suppressive function of MDSC. MDSC were phenotyped by flow cytometry as HLA-DR− Lin− CD14+CD33+ or CD11b+CD14−CD33+. While 3-15% of MDSC was observed in the PBMC of melanoma patients as their baseline, after lymphodepletion and one week post TIL infusion, the percent of MDSC increased to 10-30% and gradually dropped to baseline by week 4. To examine suppressive function, MDSC were isolated from peripheral blood at 1-2 weeks after TIL infusion and co-cultured with healthy donor T cells or patient TIL. MDSC were highly suppressive and abrogated T cell proliferation and IFN-gamma secretion. Furthermore, in patients that responded to TIL therapy, the ratio of peripheral MDSC to total CD8+ T cells was lower. These studies demonstrate that MDSC that reconstitute post- lymphodepletion are suppressive and may potentially interfere with robust T cell function. Further studies are warranted to clarify the role of MDSC in the efficacy of TIL therapy. Blocking MDSC in combination with TIL therapies represent an improved strategy for the treatment of melanoma patients.
Citation Format: Krithika N. Kodumudi, Doris Wiener, Amy Weber, Erica Royster, Linda Kelley, Amod Sarnaik, Shari Pilon-Thomas. Reconstitution of myeloid derived suppressor cells after the induction of lymphopenia and TIL therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2292.
Abstract 230: The role of integrated stress response (ISR) transcription factor ATF4 in metabolic adaptation of tumors to c-Myc activation
Authors: Tameire Feven , Monroy Maria A. , Koumenis Constantinos 
Published: July 2016

Abstract
The ability of cancer cells to adapt to non-cell autonomous (extrinsic) and cell autonomous (intrinsic) stresses is critical for maintaining cell viability and growth. The Integrated Stress Response (ISR) pathway is essential in cancer cell adaptation to extrinsic stresses such as hypoxia and nutrient deprivation both in vitro and in vivo. The ISR kinases, PERK and GCN2, phosphorylate eIF2α, transiently inhibiting protein translation during times of stress. Phosphorylation of eIF2α promotes the preferential translation of the transcription factor ATF4, which activates a gene expression program that enhances uptake and synthesis of amino acids, antioxidant defense and chaperone expression to promote recovery from nutrient deprivation and ER stress. Here, we demonstrate the importance of ISR signaling in MYC oncogene induced intrinsic stress both in vitro and in vivo.
We previously reported that activation of PERK, during c-Myc induction is vital for activating cytoprotective autophagy and suppressing c-Myc induced apoptosis. Here, we demonstrate GCN2 is also robustly activated during c-Myc induction. GCN2 activation after c-Myc induction regulates ATF4 transcription and translation. ATF4 was necessary for survival and suppression of oxidative stress during c-Myc activation. We have identified ATF4 targets that regulate amino acid uptake and involved in amelioration of oxidative stress. Furthermore, siRNA mediated knockdown or genetic knockout of GCN2 was synthetic lethal with c-Myc activation. Interestingly, PERK is still able to phosphorylate eIF2α in the absence of GCN2. However, eIF2α phosphorylation was completely inhibited in the absence of both kinases suggesting that these kinases compensate for each other and both are required for optimal phosphorylation of eIF2α after c-Myc activation. Consistent with our in vitro data, we observe higher levels of p-eIF2α and ATF4 in lymphoma cells compared to WT B cells in vivo in a mouse model of Myc driven lymphoma. These findings highlight a novel mechanism of stress response pathway activation to support c-Myc driven tumorigenesis involving an amino acid sensor kinase GCN2.
Citation Format: Feven Tameire, Maria A. Monroy, Constantinos Koumenis. The role of integrated stress response (ISR) transcription factor ATF4 in metabolic adaptation of tumors to c-Myc activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 230.
Abstract 2309: T-cell development from T cell-derived induced pluripotent stem cell
Authors: van der Stegen Sjoukje J.C. , Themeli Maria , Eyquem Justin , Mansilla-Soto Jorge , Sadelain Michel 
Published: July 2016

Abstract
The ability to differentiate T cells of defined specificity and function from T-cell derived induced pluripotent stem cells (TiPSC) may be useful for the treatment of a range of pathologies, including cancer, infection and immune deficits. We recently reported that genetic engineering of TiPSC to express a Chimeric Antigen Receptor (CAR) is an effective strategy to combine the unlimited availability of TiPSC and facilitate reprogramming of the T cell specificity and functional potential. In vivo, CD19-retargeted human TiPS-derived CAR T cells (CARTiPSC-T) display therapeutic potency in a lymphoma model. Surprisingly, despite expression of the endogenous αβ TCR, the CARTiPSC-T cells possessed innate-like phenotype and function, most similar to γδ T cells. Although innate T cells have anti-tumor activity, they lack some vital features for therapeutic efficacy including long-term memory and in vivo persistence, which characterize mature CD8+ and CD4+ αβ TCR T cells.
Additional research into the mechanisms underlying in vitro T cell differentiation of TiPSC is required to improve the development of mature TCRαβ T cells and facilitate the employment of their therapeutic potential. T cell lineage determination depends in part on the balance between Notch and TCR signaling, we are investigating their respective roles, as well as that of the CAR, in determining lineage commitment. We hypothesize that the combined CAR and early CD3/TCRαβ expression disrupts the TCR/Notch signaling balance, prohibiting mature TCRαβ T cell development.
To study the effects of the different Notch ligands, TiPSC were differentiated on OP9 cells expressing one of four Notch ligands (DLL1, DLL4, Jagged-1 or Jagged-2). Preliminary data suggests that DLL4 is able to facilitate T cell development to CD4/CD8 double positive (DP) stage, however, this is hindered by CAR expression.
To determine the role of early TCRαβ expression, elimination of TCRαβ expression was facilitated by targeted disruption of the TCRα constant region using the CRISPR/Cas9 system. Elimination of early TCRαβ expression showed improved development towards DP stage of TiPSC on OP9-DLL1.
TiPSC are a valuable system for the study of human T cell differentiation. In addition, and most importantly they are further amenable to genetic engineering with TCRs or CARs, which may be useful for the generation of therapeutic “off-the-shelf”, antigen-specific T cells.
Citation Format: Sjoukje J.C. van der Stegen, Maria Themeli, Justin Eyquem, Jorge Mansilla-Soto, Michel Sadelain. T-cell development from T cell-derived induced pluripotent stem cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2309.
Abstract 2325: Immune checkpoint(s) expression in AML patients enrolled in a phase 1-2 study with guadecitabine
Authors: Fazio Carolina , Covre Alessia , Lofiego Maria , Taverna Pietro , Azab Mohammad , Lowder James N. , Coral Sandra , Maio Michele 
Published: July 2016

Abstract
Immune checkpoint(s) blockade is becoming the therapeutic mainstay in melanoma and lung cancer. Based on these important clinical achievements, immunotherapy with immunomodulating monoclonal antibodies (mAb) is being explored as a new therapeutic modality in most human malignancies, either alone or in combination with other immunomodulating agents. We have provided extensive evidence that the second generation DNA hypomethylating agent (DHA), guadecitabine (SGI-110), plays a promising role in potentiating the immunogenicity and the immune recognition of human malignancies through the up-regulation of the expression of different immune molecules on cancer cells. These findings led us to hypothesize that DHA could represent ideal partners for immune checkpoint(s) blocking agents to improve their therapeutic efficacy. Here, we studied the expression of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and 2 (PD-L2), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in peripheral blood mononuclear cells of acute myeloid leukemia (AML) patients (N = 23), enrolled in a phase 1-2 study with guadecitabine. Patients included in this preliminary analysis were selected based on their responsiveness to therapy. Quantitative RT-PCR analyses showed a constitutive expression (gene/β-actin molecules &gt;7.5E-05) of PD1, PD-L1, PD-L2 and CTLA-4 in 82.6%, 100%, 47.8% and 8.7% patients, respectively. Guadecitabine therapy up-regulated (≥2 fold) the expression of PD1, PD-L1, PD-L2 and CTLA-4 in 57.9%, 56.5%, 18.2% and 0% patients, respectively, at any of the time-points investigated during treatment. De novo expression of PD1, PD-L2 and CTLA-4 was observed in 100%, 41.6% and 38.1% of the immune checkpoint(s)-negative patients, respectively.
Though preliminary, these results further support the strong link between epigenetics/DNA methylation and immune response, in cancer patients, and strengthen the therapeutic potential of epigenetic immunomodulation, with “consolidated” and emerging immune checkpoint(s) blocking mAb.
Citation Format: Carolina Fazio, Alessia Covre, Maria Lofiego, Pietro Taverna, Mohammad Azab, James N. Lowder, Sandra Coral, Michele Maio. Immune checkpoint(s) expression in AML patients enrolled in a phase 1-2 study with guadecitabine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2325.