tbuckley/cabot-search huggingface dataset:
Abstract CT137: Standard therapy versus active surveillance for low grade DCIS: the LORD trial
Authors: Jelle Wesseling, Frederieke van Duijnhoven, Konstantinos Tryfonidis, Aleksandra Peric, Elise van Leeuwen-Stok, Nina Bijker, Lotte Elshof, Emiel Rutgers
Journal: Cancer Research (2017)

Abstract The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-grade DCIS can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be low-grade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. It also may save many low-grade DCIS patients from intensive treatment. We will compare active surveillance with conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy for primary low-grade DCIS, detected by calcifications only, in a phase III, open-label, non-inferiority, multi-center, randomized clinical trial legally supported by the Breast Cancer Group of the European Organisation for the Research and Treatment of Cancer (EORTC-1401-BCG). The Dutch Centers are coordinated by the BOOG Study Center (BOOG 2014-04). Randomization will be 1:1 in to one of the following arms: active surveillance or standard treatment per local policy. In total, 1240 women (≥ 45 years) with asymptomatic, pure, low-grade DCIS, based on vacuum-assisted biopsies of calcifications as detected by population-based or opportunistic screening, without prior breast cancer, will be included. Assuming 25% of randomized women qualified to enroll in the study will drop out or will be excluded from per protocol population, at least 1,240 women need to be randomized to obtain the 930 patients required for the evaluation of the primary endpoint. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of 10 years. The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years. Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate and patient reported outcomes. Accrual has started in January 2017. Acknowledgements: This trial is funded by Pink Ribbon Netherlands, the Dutch Cancer Society and Dutch Cancer Society/Alpe d’HuZes. Citation Format: Jelle Wesseling, Frederieke van Duijnhoven, Konstantinos Tryfonidis, Aleksandra Peric, Elise van Leeuwen-Stok, Nina Bijker, Lotte Elshof, Emiel Rutgers. Standard therapy versus active surveillance for low grade DCIS: the LORD trial [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 CT137. doi:10.1158/1538-7445.AM2017-CT137
Abstract 3231: Identifying high quality, potent and selective pyrimidinylthienopyrrolone inhibitors of ERK1/2 kinase: LY3214996
Authors: Gaiying Zhao, William T. McMillen, Shufen Cai, Baohui Zhao, Matthew Whitesell, Wenjuan Wu, Karen Huss, Bryan Anderson, Xiu-Juan Yuan, Susan Jaken, Lisa Kindler, Robert S. Flack, Denis McCann, Brian Mathes, Andrew J. Dropsey, Jennie Walgren, Eunice Yuen, Jason Manro, Xueqian Gong, Guillermo Cortez, Johnathan McLean, Michael J. Rodriguez, Ramon V. Tiu, Shripad V. Bhagwat, Sajan Joseph
Journal: Cancer Research (2017)

Abstract The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. ERK inhibitors have the potential to address resistance caused by ERK reactivation. Herein, a potent, selective small molecule ERK1/2 inhibitor is described. LY3214996 possesses an optimal balance of potency (hERK1 IC50 5 nM, hERK2 IC50 5nM, pRSK IC50 0.43 µM), solubility (FaSSIF solubility at pH 6.5 0.133 µM), PK properties (dog, AUCoral 23800 nM*hr, CL 12.1 mL/min/kg, bioavailability 75.4%), IVTI (TED50 =16 mg/kg pRSK1) and demonstrated significant in vivo efficacy in several human cancer xenograft models. LY3214996 is currently undergoing early clinical evaluation. Citation Format: Gaiying Zhao, William T. McMillen, Shufen Cai, Baohui Zhao, Matthew Whitesell, Wenjuan Wu, Karen Huss, Bryan Anderson, Xiu-Juan Yuan, Susan Jaken, Lisa Kindler, Robert S. Flack, Denis McCann, Brian Mathes, Andrew J. Dropsey, Jennie Walgren, Eunice Yuen, Jason Manro, Xueqian Gong, Guillermo Cortez, Johnathan McLean, Michael J. Rodriguez, Ramon V. Tiu, Shripad V. Bhagwat, Sajan Joseph. Identifying high quality, potent and selective pyrimidinylthienopyrrolone inhibitors of ERK1/2 kinase: LY3214996 [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 3231. doi:10.1158/1538-7445.AM2017-3231
Abstract 5667: Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance
Authors: Gabriele D'Errico, Mireia Vallespinos, Sonia Alcala, Sandra Valle, Laura Martin-Hijano, Bruno Sainz
Journal: Cancer Research (2017)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths worldwide. This is largely due to the existence of a subpopulation of stem-like cells present within the tumor, known as cancer stem cells (CSCs) that drive metastasis and chemoresistance. In addition, we have now come to realize that the tumor-associated microenvironment not only provides structural support for tumor development, but more importantly the microenvironment provides cues to CSCs that regulate their biological properties. Chemotherapy often leads to apoptosis of cancer cells, and in previous studies we have shown that tumor-associated macrophages (TAMs) exponentially increase following chemotherapy. We hypothesized that TAMs, in response to chemotherapy-induced apoptosis, secrete factors that potentiate PDAC chemoresistance. In line with this hypothesis, we show that monocyte-derived macrophages cultured in the presence of apoptotic PDAC cells polarize towards an M2 pro-tumor phenotype and secrete factors that render naïve PDAC cells, specifically CSCs, resistant to Gemcitabine- or Abraxane-induced apoptosis, irrespective of mutations in p53. Importantly, chemoresistant cells showed increased sphere formation capacity and increased tumorigenesis as measured in an extreme limiting dilution assay in nude mice, confirming an enrichment in CSCs. Moreover, using a syngeneic orthotropic in vivo model of PDAC, we were able to significantly augment the anti-tumor potential of Gemcitabine by pharmacologically eliminating TAMs using clodronate liposomes. To determine the mechanism by which TAMs promote PDAC chemoresistance, we performed proteomic analyses on macrophage conditioned media and identified several proteins specifically induced and secreted when macrophages were co-cultured with apoptotic PDAC cells, including 14-3-3 protein zeta/delta (14-3-3ζ), a major regulator of apoptotic cellular pathways. We present additional data to show that TAM-seceretd 14-3-3ζ promotes CSC chemoresistance. Taken together, the sum of these data highlight a unique regulatory mechanism by which chemotherapy-induced apoptosis acts as a switch to initiate a pro-tumor/anti-apoptotic mechanism in PDAC, challenging the idea that apoptosis of tumor cell is therapeutically beneficial, at least when immune sensor cells, such as macropahges, are present. Citation Format: Gabriele D'Errico, Mireia Vallespinos, Sonia Alcala, Sandra Valle, Laura Martin-Hijano, Bruno Sainz. Exposure of tumor-associated macrophages to apoptotic pancreatic cancer cells promotes cancer stem cell chemoresistance [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 5667. doi:10.1158/1538-7445.AM2017-5667
Abstract 3111A: ADCT-401/MEDI3726, a novel pyrrolobenzodiazepine (PBD)-based antibody-drug conjugate (ADC) targeting PSMA-expressing prostate cancers
Authors: Francesca Zammarchi, Simon Chivers, Karin Havenith, David G. Williams, Lauren Adams, Maria Mellinas-Gomez, Simon Corbett, Peter Tyrer, Francois D'Hooge, Song Cho, Nazzareno Dimasi, Mary Jane Hinrichs, Phil W. Howard, John A. Hartley, Patrick H. van Berkel
Journal: Cancer Research (2017)

Abstract Prostate-specific membrane antigen (PSMA) is an attractive target for an ADC approach as it is over-expressed by virtually all prostate cancers and its expression is highest in poorly-differentiated, metastatic and castration-resistant cases. PSMA has limited expression in non-prostatic tissues, it is not secreted or cleaved by PSMA-expressing cells, and it is constitutively internalized, a process that may be accelerated by specific antibody binding. ADCT-401/MEDI3726 is an ADC composed of a monoclonal antibody (J591), directed against human PSMA, site-specifically conjugated (drug-to-antibody ratio of 1.8) to a highly cytotoxic DNA cross-linking PBD dimer with a valine-alanine dipeptide linker. In vitro, ADCT-401/MEDI3726 demonstrated potent and specific cytotoxicity in a panel of PSMA-expressing prostate cancer cell lines, whereas its activity was greatly reduced in PSMA-negative cell lines. In vivo, ADCT-401/MEDI3726 showed strong antitumor activity against CWR22Rv1 and LNCaP human-derived prostate cancer xenograft models. In the CWR22Rv1 model, a tumor with low, heterogeneous PSMA expression, ADCT-401/MEDI3726 achieved dose-dependent antitumor activity when administered as single dose at either 0.33 or 1 mg/kg, which resulted in significant increase in survival compared to the vehicle-treated animals. Moreover, a single dose of ADCT-401/MEDI3726 showed remarkable superior antitumor activity compared to multiple doses of another PSMA-targeted ADC stochastically conjugated to the auristatin payload vcMMAE with a DAR of ~4. In the LNCaP model, ADCT-401/MEDI3726 resulted in dose-dependent antitumor activity when dosed once at 0.11, 0.33 or 1 mg/kg. In the PSMA-negative prostate cancer-derived PC3 xenograft model, ADCT-401/MEDI3726 and an isotope-control ADC showed limited tumor growth inhibition highlighting target-mediated antitumor activity. ADCT-401/MEDI3726 demonstrated potent and specific in vitro and in vivo antitumor activity in prostate cancer-derived models of differing levels of PSMA and this warrants further development of this ADC into the clinic. Citation Format: Francesca Zammarchi, Simon Chivers, Karin Havenith, David G. Williams, Lauren Adams, Maria Mellinas-Gomez, Simon Corbett, Peter Tyrer, Francois D'Hooge, Song Cho, Nazzareno Dimasi, Mary Jane Hinrichs, Phil W. Howard, John A. Hartley, Patrick H. van Berkel. ADCT-401/MEDI3726, a novel pyrrolobenzodiazepine (PBD)-based antibody-drug conjugate (ADC) targeting PSMA-expressing prostate cancers [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 3111A. doi:10.1158/1538-7445.AM2017-3111A
Abstract 2956: Chemical library screen identifies compounds that target S100A8/S100A9 complex and MDSC accumulation
Authors: Eunmi Lee, Maria Ouzounova, Raziye Piranlioglu, Abdeljabar El Andaloussi, Sena Arbag, Gang Zhou, Hasan Korkaya
Journal: Cancer Research (2017)

Abstract We previously demonstrated that MDSC subsets accumulated in primary tumor and distant organs regulate tumor plasticity. The mouse transcriptome analysis of in vitro co-cultures and samples from syngeneic mouse model revealed that granulocytic subset of myeloid-derived suppressor cells (gMDSCs) from metastatic 4T1 tumor bearing mice regulate several hundred genes in tumor cells upon co-culture. The top genes are S100A8, S100A9, MMP8, FPR1, CCL3, and TGFβ2 which also predicted poor survival in human solid tumors including breast cancer. Therefore, we called these 6 genes as “metastatic gene signature”. It has been reported that S100A8/S100A9 heterotetramer, called calprotectin, play a key role in inflammation-associated cancer progression. To investigate the role of calprotectin (S100A8/A9) in tumor-mediated immunosuppression and metastasis, we first utilized Tasquinimod, a small molecule targeting S100A9 only. However, Tasquinimod treatment of 4T1 tumor-bearing mice had a moderate anti-tumor activity which may be due to a limited activity on granulocytic MDSC accumulation. In addition, we determined that there was a significant upregulation of S100A8 in MDSCs from Tasquinimod treated mice. This data suggested that inhibiting only S100A9 leads to activation of S100A8 and thus may be ineffective targeting of MDSCs. We therefore run a computational screen of the NCI chemical library against the crystal structure of calprotectin (S100A8/S100A9) and identified 40 lead compounds. We then performed in vitro screening assay to identify compounds that inhibit MDSC induction. We identified 3 compounds that significantly suppressed gMDSC differentiation. We are currently performing in vivo studies with these 3 candidate drugs in our murine breast cancer model and will present our findings at the AACR meeting. We believe that this study will provide a novel drug targeting S100A8/S100A9 heterotetramer, a key molecule in MDSC induction and its regulatory functions during tumor progression. Citation Format: Eunmi Lee, Maria Ouzounova, Raziye Piranlioglu, Abdeljabar El Andaloussi, Sena Arbag, Gang Zhou, Hasan Korkaya. Chemical library screen identifies compounds that target S100A8/S100A9 complex and MDSC accumulation [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 2956. doi:10.1158/1538-7445.AM2017-2956
SAT0601 Treatment of carpal tunnel syndrome (CTS) with eswt: a sham controlled double blinded randomised study
Authors: Ö Karataş, S Catal, EA Gökmen, N Samanci
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The carpal tunnel syndrome (CTS) is the most common neuropathy (1). The etiology isn9t properly known, but CTS is produced by the chronic compression of median nerve while passing through carpal canal can be associated with this disease (2). <h3>Objectives</h3> The aim of this study was to investigate the efficiency of extracorporeal shockwave therapy (ESWT) in the treatment of CTS. <h3>Methods</h3> 49 hand with the diagnosis of CTS were included in the study. Patients were randomised in ESWT (n=29 hands) and sham (n=20 hands) groups. Patients were randomly allocated to receive 1 session per week for 3 weeks of either sham or active ESWT. All patients were prescribed with tendon and nerve gliding exercises and hand-wrist splint which used night. Patients were evaluated before the treatment, and at the end of the first week, first month and third month after the last ESWT treatment session with Boston Scale (symptom severity and functional capacity), Visual Analogue Scale (VAS) for pain and paresthesia assessment, for muscle strength hand gross grasp and electroneurophysiological parameters. <h3>Results</h3> A total of 38 patients completed the study with 29 wrists in active ESWT and 20 wrists in sham ESWT groups. Groups were similar in age, sex, duration of symptoms, hand gross grasp and electrodiagnostic parameters (P&gt;0.05). In both groups, significant improvements were observed in VAS, Boston Scale and hand gross grasp after treatment. In both groups, there was no statistically significant improvement in electromyographic variables after treatment (p&gt;0.05). However there was no significiant differrence between two groups in all of clinical and electrodiagnostic parameters. <h3>Conclusions</h3> Although ESWT was effective in symptoms in CTS but this efficacy isn9t superior to placebo. Our results indicated that ESWT was effective in pain and clinical variables in CTS. Wider and high-quality studies are needed to further demonstrate the effectiveness of ESWT in treatment of CTS. <h3>References</h3> Ozturk K, Esenyel CZ, Sonmez M, et al: Comparison of carpal tunnel injection techniques: A cadaver study. Scand J Plast Reconstr Surg Hand Surg 2008;42:300–4. Gelberman RH, Hergenroeder PT, Hargens AR, Lunborg GN, Akeson WH. The carpal tunnel syndrome. A study of carpal canal pressures. J Bone Joint Surg Am 1981;63:380–3. <h3>Disclosure of Interest</h3> None declared
Abstract 2942: Immunophenotypes in young-onset colorectal cancer
Authors: M E. van Herk, M Lee, M Rytterdahl, M E. Kop, A F. Ramalheiro, R van der Breggen, T van Wezel, H Morreau, E S. Jordanova, N F. de Miranda
Journal: Cancer Research (2017)

Abstract Colorectal cancer accounts for ten percent of new cancer cases and is the fourth most frequent cause of cancer-related deaths worldwide. In recent years, mainly due to screening programs, more patients are diagnosed in early stages of tumor progression, leading to a higher survival rate. However, the incidence of young (&amp;lt;50) patients diagnosed with colorectal cancer has been on the rise. These patients often have a poor prognosis due to the fact that tumors are diagnosed at advanced stages of tumor progression. To our knowledge, no study has yet characterized immunophenotypes and immune evasive mechanisms specifically in young-onset colorectal cancers. To that end we have investigated the expression of HLA class I and PD-L1 in over 200 colorectal cancers derived from young-onset (&amp;lt; 50 years-old) patients. Furthermore, we applied a novel multispectral immunofluorescence technology to perform multiparameter immunophenotyping with CD3, CD8, PD-1, PD-L1, CD163, and Ki-67 in the same cohort. We describe that HLA class I expression is maintained in the large majority of tumors allowing thus the development of neo-antigen targeted therapies. Interestingly, reduced expression of HLA class I but not total loss was associated with liver metastases, which suggests a specific selective pressure at this organ that might warrant tailored immune therapeutic interventions. As previous studies on colorectal cancer demonstrated, PD-L1 expression is limited and often restricted to immune cell compartments. The presence of immune cell infiltrates was related to the mutation background of tumors but also to their HLA class I phenotype: tumors with altered HLA class I expression were more likely to present traces of lymphocyte-mediated anti-tumor immunity. Retained HLA class I expression in the majority of colorectal cancers associated with low infiltration by effector immune cells suggests the therapeutic induction of anti-tumor immune responses in young-onset colorectal cancers, for instance, by means of neo-antigen-targeted therapies. We are currently assessing the frequency of natural recognition of neo-antigens in an autologous setting in young-onset, late-stage colorectal cancers. This work was supported by the Fight Colorectal Cancer-Michael’s Mission-AACR Fellowship in Young-Onset, Late-Stage Colorectal Cancer Research awarded to N.F.C.C. de Miranda (15-40-1645-DEMI) Citation Format: M E. van Herk, M Lee, M Rytterdahl, M E. Kop, A F. Ramalheiro, R van der Breggen, T van Wezel, H Morreau, E S. Jordanova, N F. de Miranda. Immunophenotypes in young-onset colorectal cancer [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 2942. doi:10.1158/1538-7445.AM2017-2942
Abstract PL04-01: G-quadruplexes and DNA dynamics
Authors: Shankar Balasubramanian
Journal: Cancer Research (2017)

Abstract DNA is structurally dynamic in ways that have a consequence for biologic processes. A class of four-stranded DNA structure, called the G-quadruplexes, can be formed from G-rich single-stranded DNA. There is now a good level of understanding of the structural biophysics of G-quadruplexes along with a large body of work on the design and synthesis of small organic molecules that can target such structures. Some such molecules have been found to have antiproliferative effects on human cancer cells along with specific effects on the activity of certain genes, raising intriguing hypotheses about their existence and function in cells. Recent results from my laboratory provide new insights into when and where such non-Watson-Crick structures may exist in cellular DNA, together with a perspective on whether this structural motif in DNA presents new opportunities to think about intervention and future therapeutics. Citation Format: Shankar Balasubramanian. G-quadruplexes and DNA dynamics [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 PL04-01. doi:10.1158/1538-7445.AM2017-PL04-01
Abstract 5383: Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA)
Authors: Xuyu Cai, Yangbin Gao, Hui Shen, Peter Laird, Jian-bing Fan, Weihong Xu, Wenhua Liang, Jianxing He
Journal: Cancer Research (2017)

Abstract Current state-of-the-art lung cancer early screening involves using low-dose CT scan to identify lung nodules smaller than 3cm in diameter. However, it’s still a clinical dilemma to differentiate between malignant and benign nodules. We took the approach of methylation profiling by high-throughput bisulfite DNA sequencing in tissue samples to identify specific methylation signatures. We learned methylation patterns that differentiate malignant vs. benign lesions from tissue samples by in-depth data mining, and then used pattern matching to classify plasma samples. Given the usual low amount of ctDNA in plasma, we also developed an ultra-sensitive library preparation method to perform targeted bisulfite DNA sequencing from as low as 1ng of cfDNA or 1mL of plasma. From a training set of 88 tissue samples, which includes 60 malignant specimens with different subtypes (invasive adenomas, IA; minimally invasive adenomas, MIA; atypical adenomatous hyperplasia, AAH; adenocarcinoma in situ, AIS; carcinoid; lymphoepithelioma-like carcinoma of the lung, LELC; squamous carcinoma, SC; as well as 28 benign specimens in different categories including hematomas, granuloma, tuberculosis, inflammatory pseudotumor (IPT), sclerosing hemangiomas (SHL) and infections, we were able to achieve a sensitivity of 95% for identification of malignant lesions, with a specificity of 78.6%. From an independent validation set of 45 plasma samples, we achieved a sensitivity of 94.7% and a specificity of 85.7% for differentiating patients with malignant tumor from patients with benign lesions. Specifically, our assay is demonstrated to be highly sensitive towards early-stage lung cancer detection, with a sensitivity of 93.3% in a total of 15 patients with stage IA/B lung cancer. In summary, we have developed a highly sensitive blood-based non-invasive diagnostic assay for identification of early stage lung cancer, which can aid clinical decisions for patients with a CT scan positive for lung nodules. This approach can also be extended to non-invasive early screening for various cancer types. Citation Format: Xuyu Cai, Yangbin Gao, Hui Shen, Peter Laird, Jian-bing Fan, Weihong Xu, Wenhua Liang, Jianxing He. Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA) [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 5383. doi:10.1158/1538-7445.AM2017-5383