tbuckley/cabot-search huggingface dataset:
Wealth, Health Expenditure, and Cancer: A National Perspective
Authors: Jad Chahoud, Adele Semaan, Alyssa Rieber
Journal: Journal of the National Comprehensive Cancer Network (2016)

The US health care system is characterized by high health expenditures with penultimate outcomes. This ecological study evaluates the associations between wealth, health expenditure, and cancer outcomes at the state level.We extracted gross domestic product (GDP) and health expenditure per capita from the 2009 Bureau of Economic Analysis and the Centers for Medicare & Medicaid Services, respectively. Using data from the NCI, we retrieved colorectal cancer (CRC), breast cancer, and all-cancer age-adjusted rates and computed mortality/incidence (M/I) ratios. We used the Spearman's rank correlation to determine the association between the financial indicators and cancer outcomes, and we constructed geographic distribution maps to describe these associations.GDP per capita significantly correlated with lower M/I ratios for all cancers, breast cancer, and CRC. As for health expenditure per capita, preliminary analysis highlighted a rift between the Northeastern and Southern states, which translated into worse breast and all-cancer outcomes in Southern states. Further analysis showed that higher health expenditure significantly correlated with decreased breast cancer M/I ratio. However, CRC outcomes were not significantly affected by health expenditure, nor were all-cancer outcomes.All cancers, breast cancer, and CRC outcomes significantly correlated with wealth, whereas only breast cancer correlated with higher health expenditure. Future research is needed to evaluate the potential role of policies in optimizing resource allocation in the states' efforts against CRC and minimizing disparities in interstate cancer outcomes.
Abstract 5039: Co-targeting polo-like kinase 1(Plk1) and the Wnt/β-catenin signaling pathway in castration-resistant prostate cancer
Authors: Jie Li, Xiaoqi Liu
Journal: Cancer Research (2016)

Abstract The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events and is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in several in vivo studies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the anti-neoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, Axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1 and Plk1 phosphorylation of Axin2 facilitates the degradation of β-catenin by enhancing the binding between GSK3β and β-catenin. Plk1 phosphorylated Axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC. Citation Format: Jie Li, Xiaoqi Liu. Co-targeting polo-like kinase 1(Plk1) and the Wnt/β-catenin signaling pathway in castration-resistant prostate 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 5039.
Abstract 2277: Multiplexed gene expression profiling of resected intrahepatic cholangiocarcinoma: Implication of FGFR4-FGF19 as a novel treatment target
Authors: Changhoon Yoo, Kyu-pyo Kim, Baek-Yeol Ryoo, Seung-Mo Hong, Jung Jin Hwang, Seong-Yun Jeong, Klaus Hoeflich, Oleg Schmidt-Kittler, Stephen Miller, Eun Kyung Choi
Journal: Cancer Research (2016)

Abstract Background: The fibroblast growth factor receptor 4 (FGFR4) pathway is an essential regulatory component of bile acid synthesis and its relationship with hepatocellular carcinoma (HCC) has been reported. We investigated the gene expression and clinical significance of FGFR4 and related pathways in intrahepatic cholangiocarcinoma (IH-CCa). Methods: We assessed the expression of 98 genes in formalin-fixed paraffin embedded tumor tissue specimens from 46 patients with IH-CCa surgically resected using the NanoString platform. This included 10 FGF pathway genes (e.g. FGFR1-4, KLB, FGF3, 4, 19, 21, 23), 19 distal marker genes (e.g. CYP7A1, CYP17A1) and 31 genes relevant to HCC and CCa (e.g. AFP, TS) and 18 CNV matched genes and 20 control genes. Log-transformation of the gene expression was done for normalization and statistical analysis. Overall survival of 44/46 patients was correlated with gene expression (&amp;lt; median vs ≥ median) using a log-rank test. Two patients were excluded from analysis, due to death from postoperative complications and metastasectomy respectively. Results: The median age of our patient cohort was 56 years (range 30-78) and 34 patients (74%) were male. All but one tumor specimen (98%) were from the primary tumor resection and microscopic complete resection (R0) was achieved in 37 patients (80%). Six patients (13%) had hepatitis B virus infection with or without liver cirrhosis. FGFR4 was expressed 100 times over background in IH-CCa, the expression of FGF19, FGF21, CYP7A1, CYP17A1, AFP and KLB was lower. Overall survival was significantly stratified according to the expression of FGFR4 (p = 0.004), FGF19 (p = 0.046), FGF21 (p = 0.04), KLB (p = 0.03), CYP8B1 (p = 0.02), ADH1B (p = 0.045), CDKN1B (p = 0.005), NCOR1 (p = 0.03), NF1 (p = 0.006), NROB2 (p = 0.001), MAP2K3 (p = 0.009), MYC (p = 0.04), CYP2E1 (p&amp;lt;0.001), and LGR5 (p = 0.03). Conclusions: Our results indicate that FGFR4 might have a crucial role in IH-CCa, and its overexpression was associated with better prognosis, supporting that FGFR4 may define a subset of IH-CCa and be used as a promising target for therapeutic interventions. Citation Format: Changhoon Yoo, Kyu-pyo Kim, Baek-Yeol Ryoo, Seung-Mo Hong, Jung Jin Hwang, Seong-Yun Jeong, Klaus Hoeflich, Oleg Schmidt-Kittler, Stephen Miller, Eun Kyung Choi. Multiplexed gene expression profiling of resected intrahepatic cholangiocarcinoma: Implication of FGFR4-FGF19 as a novel treatment target. [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 2277.
Abstract 157: Single-cell DNA sequencing identifies a late dissemination model in metastatic colorectal cancer
Authors: Marco L. Leung, Anna Casasent, Yong Wang, Emi Sei, Nicholas Navin
Journal: Cancer Research (2016)

Abstract Metastatic colorectal cancer (mCRC) is a devastating disease with only 11% 5-year survival rate for stage IV patients. The genomic basis of metastasis has been difficult to study, in part due to the extensive intratumor heterogeneity at both the primary and metastatic tumor sites. Previous studies have applied bulk next-generation sequencing (NGS) methods, which have limited ability to resolve intratumor heterogeneity. To address this problem, we developed a highly-multiplexed single cell DNA sequencing method that combines flow-sorting of single nuclei, multiple-displacement-amplification, low-input library preparation, library barcoding, targeted capture and NGS to generate high-coverage data from single tumor cells. To increase throughput, we performed targeted single-cell DNA sequencing using a panel of 201-cancer genes to analyze single cells from primary tumors and liver metastases from two mCRC patients. In each patient, we sequenced 90 single tumor cells from the primary and metastatic tumor, to delineate the clonal architecture of the tumor and reconstruct their phylogenetic lineages. In addition, we sequenced populations of tumor cells at high coverage depth (200X). Our data identified a large number of nonsynonymous mutations that evolved in the root nodes during the earliest stages of primary tumor evolution and were maintained in all single cells during the clonal expansion of the tumor mass. We also identified a small number of mutations that were specific to the liver metastases, which are likely to play an important role in metastatic dissemination. Using the single cell data, we constructed phylogenetic trees, which revealed branched evolution at both organ sites. Collectively, our data suggest that both mCRC patients are consistent with a late-dissemination model, in which the primary tumors evolved for a long period of time prior to the dissemination of clones to distant organ sites. This model has important clinical implications, by suggesting that surgical intervention or therapeutic treatment of the primary CRC tumor can prevent metastasis, since single tumor cells do not disseminate at the earliest stages of tumor growth Citation Format: Marco L. Leung, Anna Casasent, Yong Wang, Emi Sei, Nicholas Navin. Single-cell DNA sequencing identifies a late dissemination model in metastatic colorectal 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 157.
Quality and Outcomes Framework: what have we learnt?:
Authors: Martin Roland, Bruce Guthrie
Journal: BMJ (2016)

Martin Roland and Bruce Guthrie assess the successes and failures of the pay-for-performance scheme and what its future should be In 2004 the UK National Health Service introduced the largest health related pay-for- performance scheme in the world—the Quality and Outcomes Framework (QOF).1 However Scotland is now abandoning the scheme, and growing disenchantment in England is likely to lead to major changes. What have we learnt, and what should happen to QOF in future? In the late 1990s, general practitioners' pay had fallen substantially behind that of specialists, and morale and recruitment in general practice were poor. The government and the British Medical Association (BMA) privately agreed that a large pay rise was needed. Money was available because in 2000 the government had committed to increasing NHS spending to mid-European levels as a percentage of gross domestic product. However, the profession had to give something in return, and the BMA dropped its longstanding opposition to "quality payments" and started to negotiate a pay-for-performance scheme that would substantially increase funding for general practice. There followed 18 months of negotiations between BMA and NHS Employers with a small number of clinical advisers to develop the outcome measures (indicators) that would form the basis of the scheme (box 1). A starting premise was that the clinical indicators should be based on evidence based guidelines so that they would be likely to command a wide degree of professional support (box 2). The framework also included indicators related to practice organisation and patient participation. The package was controversial, and the BMA allowed its members to vote on the scheme—once in outline and once when the details were known. #### Box 1: How the Quality and Outcomes Framework works
Nonmyeloablative Stem Cell Transplantation and Cell Therapy as an Alternative to Conventional Bone Marrow Transplantation With Lethal Cytoreduction for the Treatment of Malignant and Nonmalignant Hematologic Diseases
Authors: Shimon Slavin, Arnon Nagler, Ella Naparstek, Yossi Kapelushnik, Memet Aker, Gabriel Cividalli, Gabor Varadi, Mark Kirschbaum, Aliza Ackerstein, Simcha Samuel, Avraham Amar, Chaim Brautbar, Ofira Ben-Tal, Amiram Eldor, Reuven Or
Journal: Blood (1998)
Abstract 610: Effect of scaffold and growth factors on anti-cancer drug screening with multicellular spheroids: mimicking in vivo response
Authors: Norio Masuda, M. Mamunur Rahman, Kazuya Arai, Atsushi Mizuno, Manabu Itoh
Journal: Cancer Research (2016)

Abstract Background: For in vitro cancer research, cancer microenvironment is being increasingly recognized as a key factor. In the past, several 3D cell culture models have been tested as the powerful method for reproducing cancer microenvironment. However, in some cases, the growth and drug sensitivity of cells grown on anchorage-independent 3D culture models have been different to that of cells grown in vivo. Further, development of the 3D culture model including the physical (the cell-ECM interaction (scaffold)) and chemical factor (cytokine) are essential for mimicking cancer microenvironment in vitro. Therefore, we explored the effect of the growth factor dependent proliferation and drug sensitivity in scaffold/scaffold-free culture models, and try to understand which method is mimicking in vivo response due to stimulation and suitable for anti-cancer drug development. Methods: We cultured lung cancer, breast cancer, pancreatic cancer and ovarian cancer cell line on monolayer, Matrigel (ECM-embedded 3D culture, scaffold type), NanoCuluture Plate (NCP, a gel-free scaffold type 3D culture plate) and Low adhesion round-bottom plate (scaffold-free 3D culture plate). For growth curve experiment upon addition of growth factors (EGF, HB-EGF, FGF, HRG), we evaluated cell viabilities by ATP assay in several cancer cell lines. We examined drug sensitivities of cancer cell lines against clinically active anti-cancer agents by addition of growth factors. Results: Growth factor promoted the proliferation of cancer cell lines cultured on NCP while it was not enhanced the cell growth when cultured on 2D, Matrigel and Low adhesion round-bottom plate. In drug response, the cells grown on NCP by growth factor stimulation was more sensitive to drug than 2D and other 3D culture models. Conclusion: Differences of the cell growth and drug sensitivity were appeared by effect of scaffold and growth factor. Growth factor dependent cell proliferation and drug sensitivity on NCP were similar to in vivo behavior (1). These results demonstrated that scaffold and growth factor are the novel approach to be mimicking the cancer microenvironment in vitro. Therefore, it is obvious that NCP can be used as a suitable 3D culture model for mimicking in vivo response and anti-cancer drug development. 1. J Cell Sci. 2009 Dec 1;122(Pt 23):4277-86. Citation Format: Norio Masuda, M. Mamunur Rahman, Kazuya Arai, Atsushi Mizuno, Manabu Itoh. Effect of scaffold and growth factors on anti-cancer drug screening with multicellular spheroids: mimicking in vivo response. [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 610.
Sunitinib's effect on tumor infiltration of CD8 T cells in renal cell carcinoma (RCC) and modulation of their function by altering VEGF-induced upregulation of PD1 expression.
Authors: Samuel Haywood, Roy Chen, Paul Pavicic, Lin Lin, C. Marcela Diaz-Montero, Pat A. Rayman, Christopher Przybycin, James Finke, Brian I. Rini
Journal: Journal of Clinical Oncology (2016)

591 Background: The effect of VEGF inhibitors such as sunitinib to modulate RCC tumor microenvironment and the effect on immunotherapy using checkpoint inhibitors is unknown and of clinical interest. Methods: Immune infiltrate in tissue sections from clear cell renal cell carcinomas (ccRCC) (n = 13) treated with sunitinib in the neoadjuvant setting were compared to that of untreated RCC patients with localized disease (n = 15). Immune infiltrate was scored in H&amp;E stained tissue sections. Infiltrates were further characterized by IHC using antibodies against CD4 (Novocastra NCL-CD4-1F6 clone 1F6), CD8 (BiogeneX MU422-UC clone 1A5) or PD1 (Abcam ab52587 clone EPR4877). Intensity of staining was quantified using a Leica microscope equipped with a Retiga SRV camera. Scanned images of multiple tumor fields were analyzed using ImagePro Plus software. For pre-clinical studies, Balb/c mice bearing Renca tumors (RCC) were treated with sunitinib (40mg/kg) daily for 14 days, and tumors were dissociated and analyzed for CD8 and CD4 infiltrate by FACS analysis. Results: Qualitative analysis showed a more prominent accumulation of lymphocytes in tumor sections of patients receiving sunitinib. Quantitative analysis of these infiltrates revealed higher levels of CD8 + T cells in sunitinib treated patients (p = 0.04). By contrast, sunitinib treatment was associated with a reduction of intratumoral expression of PD1. Preclinical studies in the Renca model also showed an increase in the frequency of tumor infiltrating CD8 + T cells following sunitinib treatment. Remarkably, a higher fraction of these tumor infiltrating CD8 T cells were found to co-express the activation marker of cytotoxic effector cells (CD107a) when compared to untreated mice. Conclusions: These findings suggest that sunitinib not only promotes the accumulation of CD8 + T cells within the tumors, but also affects their activity by modulating PD1 expression and enhancing cytotoxic function.
Abstract 3535: Induction of MAPK- and ROS-dependent autophagic cell death in gastric carcinoma by combination of bortezomib and romidepsin
Authors: Alan K. Chiang, Pauline L. Yeung, Kwai Fung Hui
Journal: Cancer Research (2016)

Abstract Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type. This project is funded by CRCG (#104003676) grant of KFH, CRCG (#104002845) and Epstein-Barr virus research (# 200004525) grants of AKSC. Citation Format: Alan K. Chiang, Pauline L. Yeung, Kwai Fung Hui. Induction of MAPK- and ROS-dependent autophagic cell death in gastric carcinoma by combination of bortezomib and romidepsin. [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 3535.
A phase I study of proton beam therapy for locally advanced pancreatic cancer: Analysis of feasibility and anti-tumor effect
Authors: T. Kamigaki, M. Murakami, I. Matsumoto, H. Toyama, T. Fujita, S. Takase, T. Sakai, T. Ajiki, Y. Ku, Y. Hishikawa, Y. Kuroda
Journal: Journal of Clinical Oncology (2008)

15675 Background: Safety of proton beam therapy for locally advanced pancreatic cancer (PC) has not been well established. We reported results from a phase I clinical trial of 2 fraction doses of proton beam therapy of PC. Additionally, the operative findings were evaluated for some patients who underwent surgery after particle therapy. Methods: Patients were required to have unresectable or medically inoperable, locally advanced PCs without distant metastasis. Dose escalation of proton beam irradiation was implemented at a total dose from 40 GyE at level 1 up to 50 GyE at level 2. Serum tumor markers, such as CA19–9, CEA and DUPAN-2 were measured. After protons therapy, if R0 resection was expected, surgical treatment was undergone. Results: From Nov 2004 through to Oct 2006, 18 patients (12 males and 6 females) of locally advanced PC were enrolled. The median age of the patients was 64 years (42–73). For tumor location, 13 lesions were in the pancreatic head and 5 in the body and tail. Clinical stage was 5 patients with T3 and 13 with T4, 11 with N0 and 7 with N1, and all with M0. For 3 patients with T3, tumors had portal vein involvement. The median irradiated dose was 50 GyE (7 patients at 40 GyE and 11 patients at 50 GyE). Most common adverse events were Grade 1 dermatitis and gastroduodenitis. Grade 3 acute duodenitis developed in one who received 50 GyE of protons. Acute tumor reaction in 18 patients consisted of 12 of SD and 6 of PD, however serum tumor marker decreased in 10 patients. Four patients underwent surgery after proton beam irradiation. Pancreaticoduodenectomy was performed in one who received 40 GyE protons, however, histological diagnosis revealed carcinoma of the bile duct. After 50 GyE irradiation, 1 patient underwent R0 panreaticoduodenectomy with portal resection. Two patients underwent exploratory laparotomy, because of celiac artery involvement and liver metastasis, respectively. Conclusions: Proton beam therapy is tolerable in locally advanced pancreatic cancer. However, anti-tumor effect was insufficient in the present trial dose. No significant financial relationships to disclose.
Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia
Authors: S Kayser, A Benner, C Thiede, U Martens, J Huber, P Stadtherr, J W G Janssen, C Röllig, M J Uppenkamp, T Bochtler, U Hegenbart, G Ehninger, A D Ho, P Dreger, A Krämer
Journal: Blood Cancer Journal (2016)

The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.