tbuckley/cabot-search huggingface dataset:
Correlation of myeloid derived suppressor cell (MDSC) populations with clinicopathologic features in urothelial carcinoma (UC).
Authors: Moshe Chaim Ornstein, C. Marcela Diaz-Montero, Pat A. Rayman, Paul Elson, Samuel Haywood, James Finke, Jorge A. Garcia, Brian I. Rini, Andrew J. Stephenson, Steven C. Campbell, Amr Farouk Fergany, Hamid Emamekhoo, Marcelo Lamenza, Sylvia Stybor, Kim Schach, Pam Profusek, Allison Janine Tyler, Marc S. Ernstoff, Petros Grivas
Journal: Journal of Clinical Oncology (2016)

434 Background: MDSC are a heterogeneous population of potent immunosuppressive cells with potential predictive/prognostic significance in solid tumors. The association between MDSC and clinicopathologic features in patients (pts) with UC was investigated. Methods: Peripheral blood from 26 non-metastatic UC pts scheduled to undergo cystectomy or nephroureterectomy at Cleveland Clinic was collected. MDSC were enumerated in fresh unfractionated blood (WB) and in peripheral blood mononuclear cells (PBMC). (T)otal MDSC were defined as CD33+/HLADR-; out of T-MDSC, (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+) and (I)mmature (CD15-CD14-) MDSC were identified. CD11b MDSC (Linlo/HLADR-/CD33+/CD11b+) were identified in WB. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Wilcoxon rank sum test was used to assess associations between MDSC populations and clinicopathologic features. Due to the exploratory nature of the study, p &lt; .10 was considered significant. Results: Of 26 pts, 25 had surgery and 1 is under surveillance. 24 had both WB and PBMC data. 23/26 were men; median age 67. Of 26 pts, all had primarily UC histology; 7 had mixed UC histology, 11 had prior intravesical BCG, 12 neoadjuvant therapy (10 Gem/Cis, 1 Gem/Carbo, 1 unknown). Of 25 pts who had surgery, 5 had pT3/4 stage; 5 had LVI; 9 had CIS. All but 1 had negative LN. Higher levels of specific WB MDSC populations were associated with mixed histology (including squamous), CIS, and higher pT-stage (Table). When compared to a separate cohort of 11 pts with metastatic UC, the % G-MDSC in PBMC was lower in non-metastatic pts (median 0.3 vs. 1.47; p = .05). Conclusions: Although no single MDSC population correlated with all the evaluated clinicopathologic features, higher levels of certain MDSC populations appear to correlate with histology and pT stage. Further validation of blood and tissue is ongoing in a larger cohort. [Table: see text]
Pretreatment levels of serum lactate dehydrogenase (LDH) and clinical outcome in metastatic colorectal cancer patients receiving first-line chemotherapy and bevacizumab.
Authors: Elena Maccaroni, Riccardo Giampieri, Mario Scartozzi, Michela Del Prete, Luca Faloppi, Maristella Bianconi, Alessandro Bittoni, Eva Galizia, Cristian Loretelli, Laura Belvederesi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2012)

514 Background: No predictive marker for efficacy of a Bevacizumab-based therapy has been identified in metastatic colorectal cancer. Soluble LDH levels seem to be related to increased angiogenesis. The focus of this analysis is whether high levels of LDH can be related to higher benefit of bevacizumab-based therapy in this setting. Methods: Eligible patients were metastatic colorectal cancer patients treated in 1 st line setting with a chemotherapy doublet and bevacizumab in the last year. A historical control group was also formed by collecting data of patients treated with only a chemotherapy doublet. Pre-treatment LDH serum levels were collected for all patients. Cut-off level for soluble LDH was determined via ROC curve. Primary end-point was difference in progression free survival between the two groups. Secondary end-points were overall survival and response rates. Results: 82 patients treated with first line containing bevacizumab were eligible for our analysis. 138 patients were identified as control group. The two groups were comparable for major clinical characteristics. LDH cut-off level was stated at 588 mg/dl. In the control group PFS of 4.2 and 8 months were observed for LDH high and low levels (p=0.0003,HR:0.2973,95%CI:0.0318 to 0.3543). OS were 19.6 and 34.9 months (p=0.0014,HR:0.2484,95%CI: 0.0188 to 0.3884). No significant differences were seen for response rates (with 20% vs 39% partial responses, p=0.1671). In the group of patients treated with Bevacizumab, PFS of 8.5 and 7.3 months were observed respectively for LDH high and low levels (p=0.2,HR:0.6360,95%CI:0.2528 to 1.4185). OS were 26.6 and 22 months (p=0.7,HR:0.8480,95%CI:0.2307 to 2.9563). Improved response rate for LDH high patients could be seen (58% vs 14% partial responses, p=0.0243). Conclusions: These data confirm the role of soluble LDH as marker of worse outcome for unselected patients and also suggest a role as potential marker of increased effectiveness of Bevacizumab based therapy.
Pathway map development as an approach to identifying priority areas for quality improvement in Ontario.
Authors: Helen Mackay, Jasmin Soobrian, Joan Murphy, Lorraine Elit, Michael F. Milosevic, Angelika Gollnow, Jillian Ross, Claire Holloway
Journal: Journal of Clinical Oncology (2016)

108 Background: Disease Pathway Management (DPM) is the unifying approach to the way in which Cancer Care Ontario (CCO) sets priorities for cancer control, plans cancer services and improves the quality of care in Ontario. In 2014 DPM began developing a cervical cancer pathway map (CCPM) to map the patient journey along the cervical cancer care continuum. Objective: to report on the CPPM development process as a tool to identify key priorities for cervical cancer management in Ontario. Methods: DPM convened a multidisciplinary/multi-stakeholder cervical cancer working group with regional and specialty representation from across Ontario. Over 12 months, 33 individuals participated in an in-person meeting and monthly teleconferences. The CCPM was drafted using guidelines developed by CCO’s Program in Evidence Based Care (PEBC) and considering clinical guidance documents from several jurisdictions. Throughout the development process the team were asked to discuss and reach consensus on key priorities for improving care. Results: Twenty-two priority areas were identified across the continuum in: prevention, diagnosis, treatment, follow-up and survivorship. Opportunities were identified for: development/endorsement of evidence based guidelines; patient-centered approaches to screening; quality improvement; survivorship; drug funding implementation and a CPPM Knowledge Translation strategy. Potentially actionable items were aligned with relevant internal and external stakeholders including organized screening programs, the PEBC, provincial drug reimbursement programs and other quality improvement teams within CCO. Conclusions: The process of bringing multidisciplinary experts together in order to develop the CPPM successfully identified key priorities across the spectrum of care in Ontario and allowed identification of potential opportunities for quality improvement, development of practice guidelines and new models of care. In turn, the CCPM provides a patient-centred disease focused framework from which stakeholders can approach and evaluate new initiatives in the context of the cervical cancer continuum.
Impact of anti-VEGF therapy in metastatic colorectal cancer with an intact primary tumour.
Authors: Belinda Lee, Hui-Li Wong, Jeanne Tie, Rachel Wong, Margaret Lee, Louise M. Nott, Jeremy David Shapiro, Ross Jennens, Natalie Heather Turner, Ben Tran, Sumitra Ananda, Desmond Yip, Gary Edward Richardson, Phillip Parente, Lionel Lim, Greg Stefanou, Matthew E. Burge, Mahesh Y. Iddawela, Peter Gibbs
Journal: Journal of Clinical Oncology (2016)

650 Background: The management of metastatic colorectal cancer (mCRC) with anti-VEGF therapy and a fluoropyrimidine-containing chemotherapy is well established in first and second line therapy. However the role, safety and benefits of anti-VEGF therapy (Bevacizumab) in specific subgroups including those with an intact primary tumour (IPT), are not well described. Methods: Consecutive mCRC pts enrolled from January 2009 were identified from a prospective multi-site Australian registry. Survival and key safety endpoints were explored for pts with an IPT versus pts with a resected primary (RPT). Differences in outcomes were compared using log-rank test and Kaplan-Meier curves. Results: Of 1,204 pts with mCRC, 826 (69%) eligible pts were identified. Anti-VEGF therapy use in the first-line setting was similar in pts with an IPT [200/313 (64%)] vs. a RPT [357/513 (70%)]. In both groups the addition of anti-VEGF therapy was associated with greater PFS; IPT 8.5 vs. 4.7 months (HR 0.73, p=0.017) and RPT 10.8 vs. 5.8 months (HR 0.67, p=0.0002). OS was longer in anti-VEGF treated pts; IPT 20 vs. 14.8 months (HR 0.66, p=0.0046) and RPT 24.4 vs. 17.3 months (HR 0.71, p=0.0039). A trend for more GI perforations with anti-VEGF therapy use was seen in pts with IPT (4.5% vs. 1.8%, p=0.33), but not RPT (1.7% vs. 1.9%). The rate of bleeding and thrombosis was lower in the IPT group treated with bev: 1.5% vs. 5.3%, p=0.05 and 1.5% vs. 2.7%, p=0.47 respectively. In comparison, RPT pts treated with and without anti-VEGF therapy had a bleeding rate of 3.4% vs. 0.6%, p=0.07, and a thrombosis rate of 5.9% vs. 0.6%, p=0.007. Conclusions: In routine clinical practice clinicians appear comfortable using anti-VEGF therapy in pts with an IPT. Superior PFS and OS outcomes were seen with addition of anti-VEGF therapy, with no evident impact of primary tumor status. There was a trend for a higher GI perforation rate in anti-VEGF treated IPT pts, but a lower rate of other adverse events. This may reflect clinicians avoiding anti-VEGF therapy in pts considered at increased risk of these complications. Further analysis is underway to explore this possibility.
Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types
Authors: Sung Chun, Alexandra Casparino, Nikolaos A Patsopoulos, Damien C Croteau-Chonka, Benjamin A Raby, Philip L De Jager, Shamil R Sunyaev, Chris Cotsapas
Journal: Nature Genetics (2017)
NOTCH1 inhibition by the gamma-secretase inhibitor RO4929097 in pediatric glial tumors.
Authors: G. Berghtold, C. Dantas Barbosa, G. Dieffenbach, E. Daudigeos-Dubus, H. Blokus, C. Ferreira, J. Boylan, M. Abely, G. Vassal, J. Grill, B. Geoerger
Journal: Journal of Clinical Oncology (2011)

9555 Background: Notch pathway signaling is deregulated in many human cancers, notably leukemia. Our recent findings in primary ependymoma suggest the NOTCH1 pathway is also implicated in glial oncogenesis (Puget et al. J Clin Oncol 2009). Methods: The present study explored anti-proliferative effects of the new gamma-secretase inhibitor RO4929097 in pediatric glial models. Results: Notch pathway analysis by qPCR in 24 ependymoma and glioma models confirmed overexpression of the NOTCH1, the ligand DLL-1, and the target genes (HES1, HEY1 and MYC) in ependymoma xenografts and 3 out of 11 short-term cultures tested, though not in glial cell lines. Two short-term-cultures had lost NOTCH pathway activation as compared to their matched primary ependymoma tumors. All models exhibited a downregulation the gene FBXW7, a negative regulator of NOTCH. Two ependymoma primary cells presented mutations in the TAD domain of the NOTCH1 gene. RO4929097 was able to down-regulate the expression of NOTCH effectors genes HES1, HEY1 and MYC in a dose dependent manner. In vitro, RO4929097 at 300 to 3000 nM reduced cell density in three of five ependymoma short-term cultures tested and cell viability by 40% and 50% respectively in the short-term culture NEM78 as measured by MTS assay; the latter was associated with a G0/1 cell cycle arrest. We found enhanced anti-proliferative effects in vitro when NOTCH1 siRNA silencing was combined with temozolomide, cisplatinum, etoposide, but not with EGFR inhibition. In vivo, RO4929097 at 30 mg/kg q4dx3w showed 31% tumor growth inhibition in advanced stage IGRG121 glioma xenografts and enhanced growth inhibiting effects in combination with irradiation treatment in IGRG121 and IGREP37. Conclusions: Thus, NOTCH pathway activation can be selectively inhibited by RO4929097 achieving moderate anti-proliferative effects on established pediatric glial tumors. This preclinical data provides support for the clinical evaluation of RO4929097 in pediatric glial tumors.
The antitumor effect of epigallocatechin-3-gallate on gastroenterological cancer.
Authors: Shuichi Iwahashi, Mitsuo Shimada, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yusuke Arakawa, Yu Saito, Shinichiro Yamada, Gizachew Yismaw
Journal: Journal of Clinical Oncology (2015)

335 Background: Green tea is one of the most popular beverages it contains many catechins such as epigallocatechin-3-gallate (EGCG) inhibits cancer growth. The aim of this study was to elucidate the anti-tumor effect and the effect for spheres of EGCG. Methods: Human hepatoma-derived cell line (HepG2) and human colorectal carcinoma cell line (HCT-116) were used. The anticancer effects of EGCG was studied by MTT assay. We made cancer sphere from HepG2 cells, and we added EGCG to cancer sphere. And we compared the gene expressions of RT-PCR between normal HepG2 and cancer sphere groups. Results: EGCG had the anti-tumor effect in dose-dependent. Furthermore, EGCG cancelled this spheroid formation, EGCG down-regulated the Nanog and CD133, related stemnesss genes. And then, EGCG down-regulated the ABCG1and Nek2, related ABC transporter genes, expression in sphere. Conclusions: EGCG had the anti-tumor effects on gastroenterological cancer, and EGCG had the effect to sphere, same as cancer stem cell thorough the down-regulation of ABC transporter related genes. Therefore, EGCG might be used as the safe and novel antitumor agents.
Lymphocytosis Following First-Line Treatment for CML In Chronic Phase with Dasatinib Is Associated with Improved Responses: A Comparison with Imatinib
Authors: Charles A. Schiffer, Jorge E. Cortes, Giuseppe Saglio, Philipp le Coutre, Francois Guilhot, Erkut Bahceci, David Dejardin, Neil P. Shah
Journal: Blood (2010)
Survivorship care plans: Is there buy-in from oncology providers?
Authors: Talya Salz, Erin Onstad, Mary S. McCabe, Shrujal S. Baxi, Richard L. Deming, Regina A Franco, Lyn A. Glenn, Gregory R. Harper, Alcee Jumonville, Roxanne m Payne, Elissa A Peters, Andrew L. Salner, John M Schallenkamp, Sheron R. Williams, Kevin Yiee, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2013)

8 Background: The Institute of Medicine advised that cancer survivors and their primary care providers receive survivorship care plans (SCPs) to summarize cancer treatment and plan ongoing care. However, the use of SCPs remains limited. Methods: Oncology providers at 14 National Cancer Institute Community Cancer Centers Program (NCCCP) hospitals completed a survey regarding their perceptions of SCPs, including barriers to implementation, strategies for implementation, the role of oncology providers, and the importance of topics in SCPs (diagnosis, treatment, recommended ongoing care, and the aspects of ongoing care that the oncology practice will provide). Results: Among 245 providers (70% response rate), a minority reported ever providing an SCP or any of its components to patients. The most widely reported barriers were personnel to creating SCPs and time (69% and 64% of respondents, respectively). The most widely endorsed strategy among those using SCPs was the use of a template with pre-specified fields; 94% of those who used templates found them helpful. For each topic of an SCP, while 87%-89% of oncology providers felt it was very important for primary care providers to receive the information, only 58%-65% of respondents felt it was very important for patients to receive the information. Further, 33%-38% of respondents had mixed feelings about whether it was oncology providers’ responsibility to provide SCPs. Conclusions: Practices need additional resources to overcome barriers to implementing SCPs. We found resistance toward SCPs, particularly the perceived value for the survivor and the idea that oncology providers are responsible for SCP dissemination.
Phosphodiesterase 10, a novel target in colon cancer.
Authors: Suzanne Russo, Nan Li, Kevin Lee, Yaguang Xi, Bing Zhu, Bernard Gary, Veronica Ramirez, Evrim Gurpinar, Joshua Canzeroni, Alexandra Fajardo, Sara Sigler, John T. Piazza, Xi Chen, Joel Andrews, Yonghe Li, Brian Eberhardt, Larry Yet, Adam Keeton, William E. Grizzle, Gary Piazza
Journal: Journal of Clinical Oncology (2014)

503 Background: Elevation of intracellular cGMP is known to inhibit tumor proliferation and induce apoptosis, although the phosphodiesterase (PDE) isozymes that regulate cGMP levels in tumor cells have not been well studied. We report first evidence that PDE10 is elevated in colon tumors compared with normal colon and suggest that PDE10 inhibitors can be used for the treatment or prevention of colon cancer. Methods: PDE10 protein and mRNA levels were measured in human colon tumor cells (HT29, HCT116, SW480, Caco2), normal colonocytes (NCM460), human clinical samples, and ApcMin/+ mouse model. Two chemically distinct PDE10 selective inhibitors, PQ-10 and Pf-2545920, were tested against the cell lines. The NCI-60 panel of human tumor cell lines was also screened against Pf-2545920 to identify potential differences in sensitivity among histologically diverse tumor types. We also performed siRNA knockdown studies in colonocytes and tumor cell lines. To determine the effect of the PDE10 siRNA knockdown on cyclic nucleotide hydrolysis, whole cell lysates from transfected cells were assayed for PDE activity using cGMP or cAMP as substrates. Results: PDE10 levels were low in normal colonocytes (NCM460) and elevated in tumor cell lines. Similarly, PDE10 was elevated human clinical specimens and the ApcMin+/ mouse model compared with normal mucosa. PDE10 inhibitors and siRNA selectively inhibited colonic tumor growth while stable knockdown inhibited colony formation and increased doubling time. Pf-2545920 also supressed growth of all cell lines within the NCI-60 panel. In comparison with lysates from vector control cells, transfection with PDE10 siRNA reduced cGMP hydrolysis by ~35% in both HCT116 and HT29 cell lines, but did not affect cGMP hydrolysis in colonocytes; siRNA did not significantly affect cAMP degradation in all 3 cell lines. Conclusions: PDE10 plays a role in colon tumorgenesis whereby inhibitors can selectively suppress tumor cell growth. The mechanism by which PDE10 inhibition affects growth appears to involve activation of cGMP/PKG signalling. PDE10 represents a novel anticancer target for the treament and prevention of colon cancer.
Isolation of equol-producing bacterium to realize chemoprevention of prostate cancer.
Authors: H. Tsuji, K. Moriyama, K. Nomoto, N. Miyanaga, H. Akaza
Journal: Journal of Clinical Oncology (2011)

1565 Background: Equol is known to possess a stronger estrogenic activity than the other soy isoflavone derivatives and has been reported to prevent prostate cancer. Equol is exclusively produced from daidzein by intestinal bacteria, which, however, does not happen in all people. In a case-control study, the percentage of non-equol producers was significantly higher in patients with prostate cancer than in healthy individuals (Akaza et al. 2002). Therefore, controlling the certain intestinal inhabitants may be a promising strategy for the primary prevention of prostate cancer. However, details of equol-producing bacteria in the human gut have not been clarified. Methods: The suspensions of a fresh stool sample from an equol producer were incubated in various medium under anaerobic condition at 37°C for 24 h. The 7th passage of the culture supplemented with sorbose was used as the source of isolation. An isolated strain was confirmed to have the ability to convert daidzein to equol by HPLC, and was designated strain NATTS. The 16S rRNA gene sequence of strain NATTS was analyzed, and a specific primer set for strain NATTS and related strains was designed. The population levels of the species in 40 healthy Japanese adults were enumerated by RT-qPCR (Matsuda et al. 2009). Results: Several kinds of carbohydrates were found to enhance equol production from daidzein in an in vitro human fecal culture. Sorbose, one of the most effective carbohydrates, was used as the carbohydrate source for isolating a strain with ability to convert daidzein to equol in human fecal culture; Strain NATTS, a Gram-positive, non-spore-forming rod bacterium with high ability to convert daidzein to equol was found to belong to the genus Slackia by 16S rRNA sequence based analysis, and the prevalence of the Slackia sp. in Japanese adults was found to be 40% at a mean population level of 106 cells per gram of feces. Conclusions: An equol-producing bacterium, Slackiasp. strain NATTS, with a high equol-producing activity was isolated from a human fecal culture by the addition of prebiotic sorbose. The Slackia sp. strain NATTS and related strains were found to have a high prevalence in Japanese adult intestine.
Incidence of venous thromboembolism among chemotherapy-treated patients with lung cancer and effect on mortality: A retrospective database study.
Authors: H. Huang, J. Korn, R. Mallick, M. Friedman, J. Menzin
Journal: Journal of Clinical Oncology (2011)

e19532 Background: Cancer patients, especially those with lung cancer, have an elevated risk for venous thromboembolism (VTE). Additionally, chemotherapy (CTX) has been found to be associated with a higher incidence of VTE. This study assessed the incidence, timing, and risk factors for VTE, and the association between VTE and survival among CTX-treated patients with lung cancer. Methods: Using Florida Medicaid administrative claims data (FY 2000-2008), patients with any diagnosis of primary lung cancer and ≥1 claim for CTX (date of first claim was index) within 4 months of diagnosis were selected. Patients with VTE prior to CTX initiation and those enrolled in Medicare or an HMO in the index or prior month were excluded. Cox proportional hazards models were developed to assess risk factors for VTE and the impact of VTE (as a time-dependent variable) on overall survival. Results: Of 15,749 lung cancer patients, 2,242 met all study inclusion criteria (mean age 56 years, 52% female). The incidence of VTE was 6.8 per 100 person-years among patients not receiving CTX versus 11.6 per 100 person-years among those on CTX (P<.001). Among lung cancer patients undergoing CTX and developing VTE, median time to occurrence was 109 days, with 61% and 82% of patients experiencing an event within 6 and 12 months, respectively. Risk of incident VTE increased with comorbidity (adjusted hazard ratio [HR] =1.53 for Charlson comorbidity score of 1 vs 0; P=.006, and HR=1.61 for a comorbidity score of 2 vs 0; P=.013) and presence of metastatic lung cancer (HR=1.75; P<.001). Controlling for the above and other characteristics, presence of VTE was significantly associated with faster time-to-death (HR=1.80; P<.001). Conclusions: Our findings indicate that VTE was common among lung cancer patients and occurred more often among those receiving chemotherapy compared to those not receiving chemotherapy. The underlying mechanism of this association is yet unknown. Majority of VTE events occurred within 6 months of initiating CTX. The occurrence of a VTE event was associated with a significantly increased risk of mortality. Clinical studies of strategies to prevent VTE in this high-risk population are warranted.