tbuckley/cabot-search huggingface dataset:
Abstract 2833: Genetic and pharmacologic inhibition of mTOR delays mortality due to thymc lymphoma formation in mice and is associated with decreases in cell cycle proteins
Authors: Shuling Zhang, Joy M. Gary, John K. Simmons, Jinfei Xu, Benjamin J. Gamache, Ke Zhang, Nicholas Watson, Alexander L. Kovalchuk, Aleksandra M. Michalowski, Jin-Qiu Chen, Michelle A. Herrmann, Tuddow Thaiwong, Matti Kiupel, Wendy Dubois, Joseph R. Testa, Beverly A. Mock
Journal: Cancer Research (2016)

Abstract The AKT/mTOR pathway is frequently hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). To model inhibition of this pathway in lymphoma, mice with T-lymphocyte-specific, constitutively active AKT (Lck-MyrAkt2) were crossed to mice with genetically reduced mTOR expression (knock-down, KD). Mice with genetic reduction of mTOR had increased survival by 10 weeks relative to wild type mTOR mice, though both developed thymic pre-T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). Similarly, when mTOR wild type Lck-MyrAkt2 mice were treated for 8 weeks with the rapamycin analog, everolimus, an inhibitor of the mTOR TORC1 complex, survival was also increased. Gene expression profiling of thymic lymphomas from the mice revealed that mTOR KD was associated with decreased expression of Cdk6, a critical proliferative control node in T-cell development and oncogenic transformation. Pharmacologic inhibition of mTOR in tumor cells also decreased CDK6. The combination of a mTOR inhibitor (rapamycin) and a CDK4/6 inhibitor (PD-0332991, Palbociclib) synergistically decreased the overall viability and signaling downstream of drug targets in mouse lymphoma cells and in human T-ALL/LBL cell lines. This combination was also evaluated in mice using a disseminated leukemia model. In vivo treatment with this combination not only reduced tumor size by inhibiting tumor cell proliferation and arresting tumor cell cycle, but also increased overall survival. We are currently validating upstream regulators of Cdk6 as well as downstream targets in the pre-T LBL tumors from the mTOR deficient mice. Citation Format: Shuling Zhang, Joy M. Gary, John K. Simmons, Jinfei Xu, Benjamin J. Gamache, Ke Zhang, Nicholas Watson, Alexander L. Kovalchuk, Aleksandra M. Michalowski, Jin-Qiu Chen, Michelle A. Herrmann, Tuddow Thaiwong, Matti Kiupel, Wendy Dubois, Joseph R. Testa, Beverly A. Mock. Genetic and pharmacologic inhibition of mTOR delays mortality due to thymc lymphoma formation in mice and is associated with decreases in cell cycle proteins. [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 2833.
Predictors of 6-month health utility outcomes in survivors of acute respiratory distress syndrome
Authors: Samuel M Brown, Emily Wilson, Angela P Presson, Chong Zhang, Victor D Dinglas, Tom Greene, Ramona O Hopkins, Dale M Needham
Journal: Thorax (2016)

<h3>Background</h3> With improving short-term mortality in acute respiratory distress syndrome (ARDS), understanding and improving quality of life (QOL) outcomes in ARDS survivors is a clinical and research priority. We sought to identify variables associated with QOL, as measured by the EQ-5D health utility score, after ARDS using contemporary data science methods. <h3>Methods</h3> Analysis of prospectively acquired baseline variables and 6-month EQ-5D health utility scores for adults with ARDS enrolled in the ARDS Network Long-Term Outcomes Study (ALTOS). Penalised regression identified predictors of health utility, with results validated using 10-fold cross-validation. <h3>Results</h3> Among 616 ARDS survivors, several predictors were associated with 6-month EQ-5D utility scores, including two lifestyle factors. Specifically, older age, female sex, Hispanic/Latino ethnicity, current smoking and higher body mass index were associated with lower EQ-5D utilities, while living at home without assistance at baseline and AIDS were associated with higher EQ-5D utilities in ARDS survivors. No acute illness variables were associated with EQ-5D utility. <h3>Conclusions</h3> Acute illness variables do not appear to be associated with postdischarge QOL among ARDS survivors. Functional independence and lifestyle factors, such as obesity and tobacco smoking, were associated with worse QOL. Future analyses of postdischarge health utility among ARDS survivors should incorporate measures of demographics and functional independence at baseline. <h3>Trial registration numbers</h3> NCT00719446 (ALTOS), NCT00434993 (ALTA), NCT00609180 (EDEN/OMEGA), and NCT00883948 (EDEN); Post-results.
Abstract 4776: Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers
Authors: Samhita Bapat, Tanmay Dichwalkar, Priya Pancholi, Byron L. Bennett, Vikas Sehdev
Journal: Cancer Research (2016)

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to variable P53 status and overactive mechanisms that mediate drug resistance. Platinum based compounds like Cisplatin (CDDP) are frequently used for treatment of UGCs. However, clinical use of CDDP is limited due to development of drug resistance and dose limiting side-effects resulting in nausea, vomiting, neutropenia, thrombocytopenia and renal toxicity. In this study we investigated the anticancer potency of a novel CDDP derivative (dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum) (DCTF-CDDP) and compared it to CDDP in P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of CDDP or its derivative (DCTF-CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, and expression of apoptotic markers. Results: The cell viability data indicated that DCTF-CDDP treatment was comparatively more effective than CDDP at inhibiting AGS (CDDP IC50: 6.3 ± 0.2 μM; DCTF IC50: 1.7 ± 0.5μM) and FLO-1 (CDDP IC50: 2.5 ± 0.68 μM; DCTF IC50: 0.5 ± 0.6μM) UGC cancer cell viability. The clonogenic cell survival assay data also showed that DCTF-CDDP was significantly (p&amp;lt;0.05) more potent at suppressing UGC cell survival when compared to CDDP. Similarly, the western blot data also showed that treatment with increasing concentrations (1, 2.5, and 5 μM) of CDDP and DCTF-CDDP for 24h induced higher levels of P53/P73 and cleaved PARP with DCTF-CDDP treatment in UGC cells. Conclusions: Our in vitro data indicate that DCTF-CDDP is significantly more potent at inhibiting cell viability and inducing apoptosis in P53 wild type and mutant UGC cells. Our study suggests that DCTF-CDDP could be an effective CDDP derivative that can be used to achieve better therapeutic outcome at lower doses and toxic side effects. Citation Format: Samhita Bapat, Tanmay Dichwalkar, Priya Pancholi, Byron L. Bennett, Vikas Sehdev. Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers. [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 4776.
Phase II study of gemcitabine (G) and bevacizumab (B) as first-line treatment in taxane-pretreated, HER2-negative, locally recurrent or metastatic breast cancer (MBC): Interim safety analysis.
Authors: R. Borson, W. G. Harker, J. E. Reeves, J. Bromund, L. Zhao, D. F. Tai, D. A. Yardley
Journal: Journal of Clinical Oncology (2010)

1148 Background: The combination of bevacizumab with taxane-, anthracycline-, or capecitabine-based chemotherapy has yielded significant improvement in progression-free survival (PFS) in pts with MBC (Miller 2007; Miles 2008; Robert 2009). We examined the efficacy and safety of combining B with G as first-line therapy in taxane pretreated MBC pts and report an interim safety analysis of the first 39 enrolled pts. Methods: This US, multicenter, nonrandomized, open-label trial will enroll 51 pts. Eligible pts have HER2-negative, recurrent or MBC, PS 0-1, and must have received a taxane as neoadjuvant and/or adjuvant therapy with a ≥12 month disease-free interval. Pts received G 2,500 mg/m2 on d 1 plus B 10 mg/kg on d 1, both in 14-day cycles and were treated until progressive disease (PD), complete response, or intolerable toxicity. The primary endpoint is PFS and the secondary endpoints are overall response rate, 1 year survival rate, and safety. Toxicities are graded according to NCI CTC v3.0. Results: Between March 2008 and August 2009, 39 eligible women were enrolled and treated. Median age, 54 (range 28-73); ER+/ PR+, 22 and ER-/PR-/HER2-, 13; PS 0/1, 21/18. There was 1 serious drug-related adverse events (AEs) requiring hospitalization (gr 3 febrile neutropenia) and 1 discontinuation due to AEs (gr 3 hypertension) after 16 cycles. Drug-related AEs (all grades) occurring in >20% of pts were: nausea (48.7%), fatigue (41%), anorexia (25.6%), neutropenia (23.1%), constipation (20.5%), and diarrhea (20.5%). The rates of gr 1-2 epistaxis (5.1%) and thrombosis (2.6%) were low. Gr 3 drug-related AEs were neutropenia (12.8%), leukopenia (5.1%). One patient each experienced gr 3 febrile neutropenia, thrombocytopenia, fatigue, nausea, vomiting, AST, and hypertension. There were no gr 4 AEs. Sixteen pts discontinued due to PD after a median of 5.5 cycles (range 4-12). The median number of cycles received was 6.0 (range 1-23). Median dose intensities were: G, 98.7% and B, 94.7%. Conclusions: Therapy with G+B is well-tolerated with no unexpected toxicity. Enrollment is currently 49/51 pts; updated safety data will be presented at the meeting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Lilly Lilly Lilly
The effects of HOXB7 in the promotion of migration, invasion and anti-apoptosis in gastric cancer.
Authors: Moon Kyung Joo, Jong-Jae Park, Hyo Soon Yoo, Beom Jae Lee, Hoon Jai Chun, Sang Woo Lee, Sang Cheul Oh, Young-Tae Bak
Journal: Journal of Clinical Oncology (2016)

46 Background: HOX genes, a subset of the homeobox gene family, are known to be aberrantly expressed in various types of cancers. Among them, HOXB7 recently has been reported to be highly expressed in esophageal or colorectal cancers. We aimed in this study to demonstrate the critical roles of HOXB7 in development and progression of gastric cancer. Methods: We screened gene and protein expression of HOXB7 in various gastric cancer cell lines, and also compared gene expression level of HOXB7 among chronic gastritis, intestinal metaplasia and gastric cancer tissues. To figure out the oncogenic effects of HOXB7 in vitro, we performed annexin-V assay, wound closure assay and Matrigel invasion assay. We performed Western blot analysis to examine the impact of HOXB7 on AKT pathway. Results: Both mRNA and protein was substantially expressed in stomach cancer cell lines (SNU-638, SNU-719, MKN-28, MKN-45, AGS, KATO-III, NCI-N87), however, they were nearly abolished in normal gastric tissues. Gene expression was significantly higher in primary or metastatic stomach cancer, compared with chronic gastritis or intestinal metaplasia. Knockdown of HOXB7 by transfection with siRNA in AGS and SNU-638 cells significantly inhibited migration and invasion, and showed anti-apoptotic effect. Because a previous study demonstrated that enforced expression of HOXB7 could enhance PI3K/AKT pathway activity in colon cancer cells (Liao W.T. et al, Clin Cancer Res; 17(11) June 1, 2011), we investigated the modulation of AKT/PTEN pathway by HOXB7 and observed that knockdown of HOXB7 significantly downregulated phospho-AKT and upregulated PTEN in both cell lines. Furthermore, target gene products of AKT pathway including cyclin D1, survivin, Bcl-xL and MMP-9 were significantly downregulated by siHOXB7. Conclusions: Our findings suggest that HOXB7 might play a crucial role in migration, invasion and anti-apoptotic effect via modulating AKT/PTEN pathway.
PWE-060 Polypectomy Practices In The English Bowel Cancer Screening Programme: Abstract PWE-060 Table 1
Authors: S Din, A Ball, EJ Taylor, M Rutter, S Riley, S Johal
Journal: Gut (2014)

<h3>Introduction</h3> Most polyps are &lt;10 mm in size and a range of polypectomy techniques are available with wide variations in practice. We aimed to examine the techniques employed for removal of &lt;10 mm polyps in relation to polyp characteristics, completeness of excision, safety and changes over time. <h3>Methods</h3> Data relating to removal of polyps &lt;10 mm between Jan 2010 and Dec 2012 were retrieved from the national Bowel Cancer Screening Programme (BCSP) database. Categorical data was compared using <i>x<sup>2</sup></i>. <h3>Results</h3> 147174 polyps were removed during 62679 colonoscopies. A range of techniques was used (cold biopsy forceps (CBF) 19.7%, cold snare (CS) 22.1%, hot biopsy forceps (HBF) 12.2%, hot snare (HS) 35.1%, EMR 10.9%). EMR was used more frequently in the right colon compared to the left (14.3 vs. 8.3%, OR = 1.84, 95% CI: 1.78–1.90). Most pedunculated polyps were removed using HS; this was lower in the right vs. left colon (69.6 vs. 88.3%, OR = 0.30, CI: 0.28–0.33). CS was most common for non-pedunculated polyps in the right colon (29.8 vs. 19.0% in left, OR = 1.81 CI: 1.76–1.85); whereas most common in the left colon was HS (34.8 vs. 22.5% in right, OR = 1.84 CI: 1.79–1.88). Surgeons were more likely than physicians to use diathermy irrespective of site or morphology (65.6 vs. 56.5%, OR = 1.46 CI: 1.43–1.5). In 60% of polyps removed completeness of excision was not histologically assessable. 21.2% were completely excised, 5.8% incomplete and 13% not stated. For non-pedunculated polyps, histologically-confirmed complete excision was more common after EMR (23.4 vs. 6.2%, OR = 1.16, CI: 1.08–1.25) compared to other techniques (CBF 17.7%, CS 15.1%, HBF 19.1%, HS 21.5%); for pedunculated polyps it was more common after EMR (42.3%) and HS (42.0%). Complications were rare for colonoscopies (45227) where only polyps &lt;10 mm were removed. 12 (0.03%) bleeding episodes required transfusion; rates for single and multiple polypectomy cases were 0.01 and 0.04% respectively (OR = 5.01, CI: 1.10–22.8). The HS technique was most commonly used. There were 16 (0.04%) perforations; 0.02% for single vs. 0.05% for multiple polypectomies (OR = 2.20, CI: 0.77–6.34, p = 0.13). No technique dominated for single compared with HS for multiple polypectomies. Between 2010 and 2012, use of CBF, CS and EMR increased, whereas HBF and HS decreased (p &lt; 0.01) <h3>Conclusion</h3> The removal of polyps &lt;10 mm within the BCSP is safe, but histological evidence of completeness of excision is poor with all techniques. Wide variations in practice reflect the lack of evidence guiding these decisions, although use of cold resection techniques has increased over time <h3>Disclosure of Interest</h3> None Declared.
Analysis of the cardiovascular risk profile of Ph+ leukemia patients treated with ponatinib.
Authors: Hanna Jean Khoury, Jorge E. Cortes, Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D. Le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane Apperley, Moshe Talpaz, John F. DiPersio, Daniel J. DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Kumiko Yanase, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2013)

7048 Background: Coronary artery disease (CAD), peripheral arterial occlusive disease and cerebrovascular disease have been observed in pts treated with BCR-ABL tyrosine kinase inhibitors (TKIs). While uncommon, these events can be serious complications of BCR-ABL TKI therapy. Methods: The cardiovascular (CV) profile of ponatinib (45 mg/day) was evaluated in 449 pts with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to prior TKIs in the phase 2 PACE trial. At analysis (23 July 2012), median follow-up was 12 (0.1-21) mos. Myocardial ischemic events including myocardial infarction (MI), CAD, and angina were analyzed. Results: Myocardial ischemic serious adverse events (SAEs) (14 MI, 5 CAD, 2 angina) were reported in 21/449 pts (5%). 10 of these 21 pts had active cardiac disease at entry characterized by prior MI (4 pts), coronary revascularization (4 pts), or documented CAD; 5 had MI reported on study. 5/21 pts had other cardiac disease at entry (eg, valvular or pericardial disease); 5 had MI on study. Thus, 10/14 MIs occurred in 15 pts with known cardiac disease. 6/21 pts had no history of cardiac disease, but 5/6 had ≥1 CAD risk factor; 4 MIs occurred in these pts, all had risk factors. Of 21 pts with myocardial ischemic SAEs (13 CP-CML, 6 AP-CML, 2 BP-CML/Ph+ALL), mean age was 67 (42-87), and median duration since diagnosis was 12 (1-20) yrs. They were heavily pretreated (67% TKI use ≥5 yrs) with multiple CAD risk factors at entry (71% ischemia, 57% hypertension, 38% hypercholesterolemia, 33% diabetes [62% BMI &gt;25]); 81% had ≥2 risk factors, 95% had ≥1. Median time to onset and duration of SAE was 160 (9E402) and 7 (1E98) days, respectively. At analysis, 18/21 pts had the SAE reported as resolved (managed by dose interruption [50%] or no dose change [33%]), and 13/21 pts remained on study. Response rates for the subset of 21 pts with cardiac SAEs were major cytogenetic response 77% in CP-CML; major hematologic response 67% in AP-CML. Conclusions: In this uncontrolled study in heavily pretreated pts, these CV SAEs occurred mostly in pts with preexisting cardiac disease, and were primarily managed with satisfactory outcomes. Pts with preexisting CV co-morbidities should be monitored. Clinical trial information: NCT01207440.
Cost-Effectiveness of Itraconazole for the Prophylaxis of Invasive Fungal Infections for Neutropenic Patients; a Study for 3 European Countries.
Authors: Maarten J. Postma, Robin de Vries, Harriet Christopherson, Sarah Howells, Keith Tolley, Simon Daenen, Axel Glasmacher, Archibald Prentice, Angela Christie
Journal: Blood (2005)
Oral rinse test as a diagnostic aid for oral cancer.
Authors: Elizabeth Franzmann, Sally Bowden, Matthew Kim, Greg Ginn, Robert Bohannon
Journal: Journal of Clinical Oncology (2016)

e17509 Background: Oral cancer, defined as cancers of the oral cavity and oropharynx, is a deadly disease increasing in incidence. World-wide 5-year survival is only 50% due to delayed diagnosis whereas earlier detection and intervention yields survival rates as high as 80%-90%. Prior studies have shown that salivary CD44, a tumor-initiating marker, and total protein levels may identify individuals who are likely to have oral cancer, facilitating early detection. Here, we validate whether a combined CD44 and total protein laboratory test may aid in the diagnosis of oral cancer. Methods: Oral rinse specimens from 40 oral cancer cases and 46 controls were obtained from biorepositories. A CD44 sandwich ELISA and a BCA protein assay were performed on all samples. Prior work examining cancer cases at different stages established cutpoints for CD44 and total protein of at least 1.04 ng/ml and 0.25 mg/ml, respectively. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were determined. Data was obtained from 2 or more technicians for each sample. Agreement was measured using Cohen’s kappa coefficient (along with its 95% confidence interval) for each set of paired observers. Results: The sensitivity of the combined CD44 and total protein test was estimated to be 88% with a 2-sided 95% confidence interval of 77% to 98%. The specificity was estimated to be 74% with a 2-sided 95% confidence interval of 61% to 87%. Assuming disease prevalence of 9.27%, the NPV was 98.3% and PPV was 25.9%. The paired agreement ratings had kappa coefficients > 0.40, which is considered acceptable agreement. The lower limit of the 95% confidence interval was > 0.40 for the paired observations which indicates statistically acceptable agreement overall. Conclusions: This study validated previously set cutpoints for a combined CD44 and total protein laboratory assay. Results suggest a likelihood of oral cancer if CD44 levels are1.04 ng/mL or above and total protein is 0.25 mg/ml or above for cancer cases at different stages. Positive results from the combined CD44 and total protein laboratory test may be useful, along with other clinical evidence, to determine whether there is a presence of oral cancer.
Abstract LB-071: Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Authors: Piro Lito, Martha Solomon, Rasmus Hansen, Lian-Sheng Li, Neal Rosen
Journal: Cancer Research (2016)

Abstract Oncogenic mutations impair the GTPase activity of RAS, causing it to accumulate in the activated, GTP-bound conformation. Here we describe the mechanism of action of a novel compound that binds to KRASG12C to selectively inhibit proliferation and induce apoptosis in cancer cells with this mutation. The inhibitor interacted preferentially with the GDP-bound form of the protein, yet it reduced the level of GTP-bound KRASG12C. This suggested that GTPase activity is required for inhibition, which turned out to be the case. The inhibitor traps GDP-bound KRASG12C and prevents nucleotide exchange to the GTP-bound form. Genetic experiments revealed that mutants completely lacking GTPase activity, and those promoting exchange, reduced the potency of the drug. In contrast, mutants with diminished exchange were more susceptible to inhibition. In agreement with these findings, targeting receptor signaling potentiated KRASG12C inhibition, whereas its activation had the opposite effect. This mechanism reveals that KRASG12C undergoes nucleotide cycle in cancer cells and provides a basis for the development of effective combination therapies to treat KRASG12C-driven cancers. Citation Format: Piro Lito, Martha Solomon, Rasmus Hansen, Lian-Sheng Li, Neal Rosen. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. [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 LB-071.