tbuckley/cabot-search huggingface dataset:
Combined hedgehog and EGFR inhibition in pancreatic cell lines treated with gemcitabine.
Authors: I. Osuorji, A. Drelichman, C. Lobocki, J. Tilak
Journal: Journal of Clinical Oncology (2011)

e14544 Background: The Hedgehog pathway is critical for cell growth and differentiation. It is altered in pancreatic cancer cells leading to ligand overexpression, which impacts both cancer and stromal cells in an autocrine and paracrine fashion. Hedgehog signaling may also be involved in the self-renewal of cancer stem cells, which are resistant to chemotherapy. EGFR is overexpressed in many pancreatic cancers, and has become an important target in cancer therapy. The purpose of this study was to examine the growth inhibitory and apoptotic effects of Hedgehog inhibition in combination with EGFR inhibition and the chemotherapeutic agent gemcitabine in human pancreatic cancer cell lines. Methods: Four pancreatic cancer cell lines, BX-PC3, MIA-PACA2, Panc-1, and Capan-1, with varied sensitivities to gemcitabine were studied. Cyclopamine and erlotinib were used to inhibit Hedgehog and EGFR pathways, respectively. Growth inhibition was examined by the MTT colorimetric assay after 96 hrs of drug treatment, and the combination index (CI) method of median dose effect analysis was used to analyze the interaction between drugs. Apoptosis was evaluated by quantitating Caspase-3 activation, Gli 1 expression was analyzed by RT-PCR, and CD133, CD133+, CD44+, CD24+ and ESA expression was assessed by flow cytometry. Results: Synergistic or additive interactions were observed using the novel combination of cyclopamine and erlotinib in all cell lines studied. While gemcitabine plus erlotinib showed synergistic activity in the more highly proliferative MIA-PACA2 and Panc-1 cells lines, but not in the slower growing BxPC-3 and Capan-1 cell lines. Cyclopamine and gemcitabine were antagonistic in all cell lines, and the addition of erlotinib did not improve this finding. Gemcitabine alone induced apoptosis 9 to 36-fold, but no enhancement was seen using the drug combinations. The expression of CD133 decreased from 64% to 25.9% in Capan-1 using the combination of cyclopamine and erlotinib. Conclusions: Cyclopamine and erlotinib combination in pancreatic cancer cell lines with high proliferation rate were synergistic. Animal studies do demonstrate this is warranted.
Safety of intravenous amikacin in the treatment of pulmonary non-tuberculous mycobacterial disease
Authors: Claire Ellender, Geoffrey Eather, Anastasios Konstantinos
Journal: European Respiratory Journal (2013)

Intravenous amikacin is used in the treatment of pulmonary non-tuberculous mycobacterial (NTM) disease, but has been associated with nephrotoxicity, ototoxicity and vestibulotoxicity. This study examined the rates of successful treatment and adverse events in patients treated with amikacin for pulmonary NTM (2000-2011).   Method : A retrospective cohort review of 35 patients with pulmonary NTM ( M. intracellulare  57%,  M. abscessus  29%  M. avium  11%) was performed. Patient and disease characteristics, along with treatment outcomes were recorded. Successful treatment was defined as:  (i)  absence of adverse events;  (ii)  clinical improvement;  (iii)  culture conversion. Gender ratio was female:male = 2:1; average age 60 years. On average patients received amikacin 2.9g/week for 8weeks.   Results : No cases of long term toxicity occurred in any patients, however treatment was ceased prematurely in 5/35 (14%) due to abnormalities detected on audiometry or due to subjective temporary hearing loss. No cases of nephrotoxicity were found. Treatment success was achieved 15/35 (43%). Age, gender, fibrocavitary disease and duration of treatment was not predictive of treatment success. Of the potential predictors assessed only trough amikacin levels >2mg/L predicted potential toxicity (p=0.01).    Conclusion  : In well selected patients with careful monitoring intravenous amikacin can be used without long term toxicity to treat pulmonary NTM. Trough levels >2mg/L were associated with otoxtoxicity.
Functional Pathway Analysis Of JAK2 Mutated and Wild Type Myeloproliferative Neoplasms As a Tool For Patient Stratification and Therapeutic Selection
Authors: Matt Westfall, Rachael E. Hawtin, Diane Longo, Michelle Cholankeril, Reena K. Vora, Michelle Atallah, Alessandra Cesano, Steven L Allen, Scott Z. Fields
Journal: Blood (2013)
Abstract 14283: Time Dependant Changes in Systolic Blood Pressure after Renal Artery Stenting: Role of Stenosis Severity
Authors: Wencan He, Jie Chen, Dong Zhang, Taylor Dawson, Shifa Kanjwal, Steven Haller, Haifeng Yu, William Colyer, Mark Burket, Pamela Brewster, Joseph Shapiro, Christopher J Cooper
Journal: Circulation (2012)
Abstract 19236: Effect of Continuous Flow Left Ventricular Assist Device on Diastolic Pulmonary Artery Pressure-to-Pulmonary Capillary Wedge Pressure Gradient in End Stage Heart Failure Patients with Pulmonary Hypertension
Authors: Thenappan Thenappan, Rebecca Cogswell, Forum Kamdar, Christopher Holley, Laura Harvey, Monica Colvin-Adams, Peter Eckman, Sirtaz Adatya, Ranjit John, Ken Liao, Marc R Pritzker
Journal: Circulation (2014)

Background: Continuous flow left ventricular assist devices (LVAD) reduces transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) in end-stage HF patients with pulmonary venous hypertension (PVH). However, TPG and PVR are flow dependent and may not reflect intrinsic pulmonary vascular remodeling. Diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient (DPG) has been shown to more accurately reflect pulmonary vascular remodeling. Objective: We sought to evaluate the effect of LVAD on DPG in end-stage HF patients with PVH (mPAP &gt; 25 mm Hg and PCWP &gt; 15 mm Hg). Methods: We retrospectively reviewed clinical and hemodynamic data on 116 end-stage HF patients with PVH who underwent LVAD implantation and analyzed changes in DPG between pre- and first post-LVAD right heart catheterization (RHC). Results: The mean age was 55 ± 14 years and 78% were males. Of the 116 patients, 83 patients had pre-LVAD DPG 7 mm Hg (Combined post-and pre-capillary PVH). The median duration between the pre-and post-LVAD RHC was 147 (IQR: 106-302) days. Table below compares pre-and post-LVAD hemodynamics. In patients with combined post-and pre-capillary PVH, LVAD therapy significantly decreased DPG (9 ± 4 vs. 6 ± 6; P&lt;0.001). However, 42% of these patients did not lower DPG to &lt;7 mmHg with LVAD therapy (non-responders). On multivariate regression, higher pre-LVAD DPG was the only independent factor associated with non-responders. Pre-LVAD DPG &gt;8 mm Hg had 77% sensitivity and 88% specificity for identifying non-responders (AUC 0.82). Conclusion: Although DPG decreased after LVAD therapy, it remained significantly elevated (&gt;7mm Hg) in a subset of patients with combined post-and pre-capillary PVH. DPG &gt;8 mm Hg is significantly associated with non-response to LVAD therapy. Additional studies are warranted to assess the impact of these findings on outcomes.
Spliceosome Mutations Are Frequent In Patients With Myelodysplastic Syndromes Who Failed Hypomethylating Therapy: Possible Implications Of Spliceosome Inhibitors As Alternative Treatments
Authors: Valeria Visconte, Fabiola Traina, Ali Tabarroki, Edy Hasrouni, Jing Ai, Matt Kalaycio, Anjali S. Advani, Hien K. Duong, Yogen Saunthararajah, John Barnard, Mikkael A. Sekeres, Ramon V. Tiu
Journal: Blood (2013)
Phase II study of marqibo in adult patients with refractory or relapsed philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL).
Authors: S. M. O'Brien, W. Aulitzky, D. Ben Yehuda, J. Lister, G. J. Schiller, K. Seiter, S. E. Smith, W. Stock, J. A. Silverman, H. Kantarjian
Journal: Journal of Clinical Oncology (2010)

6507
Renal Vascular Function in Hypercholesterolemia Is Preserved by Chronic Antioxidant Supplementation
Authors: JOHN M. STULAK, AMIR LERMAN, MARTIN RODRIGUEZ PORCEL, JAMES A. CACCITOLO, J. CARLOS ROMERO, HARTZELL V. SCHAFF, CLAUDIO NAPOLI, LILACH O. LERMAN
Journal: Journal of the American Society of Nephrology (2001)

Hypercholesterolemia impairs systemic vascular reactivity in response to endothelium-dependent vasodilators, which may be mediated partly through increased formation of lipid peroxides. However, it is unclear whether these pathophysiological mechanisms play a role in renal vascular impairment in experimental hypercholesterolemia. Hence, pigs were studied after a 3-mo normal (n = 7) or high cholesterol (HC) (n = 7) diet, HC diet supplemented daily with antioxidant vitamins E (100 IU/kg) and C (1000 mg; HC+vitamins, n = 5), or normal diet supplemented with vitamins (N+vitamins, n = 5). Renal blood flow was measured with electron-beam computed tomography before and during infusion of acetylcholine (Ach). Endothelial function, endothelial and inducible nitric oxide synthase (NOS), and nitrotyrosine immunoreactivity were studied in renal arteries ex vivo. Despite similar cholesterol levels, LDL oxidizability (lag time, malondialdehyde, and relative electrophoretic mobility) was increased in pigs that were fed the HC diet but was significantly decreased in pigs that were fed the HC+vitamins diet. Renal blood flow response to Ach was blunted in pigs that were fed the HC diet but was preserved in pigs that were fed the HC+vitamins diet. Maximal relaxation to Ach was attenuated in pigs that were fed the HC diet compared with those that were fed the normal diet (51.5 +/- 6.4% versus 97.0 +/- 2.9%; P < 0.01) but was preserved in pigs that were fed the HC+vitamins diet (103.1 +/- 3.0%; P = 0.39) and N+vitamins diet (87.7 +/- 3.0%; P = 0.1), as were relaxation responses to calcium ionophore A23187. Vascular smooth-muscle relaxation to diethylamine was enhanced in endothelium-denuded HC vessel but was restored in pigs that were on the HC+vitamins regimen. In HC, immuno-reactivity of endothelial NOS was decreased, that of inducible NOS was increased, and both were preserved in pigs that were fed the HC+vitamins and N+vitamins diets, whereas nitrotyrosine was not detected. The present study demonstrates that antioxidant intervention in experimental HC reduces LDL oxidizability and preserves renal vascular responses to endothelium-dependent vasodilators. Therefore, this beneficial effect potentially can protect the kidney from hypercholesterolemia-induced damage.
Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Final safety and efficacy report.
Authors: M. G. Teneriello, A. N. Gordon, P. Lim, M. Janicek
Journal: Journal of Clinical Oncology (2010)

LBA5008 Background: Safety and efficacy of GC or TC induction followed by elective T consolidation (Tcon) were evaluated. Methods: Patients (pts) with stage IC-IV epithelial OC were randomized to GC: G 1,000 mg/m 2 on days 1, 8 plus C AUC=5 on day 1; or TC: T 175 mg/m 2 plus C AUC=6 on day 1 for a total of six 21-day cycles. Pts with a complete response (CR) could receive Tcon 135 mg/m 2 every 28 days for 12 cycles. Non-CR pts received single-agent crossover (CO) therapy (CO-T 175 mg/m 2 on day 1 or CO-G 1,000 mg/m 2 on days 1, 8) every 21 days until CR or progression of disease (PD). PD or death in 636 pts was required to compare GC and TC with 80% power for progression-free survival (PFS), the primary endpoint. Efficacy results were compared by log-rank test. Results: The trial was stopped in 8/2009 after an ad hoc futility analysis showed low probability of a positive PFS result. Of 919 pts enrolled, 88 pts were excluded (clerical errors); 831 pts were entered; 820 pts had induction; 352 pts had Tcon (GC-Tcon=169, TC-Tcon=183); 155 pts had crossover (CO-T=77, CO-G=78); 313 pts discontinued after induction (GC=165, TC=148). Baseline pt characteristics were balanced across arms. Overall response and adverse events for induction regimens were similar to interim results (Gordon, Clin Ovar Cancer, 2009). For GC and TC, median PFS were 20.0 and 22.2 months; median overall survival (OS) were 43.8 and 57.3 months, respectively. There was no significant difference in PFS (p=0.199) comparing GC and TC. Despite high censorship (GC: 52.8%, TC: 61.4%), OS was greater for TC (p=0.013) compared to GC, but there was no statistical difference after adjusting for significant covariates. For pts with CR, median OS was 65.6 months with Tcon versus 51.4 months without Tcon (p=0.041). Median OS was not reached for TC-Tcon and was 56.1 months for GC-Tcon (p=0.035). For pts not receiving Tcon or receiving either CO-T or CO-G crossover, there was no difference in OS. Conclusions: PFS was similar for GC and TC. Tcon improved OS. However, OS analysis was limited by study design and high censorship. GC does not offer an advantage over standard of care TC for first-line chemotherapy in advanced OC. No significant financial relationships to disclose.
Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials
Authors: J. Lutzky, J. Wolchok, O. Hamid, C. Lebbe, H. Pehamberger, G. Linette, V. de Pril, R. Ibrahim, A. Hoos, S. O'Day
Journal: Journal of Clinical Oncology (2009)

9034 Background: The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte antigen-4. The most common AEs associated with ipilimumab are irAEs, and both antitumor and irAE responses likely reflect its immune-mediated mechanism of action. In this report, a potential association between disease control (DC) or overall survival (OS) and irAEs in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in 3 Phase II clinical trials was explored. Methods: Across 3 Phase II studies (CA184008, 022, and 007), ipilimumab (10 mg/kg) was given every 3 weeks (Q3W) x 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (wk) 24 (maintenance). In study 022, pts were randomized to 0.3, 3, and 10 mg/kg groups, whereas study 008 was a single-arm trial of ipilimumab 10 mg/kg. In study 007, ipilimumab 10 mg/kg was administered either with placebo or daily prophylactic budesonide. Disease control (CR/PR/SD) was evaluated using modified World Health Organization (mWHO) and immune- related response criteria (Hodi FS, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3008). Association between DC and grade 0/1 vs. grade ≥2 irAEs was examined (studies 007, 008, and 022). Association between OS and irAEs which developed within 12 wks of ipilimumab treatment was also explored using landmark analyses from Day 81 (studies 008 and 022). Results: Across the 3 phase II studies, the rate of DC by mWHO in pts with grade 0/1 irAEs was 20–24% and in pts with grade ≥2 irAEs was 34–43%. The number of pts with DC was higher among those who experienced an irAE compared with those who did not, but DC was not statistically significantly associated with grade 0/1 vs grade ≥2 irAEs. For pts who lived up to Day 81 in studies 008 and 022, median OS (95% CI) from Day 81 was 14.8 mo (10.0–21.7) for any irAE and 8.21 mo (5.29–13.7) for no irAE within 12 weeks; median OS was 13.6 mo (5.78-NR) for any grade ≥2 irAE and 11.3 mo (7.95–15.8) for no grade ≥2 irAE within 12 weeks. Conclusions: DC and survival benefits with ipilimumab are observed among pts that develop an irAE and among pts that do not develop an irAE. Thus, pts who do not experience an irAE may still demonstrate clinical benefit with ipilimumab. [Table: see text]
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Authors: A S Morrison, J E Buring, W G Verhoek, K Aoki, I Leck, Y Ohno, K Obata
Journal: JNCI Journal of the National Cancer Institute (1982)

The relation of coffee drinking to the incidence rate of cancer of the lower urinary tract ("bladder cancer") was evaluated. Broadly based series of cases and series of controls drawn from the general population of each area were assembled and interviewed in Boston, Massachusetts (587 cases, 528 controls), Manchester, England (541 cases, 725 controls), and Nagoya, Japan (289 cases, 586 controls). Compared to drinkers of an average of less than 1 cup of coffee per day, those who drank more had a relative risk of bladder cancer estimated as 1.0 (0.8-1.2, 95% confidence interval). With adjustment for cigarette smoking habits, only small and irregular changes in risk were seen with increasing frequency of coffee consumption. Duration of coffee drinking showed little relation to risk of bladder cancer may be due to incomplete control of the effect of cigarette smoking. If there is a true association of coffee drinking and bladder cancer it is likely to be weak.
A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer
Authors: Cynthia X. Ma, Cesar Sanchez, Feng Gao, Robert Crowder, Michael Naughton, Timothy Pluard, Allison Creekmore, Zhanfang Guo, Jeremy Hoog, A. Craig Lockhart, Austin Doyle, Charles Erlichman, Matthew J. Ellis
Journal: Clinical Cancer Research (2016)

Abstract Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor–positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2− breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%–63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+HER2− breast cancer. Clin Cancer Res; 22(11); 2650–8. ©2016 AACR. See related commentary by Jansen et al., p. 2599
Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer
Authors: Antonio Calles, Xiaoyun Liao, Lynette M. Sholl, Scott J. Rodig, Gordon J. Freeman, Mohit Butaney, Christine Lydon, Suzanne E. Dahlberg, F.Stephen Hodi, Geoffrey R. Oxnard, David M. Jackman, Pasi A. Jänne
Journal: Journal of Thoracic Oncology (2015)

IntroductionClinical responses to immune checkpoint blockade by anti-programmed cell death protein-1 (PD-1)/PD-L1 monoclonal antibodies in non–small-cell lung cancer (NSCLC) are associated with PD-L1 expression and smoking status. We aimed to determine the expression profile of PD-1 and its ligands, PD-L1 and PD-L2, in both smokers and never smokers patients with KRAS-mutant NSCLC.MethodsWe retrospectively analyzed the clinical and molecular characteristics of 114 KRAS-mutant NSCLC patients (84 smokers and 30 never smokers) and their clinical tumor samples for the expression of PD-1, PD-L1, and PD-L2 by immunohistochemistry (IHC). We used murine monoclonal antibodies anti-PD-L1 (clone 9A11) and anti-PD-L2 (clone 9E5) to examine for tumor cell expression (0, negative; 1, weak; 2, moderate; 3, intense) and anti-PD-1 (clone EH33) for tumor-infiltrating lymphocytes.ResultsPD-L1 expression was detected in 27 of 114 patients (24%; 95% confidence interval [CI], 16–33%) and associated with smoking status (current smokers, 44%; former smokers, 20%; never smokers, 13%; p = 0.03). Higher intensity of PD-L1 expression (IHC-2+/IHC-3+) was more frequently observed in smokers and associated with more pack-years. PD-L2 was positive in 54 of 114 patients (47%; 95% CI, 38–57%) and not related to smoking status. PD-1-positive tumor-infiltrating lymphocytes were present in 77 of 114 tumor specimens tested (68%; 95% CI, 59–77%) including 21 of 27 samples with PD-L1 expression and 39 of 54 samples with PD-L2-positive expression. We found that PD-L1 expression fades with the age of the specimens used for analyses decreasing beyond 3 years (p = 0.016).ConclusionsThe expression of PD-1 and its ligands PD-L1 and PD-L2 is heterogeneous within KRAS-mutant NSCLC and suggests an inducible expression of PD-L1 by smoking.
NHS funding confused by lack of clarity Guidance issued on discretionary points Deaf patients do not get such good treatment Patients with hip fracture need better care
Authors: Linda Beecham
Journal: BMJ (2000)

The BMA says that lack of clarity is confusing the issue of NHS spending in England and calls for less “spinning” of funding announcements.

In a briefing paper from its health policy and economic research unit the association says that establishing a clear picture of the exact level of funds available to the NHS and the way that it is distributed is not straightforward. The paper examines several press notices announcing spending decisions. It concludes: “The three year settlement for the NHS established by the comprehensive spending review has provided some stability for the NHS. However, to some extent this has been undermined by the way that the funding allocations have been presented. Top slicing, by means of the modernisation fund and, in some instances, repeat announcements of the same new funding have made it difficult for those delivering services to understand what money is available and to plan accordingly.” The BMA says that in future the government should make clear what the source of funding is.

The paper will …