tbuckley/cabot-search huggingface dataset:
The role of cognitive activity in cognition protection: from Bedside to Bench
Authors: Bin-Yin Li, Ying Wang, Hui-dong Tang, Sheng-Di Chen
Journal: Translational Neurodegeneration (2017)

Cognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most training trials proved that a well-organized task is clinically effective in cognition improvement. We will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well-designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families. The positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes.
Combination treatment with ipilimumab and immunoembolization in metastatic uveal melanoma: A feasibility study.
Authors: Marlana M. Orloff, Kevin Pan, Carin F Gonsalves, David J Eschelman, Michael J. Mastrangelo, Takami Sato
Journal: Journal of Clinical Oncology (2015)

e20015 Background: Despite promising results in metastatic cutaneous melanoma, ipilimumab has shown a rather disappointing response rate (5%) in metastatic uveal melanoma (MUM). To improve its efficacy, we combined ipilimumab with immunoembolization (IEMBO) for the management of MUM. The rationale for this combination includes (1) control of hepatic metastasis with liver-directed treatment, and (2) facilitation of local and systemic immune responses by ipilimumab and locally-infused cytokines. The purpose of this study is to evaluate the feasibility and tolerability of this combination treatment. Methods: Between 2012-2015, 18 MUM patients with < 20% hepatic involvement, received combination of ipilimumab with IEMBO as their first-line treatment. Ipilimumab was given at standard dosing and schedule (3mg/kg every 21 days, 4 infusions). IEMBO with 1,500 mcg of GM-CSF and 2 MIU of IL-2 was given every 4 weeks until maximum clinical benefit. Treatment response was evaluated using CT and MRI after every 2 treatments with IEMBO. A retrospective assessment of these 18 patients was conducted for feasibility and tolerability of this combination treatment. A chart review assessed adherence to schedule, toxicities, and response. Results: Of the 18 patients, 15/18 (83%) were maintained on the suggested schedule of IEMBO and ipilimumab. Three patients had a 14-28 day delay in IEMBO or ipilimumab due to immune-related side effects; however, all completed scheduled 4 treatments. Notable toxicities included diarrhea ≥ G2, 5/18 (28%); rash/pruritus ≥ G2, 5/18 (28%); and hypothyroidism ≥ G2, 4/18 (22%). Anticipated serious hepatic toxicity was not common; G1, 1/18 (5%) and G3, 1/18 (5%). No G4/G5 toxicity was seen. In 15 patients who completed the first two IEMBO treatments, 13 patients (87%) achieved stabilization of hepatic metastasis. Eight patients subsequently showed progression of disease with median time to treatment failure (TTF) of 185.5 days (55-395 days). Conclusions: Combination treatment with IEMBO and ipilimumab is a feasible and tolerable approach. Observed stabilization of metastatic disease with manageable toxicity warrants prospective evaluation of this combination treatment.
Evaluating surgery and first-line imatinib (ima) treatment patterns for patients with gastrointestinal stromal tumors (GIST).
Authors: Michael Eaddy, Brian S. Seal, Mark R. Green, Dana Stafkey-Mailey
Journal: Journal of Clinical Oncology (2013)

10590 Background: In 2002, ima was FDA approved for advanced metastatic GIST, followed in 2008 with an indication for adjuvant therapy. Real-world data on changing patterns of ima therapy, including adjuvant management, is sparse. This study evaluated changes in treatment patterns, resection rates, and corresponding costs of care among patients receiving first-line (1LT) ima for GIST over an 8-yr period, with a breakpoint around time of initial reporting of phase III adjuvant therapy data showing survival benefit. Methods: The study was conducted Jan 1, 2003–Dec 31, 2010 utilizing pharmacy/medical claims data from a large health plan. Patients with a GIST-related ICD9 code who also received ima were eligible, and excluded if they received any chemotherapy prior to date of first diagnosis or ima. All were designated into 1 of 3 cohorts: metastatic disease at first recognition (MP), non-metastatic non-surgical (NS) patients, and non-metastatic patients undergoing a GIST-related surgical procedure before ima (SP). Patients were followed from diagnosis to end of study period or loss of continuous eligibility. Results: Patient assignment across the disease extent and surgery/no surgery cohorts by the phase III reporting event is shown in the Table. A change in distribution of primary disease presentation and/or management across two time intervals is suggested by marked decrease in percentage of MP (54.9%→36.1%) and greater than doubling of SP patients presumably receiving adjuvant therapy following initial resection attempt. In the study population, 18.8% of patients who initiated 1LT with ima went on to 2LT (73.7% sunitinib); 5.9% receive 3LT (44.4% nilotinib and 38.9% sorafenib); &lt;1% receive 4LT (66.7% sorafenib). In general, 1LT was more costly than subsequent therapies. Across all lines of care, oral TKI drug acquisition cost was the dominant determinant of total cost of care. Conclusions: A change in distribution of primary disease presentation and/or management across the two time intervals is suggested. In each cohort, overall cost of care was largely a function of TKI acquisition cost. [Table: see text]
Meta-analysis of disease free survival (DFS) as a surrogate for overall survival (OS) in localized renal cell carcinoma (RCC).
Authors: Lauren Christine Harshman, Wanling Xie, Raphael Brandao Moreira, Ruiz Gustavo, Christopher Sweeney, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

459 Background: OS is a critical endpoint for adjuvant RCC trials testing the benefit of early systemic therapy to increase cure rates, but requires long duration and significant patient resources. We explored the potential use of DFS as a surrogate for OS when assessing the efficacy of adjuvant therapy in localized RCC. Methods: We performed a systematic literature review following the PRISMA statement. Inclusion criteria required randomized controlled trials (RCT) for adjuvant systemic therapy in localized RCC, which reported on both DFS and OS. DFS was defined from randomization or nephrectomy (R/N) to the first evidence of clinical recurrence (loco-regional or distant) or death from any cause. OS was defined from R/N to death from any cause. We extracted data on hazard ratio (HR) and 5-year event free rate from Kaplan Meier estimates. We performed a meta-analysis and correlated these estimates for OS and DFS, weighted by number of DFS events. R-square &gt;0.7 would indicate a strong correlation and potential surrogacy. Results: Of the more than 315 studies screened, 10 studies investigating various forms of cytokine and vaccine immunotherapy and angiogenesis inhibitors (e.g., sunitinib, sorafenib, thalidomide) between 1987 and 2016 were eligible for the analyses. The total enrolled patients were 5,497, with median follow-up ranging 3 to 10 years. Conclusions: Across trials of adjuvant systemic therapy for localized RCC, we observed a moderate correlation between 5 yr DFS and OS rate and between treatment effects (HRs) on these endpoints. Future meta-analyses of more mature trials in the era of modern adjuvant targeted therapy are needed to evaluate the surrogacy of intermediate endpoints. Further granularity may be achieved using individual patient data to assess different and earlier time points for surrogacy than are commonly reported. [Table: see text]
Fibroblast growth factor receptor 1 (<i>FGFR1</i>) gene copy number gain in adenocarcinoma and squamous cell carcinoma of the lung.
Authors: Ximing Tang, Yuwen Xue, Xinying Su, Nusrat Harun, Yiran Cai, Carmen Behrens, Vassiliki Papadimitrakopoulou, David Blowers, Cesar Moran, Neda Kalhor, David C. Rice, Garry Beran, J. Jack Lee, Elaine Kilgour, Ignacio Ivan Wistuba
Journal: Journal of Clinical Oncology (2013)

7552 Background: FGFR-1 is a novel target for therapy in non-small cell lung carcinoma (NSCLC). FGFR1 gene has been shown to be amplified in ~20% of squamous cell carcinomas (SCC) of the lung. The frequency of FGFR1 copy number gain (CNG) and gene amplification (GA) in lung adenocarcinoma (AC) is unknown, and the clinicopathological and molecular characteristics of the NSCLC tumors with FGFR1gene increase have not been fully described. Methods: We examined FGFR1 gene copy number (GCN) by fluorescent in-situ hybridization (FISH) and FGFR1 protein expression by immunohistochemistry in 475 surgically resected NSCLCs (162 SCCs, and 313 ACs) stages I-III in tissue microarrays. Three FGFR1 FISH categories were identified: a) no CNG; b) CNG, defined as ≥4 gene copies in ≥40% of cells; c) GA, defined as ratio of copies of FGFR1:CEP8 ≥2 or presence of tight gene clusters in ≥10% of cells. FGFR1 protein expression in the cytoplasm and membrane of tumor cells was quantified using H score. Results: FGFR1 GA was detected only in SCCs (14 cases, 9%). CNG was detected in both SCC (39 cases, 24%) and AC (80 cases, 26%). In AC, significantly higher frequency of CNG was detected in patients with smoking history (P=0.008) and in tumors with low differentiated histology (P=0.0005). No correlation was detected between FGFR1 CNG and mutation of KRAS and EGFR in AC. In SCC, tumors with FGFR1 CNG/GA had higher cytoplasmic FGFR1 protein expression than those with no copy changes (49±39 vs. 26±21, P&lt;0.001), and the protein expression correlated with GCN (R=0.55; P&lt;0.001). In multivariate analysis, patients with stage I/II SCCs having FGFR1 gene copy ≥6 or GA showed a significantly better overall survival (HR=0.26; 95% CI: 0.08-0.84, P=0.02) than patients with &lt;6 gene copy, after adjusting for smoking, gender and tumor size. An increase on FGFR1copy number was detected in 8/45 (18%) brain metastasis compared with primary tumors. Conclusions: In NSCLC, FGFR1 GA occurs only is a small subset of SCCs (9%), whereas CNG is a relatively frequent phenomenon in both SCC (24%) and ACs (25%). FGFR1 copies ≥6 or GA is associated with better outcome in patients with surgically resected stages I/II SCCs of the lung.
Comparison of neoadjuvant chemoradiation versus peri-operative chemotherapy for adenocarcinoma of the distal esophagus and gastroesophageal junction.
Authors: Matthew Bertke, Marie Kate Gurka, Vivek R. Sharma, Rebecca A. Redman, Charles Raben Scoggins, Robert C. G. Martin
Journal: Journal of Clinical Oncology (2017)

198 Background: Both neoadjuvant chemoradiation (NACRT) and peri-operative chemotherapy (PCTX) are viable treatment options when combined with surgical resection for locally advanced distal esophageal and gastroesophageal junction (GEJ) cancers. There is a paucity of data comparing these treatment regimens; therefore, the goal of this study was to compare the outcome of these two approaches at our institution. Methods: This is a retrospective review of a prospectively managed database, in which 66 patients with adenocarcinoma of the distal esophagus or GEJ who received either NACRT or PCTX from 2006 to 2015 were identified. Groups were balanced in regards to age, sex, subsite, T stage, and N stage. Patients treated with NACRT received either carboplatin/taxol or 5FU-based chemotherapy. PCTX regimens included ECF, EOX, DCF, or 5-FU based chemotherapy. Survival was calculated by the Kaplan–Meier method with a log‐rank test used for comparison between groups. Differences between subgroups were compared with Fisher’s Exact test. Results: A total of 47 patients were treated with NACRT and 19 with PCTX with a median follow-up of 14 months. All but three patients underwent definitive resection. No patients died within 90 days of surgery and the rate of operative complications was similar between the two groups (p = 0.77). The pathological complete response rate was 12.1% overall, with 14.9% in NACRT and 5.3% in PCTX. Median overall survival was 16.6 months and was not different between treatment subgroups (p = 0.77). Fewer treatment failures were seen with NACRT compared to PCTX (29.8% vs. 57.9%, p = 0.050), probably driven by improved local control in the NACRT arm (95.7% vs. 73.6%, p = 0.017). Distant failure was not significantly different between NACRT and PCTX (27.7% vs. 42.1%, p = 0.38). Conclusions: Pre-operative chemoradiation provided better overall disease control compared to peri-operative chemotherapy. However, improved survival could not be demonstrated, possibly due to the similar rates of distant failure and the study being underpowered due to small number of patients.
Metformin and biomarkers relevant to neoplasia in nondiabetic patients.
Authors: Michael N. Pollak, Marie-Jose Blouin, Carol-Ann Vasilevsky, Luca Cefis, Russell Frank, Yuzhen Tao, Zhen Li, Yinggang Tu, Ye Wang, Mahvash Zakikhani, Mark Trifiro, Matthias Schwab
Journal: Journal of Clinical Oncology (2013)

e14615 Background: Use of the anti-diabetic drug Metformin has been associated with reduced risk or improved prognosis of several cancers in both lab models and retrospective population studies of diabetics. Plausible mechanisms of action include (1) reduction in serum levels of insulin or inflammatory cytokines and (2) direct effects on target cells due to action of the drug as an inhibitor of mitochondrial respiration, including activation of AMPK. Methods: Non-diabetic subjects (n = 47) consented to bloodwork and sigmoid biopsy at screening colonoscopy, metformin administration (500 mg TID) for 10 weeks, and end-of-study sigmoid biopsy and bloodwork. Serum assays were performed on both fasting and post standard oral glucose load specimens. Metformin levels were measured by mass spectroscopy. Anti-phospho-histone-3 immunostaining was used to quantify proliferation. Results: Metformin reduced fasting levels of c-peptide, insulin, and IL-6 levels by &lt; 10%, a magnitude of change that laboratory studies suggest is unlikely to be biologically significant. However, postprandial insulin levels following metformin were reduced by 18 % relative to baseline postprandial levels, a finding of potential physiologic relevance. Serum metformin level showed considerable variation between subjects (1005 ± 769 ng/ml) and this variation was not correlated with effects of metformin on epithelial proliferation. Proliferation index fell from 5.9 to 3.3, (p&lt;0.03), a change greater than predicted by in vitro studies of direct action of metformin at the concentrations measured in serum. Conclusions: Metformin lowers insulin levels even in non-diabetic subjects, and post prandial insulin levels are more sensitive indicators of metformin action than fasting biomarkers. As high insulin level has been linked to increased cancer risk and/or worse prognosis (eg J Natl Cancer Inst. 2004;96:546), this systemic action suggests clinical applications. However, direct exposure of colonic epithelial cells to high luminal concentrations of metformin may also be relevant and is one of several factors that may explain the greater inhibitory effect of the drug on colonic epithelium proliferation than that previously reported for breast or prostate.
Analysis of predictive clinical markers of outcome in patients with metastatic clear-cell renal cell carcinoma (mRCC) treated with tyrosine-kinases inhibitors (TKI) in first line: A C Camargo Cancer Center experience.
Authors: Camila Nassif Martins Ferreira, José Augusto Rinck, Christiane Silveira Marinho Albuquerque, Tatiana Vieira Costa, Ana Claudia Machado Urvanegia, Marcelo Corassa, Maria Nirvana Cruz Formiga, Aldo Lourenço Abbade Dettino, Milena Shizue Tariki, Flavio Augusto Ismael Pinto, Thiago Bueno Oliveira, Marcela Marinelli Salvadori
Journal: Journal of Clinical Oncology (2017)

525 Background: TKI have improved the prognosis of patients with mRCC, but rarely lead to durable response. Predictive clinical biomarkers have been studied in the last few years, but most are still controversial. Objective: Identify the role of the clinical and laboratorial biomarkers of prognosis and outcome in mRCC. Methods: A retrospective study with mRCC treated with VEGFR-TKi in first line at A C Camargo Cancer Center (Jan-07 to Apr-16). Studied biomarkers: induced hypertension (HTN), acquiried hypothyroidism, proteinuria, and neutrophil to lymphocyte ratio (NLR). Data were analized in relation to progression free survival (PFS), overall survival (OS), and objetive response rate (ORR) stratified by each marker. Results: We included 94 patients (76.6% sunitinib, 21.3% pazopanib, 2.1% sorafenib). Overall, ORR to VEGFR-TKI was 41.1%; clinical benefit rate was 82.1% (43% Stable disease). Median PFS was 11.4 months (mo)(CI 95% 8.7-14.1) and median OS was 32.1 mo(CI 95% 23.4-40.8). HTN was numerically associated with longer PFS (20.1 vs. 8.2 mo) and OS (37.2 vs. 28.2 mo), but not statistically significant. Only high level TSH (&gt;10) was associated with significant longer PFS and OS, p=0.001 and p&lt;0.001, respectively. There was no association between proteinuria and better outcome. Finally, NLR≥3 pre-treatment was independent prognostic factor, and NLR≥3 post treatment (12 a week) predicted poor OS (9.6 vs 33.9 mo). A “NLR conversion” (before ≥3, turn to &lt;3) was associated with longer OS (28.2 vs. 11.6 mo, p=0.0012). Conclusions: TSH elevation is a good biomarker of better outcome in patients in treatment with TKI. NLR is an important inflamatory marker associated with shorter survival and NLR conversion can be an early biomarker of better outcome to mRCC patients in first line.
Phase Ib study of apalutamide (APA) with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Update on safety and efficacy.
Authors: Edwin M. Posadas, Kim N. Chi, Ronald De Wit, Maja J. De Jonge, Gerhardt Attard, Terence W. Friedlander, Margaret K. Yu, Peter Hellemans, Caly Chien, Charlene Connelly Abrams, Martha Gonzalez, Geralyn Carol Trudel, Vijay Chauhan, Juhui James Jiao, Fred Saad
Journal: Journal of Clinical Oncology (2017)

173 Background: APA and AA target the androgenreceptor (AR) axis via different mechanisms and may have complementary activity in mCRPC. APA is an advanced AR antagonist that targets the AR ligand-binding domain with high affinity (Clegg. Cancer Res. 2012). APA prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. This phase 1b study evaluates potential PK interactions between APA and AA + P. Here we report antitumor activity and safety of APA in combination with AA + P from 57 pts versus 29 pts presented at ASCO 2015 (NCT02123758). Methods: Pts with progressive mCRPC and ECOG PS ≤ 2 received AA (1000 mg/d) + P (5 mg BID) on Cycle 1 Day 1 (C1D1) with addition of APA (240 mg/d) on C1D8 in 28-day treatment (tmt) cycles. Efficacy assessment was based on RECIST 1.1 and PCWG2 criteria. Results: 57 pts started tmt on study; median tmt duration was 17 weeks. Median age was 70 years (range, 49-89) and median baseline PSA was 111 µg/L (range, 4-2597). Bone, nodal, and visceral disease were present in 50 (88%), 31 (54%), and 17 (30%) pts, respectively. 29 (51%), 29 (51%), and 23 (40%) pts were previously treated with a taxane, AA, or enzalutamide (ENZ), respectively. 47 pts discontinued tmt: disease progression (n = 39), consent withdrawal (n = 3), physician decision (n = 1), death (n = 1), and other (n = 3). In AA- and ENZ-naïve pts (n = 18), 67% had PSA decline ≥ 50%. In AA- or ENZ-treated pts (n = 39), 15% had PSA decline ≥ 50%. Most commonly reported ( &gt; 10% of pts) drug-related AEs: fatigue (42%), diarrhea (21%), vomiting (21%), nausea (19%), hypokalemia (19%), decreased appetite (16%), hot flush (12%), abdominal pain (12%), and dysgeusia (11%). Grade ≥ 3 drug-related AEs reported in &gt; 1 pt: fatigue (7%), hypokalemia (3.5%), hyponatremia (3.5%), and hypertension (3.5%). 1 pt discontinued study drug for grade 3 fatigue. Conclusions: Interim data indicate that 240 mg/d of APA with 1000 mg/d of AA + P has antitumor activity and an acceptable safety profile in mCRPC. Clinical trial information: NCT02123758. [Table: see text]
Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction
Authors: Brian P. Halliday, Ankur Gulati, Aamir Ali, Kaushik Guha, Simon Newsome, Monika Arzanauskaite, Vassilios S. Vassiliou, Amrit Lota, Cemil Izgi, Upasana Tayal, Zohya Khalique, Colin Stirrat, Dominique Auger, Nilesh Pareek, Tevfik F. Ismail, Stuart D. Rosen, Ali Vazir, Francisco Alpendurada, John Gregson, Michael P. Frenneaux, Martin R. Cowie, John G. F. Cleland, Stuart A. Cook, Dudley J. Pennell, Sanjay K. Prasad
Journal: Circulation (2017)

Background: Current guidelines only recommend the use of an implantable cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) &lt;35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70% to 80% of such patients have an LVEF &gt;35%. Patients with an LVEF &gt;35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD. Methods: We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF ≥40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation. Results: Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9–21.8; P &lt;0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR, 4.9; 95% CI, 1.8–13.5; P =0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6–266.6; P &lt;0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9–22.3; P &lt;0.0001), SCD (HR, 4.8; 95% CI, 1.7–13.8; P =0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8–271.4; P &lt;0.001). Estimated HRs for the primary end point for patients with an LGE extent of 0% to 2.5%, 2.5% to 5%, and &gt;5% compared with those without LGE were 10.6 (95% CI, 3.9–29.4), 4.9 (95% CI, 1.3–18.9), and 11.8 (95% CI, 4.3–32.3), respectively. Conclusions: Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation. Clinical Trial Registration: URL: http://clinicaltrials.gov . Unique identifier: NCT00930735.