bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data
Authors: Davies Michael J. , Merton Katherine , Vijapurkar Ujjwala , Yee Jacqueline , Qiu Rong 
Published: March 2017

Abstract
Background
Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors.

Methods
Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports.

Results
At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (−0.95 and −1.07%) versus no history of CV disease (−0.71 and −0.90%), history of hypertension (−0.72 and −0.89%) versus no history of hypertension (−0.73 and −0.95%), baseline statin use (−0.77 and −0.99%) versus no statin use (−0.69 and −0.85%), and 0–1 CV risk factor (−0.72 and −0.87%) versus ≥2 CV risk factors (−0.74 and −1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.

Conclusions
The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors.
Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design
Authors: Rübsamen Nicole , Akmatov Manas K. , Castell Stefanie , Karch André , Mikolajczyk Rafael T. 
Published: March 2017

Abstract
Background
Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice).

Methods
We used data from a longitudinal panel, the Hygiene and Behaviour Infectious Diseases Study (HaBIDS), conducted in 2014/2015 in four regions in Lower Saxony, Germany. Individuals were recruited using address-based probability sampling. In two regions, individuals could choose between paper-and-pencil and online questionnaires. In the other two regions, individuals were offered online-only participation. We compared sociodemographic characteristics of respondents who filled in all panel questionnaires between the mixed-mode group (n = 1110) and the online-only group (n = 482). Using 134 items, we performed multinomial logistic regression to compare responses between survey designs in terms of type (missing, “do not know” or valid response) and ordinal regression to compare responses in terms of content. We applied the false discovery rates (FDR) to control for multiple testing and investigated effects of adjusting for sociodemographic characteristic. For validation of the differential response patterns between mixed-mode and online-only, we compared the response patterns between paper and online mode among the respondents in the mixed-mode group in one region (n = 786).

Results
Respondents in the online-only group were older than those in the mixed-mode group, but both groups did not differ regarding sex or education. Type of response did not differ between the online-only and the mixed-mode group. Survey design was associated with different content of response in 18 of the 134 investigated items; which decreased to 11 after adjusting for sociodemographic variables. In the validation within the mixed-mode, only two of those were among the 11 significantly different items. The probability of observing by chance the same two or more significant differences in this setting was 22%.

Conclusions
We found similar response patterns in both survey designs with only few items being answered differently, likely attributable to chance. Our study supports the equivalence of the compared survey designs and suggests that, in the studied setting, using online-only design does not cause strong distortion of the results.
Impact of sarcopenia on survival outcomes in patients (pts) with metastatic gastric cancer (mGC).
Authors: Sugiyama Keiji , Narita Yukiya , Mitani Seiichiro , Honda Kazunori , Masuishi Toshiki , Taniguchi Hiroya , Kadowaki Shigenori , Ura Takashi , Ando Masashi , Tajika Masahiro , Muro Kei 
Published: March 2017

141 Background: Sarcopenia is a poor prognostic factor in several cancers. This study aimed to assess the predictive value of sarcopenia on survival outcomes among pts with mGC. Methods: We retrospectively analyzed 170 consecutive pts with mGC starting first-line chemotherapy at the single institution during January 2013–December 2014. Inclusion criteria were as follows: treatment with fluoropyrimidine plus platinum-based regimen, ECOG PS 0–2, and adequate organ function. Skeletal muscle index (SMI) was calculated from cross-sectional area of muscle at L3 using CT scan divided by the square of the height. Baseline sarcopenia (S) was defined as 53.4 cm2/m2 for men and 38.5 cm2/m2for women. Muscle loss after chemotherapy (L) was defined as 10% ≤ reduction in SMI. Univariate and multivariate analyses were conducted to identify whether S and L were independent prognostic factors of time to treatment failure (TTF) and overall survival (OS). Multivariate analysis included variables with p values ≤ 0.1 in univariate analyses. Results: Ninety-seven pts met the inclusion criteria; 83 (86%) were classified with S, and 39 (31%) with L. PS (0 vs. 1 and 2) and ALP (ULN> vs. ULN≤) were significantly associated with L. Overall response rate for S, non-S, L, and non-L was 60%, 63%, 63%, and 61%, respectively. S was not associated with TTF or OS. However, L was significantly associated with a shorter TTF (4.7 vs. 7.3 m, HR=1.82; 95% CI: 1.16-2.85, p=0.009) and tended toward worse OS (14.2 vs. 19.7 m, HR=1.31; 95% CI: 0.78-2.20, p=0.29). Variables with p values ≤ 0.1 in univariate analyses for TTF were L, LDH (ULN≤), ALB (ULN>), and histology (poorly differentiated). Histology was only variables with p values ≤ 0.1 for OS (p=0.002). As per multivariate analyses, only L was a significant prognostic factor of TTF. Conclusions: L is an independent negative prognostic factor of TTF in pts with mGC. Intervention for muscle loss can be a therapeutic approach for mGC. [Table: see text]
Resminostat and sorafenib combination therapy for advanced hepatocellular carcinoma in patients previously untreated with systemic chemotherapy.
Authors: Kudo Masatoshi , Ryoo Baek-Yeol , Lim Ho Yeong , Kim Do Young , Okusaka Takuji , Ikeda Masafumi , Hidaka Hisashi , Yeon Jong-Eun , Mizukoshi Eishiro , Morimoto Manabu , Lee Myung Ah , Yasui Kohichiroh , Kawaguchi Yasunori , Heo Jeong , Morita Sojiro , Kim Tae-You , Furuse Junji , Katayama Kazuhiro , Aramaki Takeshi , Tak Won-Young 
Published: March 2017

252 Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count > = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788.
Efficacy and safety of ramucirumab (RAM) for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma across age subgroups in two global phase 3 trials.
Authors: Muro Kei , Cho Jae Yong , Bodoky Gyorgy , Goswami Chanchal , Chao Yee , dos Santos Lucas Vieira , Shimada Yasuhiro , Topuzov Eldar , Van Cutsem Eric , Tabernero Josep , Zalcberg John Raymond , Chau Ian , Cheng Rebecca , Hsu Yanzhi , Emig Michael , Orlando Mauro , Wilke Hansjochen , Fuchs Charles S. 
Published: March 2017

3 Background: REGARD and RAINBOW are two phase 3 studies which demonstrated significant survival benefits and manageable toxicity in patients with advanced gastric cancer (GC) randomized in the second-line setting to receive RAM or placebo. We examined outcomes by age (≤45, 45-70, ≥70, ≥75 years). Methods: Patients were randomized 2:1 to receive RAM 8 mg/kg + best-supportive care (BSC) or placebo (PL) + BSC (REGARD); or 1:1 RAM 8 mg/kg + paclitaxel (PTX) or PL + PTX (RAINBOW). Kaplan-Meier analysis and Cox proportional hazards regression were performed for overall survival (OS) and progression-free survival (PFS). Subpopulation treatment effect pattern plot (STEPP) assessed efficacy and the incidence of adverse events (AEs) across age subgroups. Results: Baseline characteristics were generally well balanced between arms amongst the age subgroups. Efficacy outcomes are summarized in the Table. STEPP analysis revealed no obvious patterns for differential risks in terms of efficacy and AEs (any grade or grade ≥3) according to age. Conclusions: Compared with PL, the efficacy of RAM was maintained in all age groups, with similar rates of toxicity. Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of RAM for the treatment of GC, irrespective of age. Clinical trial information: NCT00917384 and NCT01170663. [Table: see text]
Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study).
Authors: Le Dung T. , Ko Andrew H. , Wainberg Zev A. , Picozzi Vincent J. , Kindler Hedy L. , Wang-Gillam Andrea , Oberstein Paul Eliezer , Morse Michael , Zeh Herbert , Weekes Colin D. , Reid Tony R. , Murphy Aimee , McDougall Katherine , Whiting Chan C. , Nair Nitya , Enstrom Amanda , Ferber Sandy , Dubensky Thomas Walter , Brockstedt Dirk G. , Jaffee Elizabeth M. 
Published: March 2017

345 Background: GVAX is composed of irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and induce broad tumor antigen responses. Low-dose cyclophosphamide (CY) is administered with GVAX to inhibit regulatory T cells. CRS-207 is live, attenuated, double-deleted Listeria monocytogenes(LADD) engineered to express mesothelin. CRS-207 boosts T cell responses against mesothelin and stimulates innate and adaptive immunity. In an earlier Phase 2 study in patients with mPDA, CY/GVAX + CRS-207 resulted in a significant improvement in overall survival (OS) compared to CY/GVAX alone. Methods: Patients with previously-treated mPDA were randomized 1:1:1 to receive 2 doses of CY/GVAX + 4 doses of CRS-207 (Arm A), 6 doses of CRS-207 alone (Arm B), or physician’s choice of single-agent chemotherapy (Arm C). Two cohorts were included based on number of prior lines of therapy; the primary cohort (PC) represented those with ≥ 2 prior lines. The primary objective was to compare OS between Arms A and C in the PC. Additional objectives include OS analyses between all treatment arms, safety, tumor responses and immune analyses. Results: 303 patients were enrolled: 213 in the PC and 90 in an exploratory 2nd-line cohort (SC). Common AEs associated with CRS-207 treatment included transient fevers, chills, and nausea. High dropout rates were observed in Arm C prior to treatment (40% in PC, 63% in SC). Clinical trial information: NCT02004262 . Subset and immune analyses, as well as OS data from SC, will be presented at the meeting. Conclusions: The combination of CY/GVAX + CRS-207 did not show a survival benefit over chemotherapy in patients with previously-treated mPDA, although survival of patients receiving CRS-207 alone appeared similar to chemotherapy. The regimens were well tolerated with no new significant safety findings. The high dropout rate in the chemotherapy arm demonstrates a potential challenge for conventional controls in immunotherapy trials. [Table: see text]
Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer.
Authors: Bendell Johanna C. , Patel Manish R. , Brachmann Carrie Baker , Huang Xi , Maltzman Julia D. , Smith Victoria , Vosganian Gregory Sumpao , Wainberg Zev A. , Starodub Alexander 
Published: March 2017

363 Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present data from patients (pts) with advanced pancreatic adenocarcinoma enrolled in an ongoing multi-indication phase 1 study (NCT01803282) evaluating GS-5745. Methods: Following a monotherapy dose finding stage, pts with locally advanced or metastatic pancreatic cancer received gemcitabine (G) + nab-paclitaxel (Abraxane, A) and GS-5745 800 mg IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 36 pts were enrolled (1 continues to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include fatigue (75%), alopecia (55.6%), peripheral edema (55.6%) and nausea (50%). Grade ≥ 3 AEs observed in ≥ 10% of pts included neutropenia (25%), anemia (19.4%) and fatigue (13.9%). The median progression free survival (PFS) for all pts is 7.8 (90% confidence interval (CI) = [6.1, 11]) months (mos), median duration of response (DOR) is 5.8 mos and the objective response rate (ORR) is 44.4%. Of the 31 pts who were treatment naïve in the metastatic setting, median PFS is 9.2 (90% CI = [6.1, 11]) mos, median DOR 5.8 mos and the ORR 51.6%. Median baseline circulating MMP9 was 44.3 (range 12.4-549.6) ng/mL and 31 of 32 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: GS-5745+GA demonstrated numerically higher ORR and PFS compared to historical data without additional toxicity. Additionally, reductions in circulating MMP9 levels post treatment suggest target engagement by GS-5745 . These results suggest this combination may warrant additional study in first line metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01803282.
Randomized, open-label trial of gemcitabine/nab-paclitaxel (G/NP) ± pamrevlumab (P) as neoadjuvant chemotherapy in locally advanced, unresectable pancreatic cancer (LAPC).
Authors: Picozzi Vincent J. , Rocha Flavio G. , Helton Scott , Pishvaian Michael J. , Jackson Patrick G , Mody Kabir , Asbun Horacio , Carney Mairead , Etheridge Tina , Neff Thomas B , Porter Seth , Zhong Ming , Valone Frank , Kouchakji Elias , Imperial Joanne C. , Carrier Ewa 
Published: March 2017

365 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stroma and connective tissue growth factor (CTGF) overexpression. Although prolonged overall survival (OS) can be achieved through resection, only approximately 15% to 20% of patients are treated with surgery. Previously, pamrevlumab (P), a fully human monoclonal antibody blocking CTGF, was combined with gemcitabine/erlotinib (G/E) in a study of advanced PDAC. P plasma levels of > 150 μg/mL and low baseline CTGF levels resulted in prolonged OS. We hypothesize that neoadjuvant (NA) treatment of LAPC with P + G/nab-paclitaxel (NP) may alter LAPC’s stroma, increase R0 resectability, and improve OS similar to that of patients resectable at presentation. Methods: LAPC subjects, confirmed by NCCN criteria and staging laparoscopy, were randomized 2:1 to G/NP ± P for 6-cycle/24-week treatment. Safety and efficacy (resection rate, OS, progression-free survival, tumor response) were assessed. Resection was performed in subjects who met protocol-defined criteria with no contraindications. Results: As of 26 Sep 2016, 25 subjects were enrolled. Of 14 subjects in Arm A (G/NP + P), 7 completed, 2 discontinued. Of 11 subjects in Arm B (G/NP), 4 completed, 4 discontinued. 6 subjects (43%) in Arm A and 4 (36%) in Arm B experienced SAEs; no P-related SAEs were reported. Out of 7 eligible Arm A subjects, 3 were not resected. Successful resection was achieved in 4 Arm A subjects (3 R0, 1 R1) and 1 Arm B subject (R0) (Table). Conclusions: The combination of G/NP + P is feasible and well-tolerated with no incremental safety signals in this study. The addition of P suggests a trend toward increased resectability among LAPC subjects. Clinical trial information: NCT02210559. [Table: see text]
Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: Preliminary data from MyPathway.
Authors: Javle Milind M. , Hainsworth John D. , Swanton Charles , Burris Howard A. , Kurzrock Razelle , Sweeney Christopher , Meric-Bernstam Funda , Spigel David R. , Bose Ron , Guo Shuangli , Bernaards Coen , Beattie Mary Stanley , Scappaticci Frank A. , Hurwitz Herbert 
Published: March 2017

402 Background: Biliary cancers have a high mortality rate, with limited treatment options. While HER2 is overexpressed in 9-20% of biliary cancers, it has not been fully explored as a therapeutic target. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present preliminary data for patients with HER2-positive metastatic biliary cancer receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Patients in this subset analysis had refractory metastatic biliary cancer with HER2 amplification/overexpression or putative activating mutations by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 11 patients with HER2-positive biliary cancer (HER2-amplified/overexpressed, n = 8; HER2-mutated, n = 3 [D277Y, S310F, and A775-G776insYVMA]) have been enrolled. At a median follow-up of 4.2 (range 2.0–12.0) months, 4 patients had partial responses (PR) and 3 had stable disease (SD) for > 4 months (Table). Safety was consistent with the package inserts. Conclusions: Preliminary results indicate that pertuzumab + trastuzumab has activity in HER2 amplified/overexpressed/mutated metastatic biliary tumors, suggesting HER2 as a therapeutic target for these rare cancers. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Comparative effectiveness of initiating colorectal cancer (CRC) screening (Scr) at age 45.
Authors: Barzi Afsaneh , Siegel Rebecca , Fedewa Stacey A. , Lenz Heinz-Josef , Quinn David I. , Jemal Ahmedin , Sadeghi Sarmad 
Published: March 2017

531 Background: The incidence of CRC in age group 45-50 is rising based on SEER data. We investigated the outcomes of lowering Scr age to 45 from a societal perspective. Methods: A Markov model was built to represent the natural history and incidence of CRC in US general population (GP). Individual level simulation was used to compare 14 Scr strategies (ST). Effectiveness in life years (LY) & number of prevented (Prev) CRCs, and costs in US$ ($) inclusive of CRC Scr and treatment were measured. LY and $ were discounted at 3%. Incremental cost effectiveness ratios (ICERs) were calculated. Individuals in a cohort of GP aged 45-75 were followed for up to 35 years with Scr starting at age 50 (@50) or 45 (@45). Results: Colonoscopy (CS) @50 ranked 1 with the highest LY and lowest $ & ICER followed by CS @45 (ranked 2) with an ICER of $23074. All other STs had lower LY & higher $ and were dominated by CS. By starting Scr @45, the number of Prev CRC increased favoring Scr @45. LY changes were minimal but favored Scr @45. When CS was removed from Scr options, Fecal Occult Blood Test (FOBT) @45, CT Colonography (CT) every 10 years @50 and CT every 5 years @45 dominated remaining STs with ICERs of $0, $5585, and $31058, respectively. When CT and FOBT were removed from Scr options, FOBT+FS @45 and DNA @45 dominated remaining STs with ICERs of $0 and $650790, respectively. Results remained stable in sensitivity analyses. Conclusions: LY, Prev CRC improved as a result of Scr @45. When dominating STs were sequentially removed, STs beginning @ 45 remained cost effective with ICERs of <$50,000. The advantages of @45 are the result of earlier start and longer duration of Scr. Of note, DNA was not cost effective with ICER of >$650K after CS and CT were removed from calculations. [Table: see text]