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Table S2. Baseline Characteristics in the Tumor SPARC-Evaluable Population

Purpose: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint.Experimental Design: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted.Results: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy.Conclusions: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression. Clin Cancer Res; 21(21); 4811–8. ©2015 AACR.

Figure S1 . Representative SPARC staining. (A) Representative SPARC staining in stroma. (B) Representative SPARC staining in tumor epithelia.

supplemental figure legend

Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma. Clinical Trial Registration: NCT04002297 ( ClinicalTrials.gov )

AIM The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first-line nab-paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.83; P

This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC). Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m2 days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks. Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0–48.0). Median PFS was 8.1 weeks (95% CI 7.7–8.6) and 7.9 weeks (95% CI 7.6–8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0–32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule. In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported. NCT02103062.

Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer.Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities.Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS.This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.

Introduction: Transdisciplinary treatment is one of the pillars for reaching a reduction in mortality and complications in patients (p) with type 2 diabetes (T2D). Different indicators allow us to know the quality of care in outpatients. We do not know the different modalities of control and treatment according to the specialty of the attending physician in this group of patients. Objectives: Evaluating if control by a specialist in diabetes improves the quality indicators of the process of care in patients with T2D. Materials and Methods: During 3 months in the year 2019, a survey was made for patients with T2D in 44 cardiology practices in Argentina. The doctor in charge of T2D control was registered and the sample was divided into 2: group 1, where the T2D control was in charge of a specialist (an endocrinologist or a diabetologist), and group 2, where T2D control was in charge of a doctor not specialized in diabetes (clinical/general practitioner, cardiologist, or others). For this work, we will use 3 indicators of process quality: 1- ocular fundus, 2- Monofilament Test and 3- Microalbuminuria, all undertaken during the year previous to consultation.

Introducción: el tratamiento de las denominadas enfermedades crónicas no transmisibles dentro de las cuales se encuentra la diabetes mellitus tipo 2 (DM2), requiere por lo general de cambios en el estilo de vida y medidas farmacológicas. La falta de adherencia es un problema frecuente a nivel mundial, oscilando entre un 30 y 50% en las distintas series. Los pacientes que no son adherentes presentan una mayor incidencia de eventos cardiovasculares e incluso mortalidad que los pacientes adherentes, incrementando además los costos en los sistemas de salud.Objetivos: evaluar la adherencia al tratamiento farmacológico indicado en una población de pacientes con DM2 y alto riesgo cardiovascular. Evaluar si existen diferencias entre pacientes con adherencia y sin adherencia en cuanto a características clínicas y alcance de objetivos terapeúticos.Materiales y métodos: se realizó un estudio transversal, observacional y multicéntrico. Se registraron en forma consecutiva pacientes (p) con DM2 asistidos en el consultorio de cardiología de mayo a julio de 2019. Del total de p con DM2 ingresaron al estudio los primeros dos de cada día de atención. Se evaluó la adherencia mediante el test de Morisky-Green que consta de cuatro preguntas con dos opciones de respuesta posibles: SÍ/NO. Se definió adherencia a las cuatro preguntas respondidas en forma afirmativa. En caso de presentar 1 respuesta negativa se consideró no adherente a ese paciente. Se definieron objetivos terapéuticos: 1) presión Arterial

Introducción: los pacientes (p) con diabetes mellitus tipo 2 (DM2) tienen un riesgo aumentado de presentar complicaciones cardiovasculares (CV), siendo además la principal causa de muerte en esta población. Ciertas intervenciones a nivel de estilo de vida y tratamientos farmacológicos han demostrado reducción de eventos CV por lo que se encuentran dentro de la primera línea de recomendaciones en las principales guías de tratamiento.Objetivos: evaluar la adherencia a un estilo de vida saludable y la utilización de tratamientos farmacológicos con beneficio cardiovascular en una población de p con DM2. Observar si existen diferencias entre p con y sin enfermedad cardiovascular (ECV).Materiales y métodos: estudio transversal, observacional y multicéntrico. Se registraron en forma consecutiva p asistidos en consultorio de cardiología de mayo a julio de 2019. Del total de p evaluados con DM2 ingresaron al estudio los primeros dos de cada día de atención. Se definió estilo de vida saludable: 1) actividad física (actividad física >150 minutos/semana); 2) perímetro de cintura (PC) normal(5 porciones de frutas y verduras/día; 5) no tabaquismo y estrategias farmacológicas con beneficio CV. 1) uso de estatinas; 2) uso de iSGLT2 y ARGLP-1; 3) uso de ácido acetil salicílico (AAS) en prevención secundaria. Se utilizaron medias, medianas, desvíos estándar según correspondiera. Test de T para comparar medias y chi cuadrado o test de Fisher para las variables dicotómicas.

Purpose: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint. Experimental Design: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted. Results: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. Conclusions: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression. Clin Cancer Res; 21(21); 4811–8. ©2015 AACR.

Background. nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. Materials and Methods. Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. Results. Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. Conclusion. The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

Introduction The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P

Metastasis, also called secondary neoplastic disease, is a tumour newly formed in a site different from that of origin, as a consequence of cancer progression and dissemination largely through blood and lymphatic vessels. The ability to form metastases is the main property that distinguishes malignant from benign tumours. Treatments for metastatic cancer are similar in practice to those for primary tumours, but such treatments are mostly palliative; indeed, almost all deaths caused by solid tumours occur in the metastatic phase. Increasing evidence supports the concept that therapies for primary tumours are inadequate to treat metastasis and can even promote formation of metastases, while exerting local growth control. Furthermore, recurrent tumours, which are denoted by increased aggressiveness and therapy resistance in comparison with the primary tumour, have an increased metastatic potential. Genetic modifications occurring during tumour progression lead to substantial differences between the primary and metastatic tumours. This emphasises the importance of designing novel therapies for metastasis. In the last decade, a number of studies have contributed to the understanding of the genetic rearrangements underlying the conversion of cancer cells into the metastasis founder cells. The present article aims at reviewing recent advances in metastasis research and attempts to discuss the reasons for which the therapeutic strategies against primary tumours may not satisfactorily address their metastatic counterparts.

Background The phase 3 MPACT trial in patients with metastatic pancreatic cancer demonstrated superior efficacy of nab-paclitaxel (nab-P) + gemcitabine (Gem) vs Gem monotherapy for all endpoints examined including overall survival, the primary endpoint. In the MPACT trial, patients were treated until progressive disease (PD) or unacceptable toxicity. The current exploratory analysis investigated outcomes of patients from the MPACT trial who were treated until PD, in order to understand how to maximize treatment benefit from nab-P + Gem. Methods The trial design has been described in detail previously. Progressive disease was determined by the investigator on the basis of radiological imaging. Results Among patients who were treated until PD, overall survival was significantly longer for those who received nab-P + Gem vs Gem (median, 9.8 vs 7.5 months; P 50 % went on to receive a subsequent therapy. The safety profile for patients treated until PD was similar to what was reported in the overall MPACT trial. Conclusion The nab-P + Gem regimen is an active first-line treatment option; most patients were treated until PD, and this exposure was associated with improved efficacy outcomes. Prolonged first-line treatment exposure and ability to receive subsequent therapies likely contributed to the improved survival among these patients. Our data highlight the importance of managing adverse events and indicate that patients should be treated until PD when possible. Trial registration ClinicalTrials.gov NCT00844649 (MPACT trial); Registration date of this prospective phase III trial: February 13, 2009; current exploratory subanalysis was conducted retrospectively. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2798-8) contains supplementary material, which is available to authorized users.

Background: This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT). Methods: Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival. Results: The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status⩾70 and neutrophil-to-lymphocyte ratio⩽5 at the end of 1L treatment. Conclusions: These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.

The current management of the stenosis of the coronary arteries relies on the insertion of a metal mesh tube, namely stent, into the obstructed vessel. Coronary stents have been envisaged to reduce the restenosis after balloon angioplasty. Nonetheless, one of the major complications after successful revascularization is the late in-stent restenosis. Such lesion consists mainly of inflammatory reaction and neointima formation as a consequence of the mechanical injury of the vessel. In this review, we examine the molecular players underlying the in-stent restenosis, with particular reference to the role of the mTOR pathway and the intracellular receptor immunophilins. The 'limus' based drugs, which are developed or are under development in drug-eluting stent technology, will be also discussed.

The paper shows, with a practical application, how the hazard identification and evaluation phase of the Safety Management System (SMS) in a major risk installation (as defined by EC Directive CEE 96/82 (Seveso II) is the sizing criteria for the whole SMS, with its procedures. Probabilistic risk assessment techniques are applied to a foaming agent production plant. The links between quantitative risk analysis steps and results and SMS procedure are explicitly shown. In conclusion, it is shown how a correct and careful risk analysis is necessary to design and implement a SMS able to pursue the policy’s objectives allowing an effective revision of the policy itself.

The activity of transcription factors is often modulated by signal responsive protein kinases. Rel/NF-kappaB transcription factors are regulated by IkappaB inhibitors, the phosphorylation of which causes ubiquitination and degradation, resulting in nuclear translocation of NF-kappaB and activation of target genes. Here we report pulldown and immunoprecipitation experiments showing that a mammalian 66 kDa protein kinase binds murine c-Rel, both in vitro and in vivo. This kinase appears to have at least two binding sites on c-Rel, a proline-directed serine/ threonine substrate specificity similar to MAP kinases and to specifically phosphorylate the C-terminal domain of murine c-Rel at an ERK consensus site.

Polyacrylamide gel electrophoresis is a reliable and widely used technique for the separation, identification and characterization of proteins and protein mixtures. With the introduction of high resolution two-dimensional polyacrylamide gel electrophoresis in 1975 upward to 2000 individual polypeptides spots are easily separated on a single electrophoretic gel thereby necessitating the availability of highly sensitive protein detection methods. Although a plethora of protein-staining and -visualization protocols have been described utilizing both radioactive and non-radioactive reagents, many times the use of mono-dimensional detection procedures is insufficient to address the experimental questions asked. The present review highlights the utilization of combined protein-labeling and -staining methodologies in gel electrophoresis including selected applications in polyacrylamide gels and solid membrane matrixes.

333 Background: The impact of 2L Tx in MPC is not well described. The phase III MPACT trial (N = 861) demonstrated superior efficacy for nab-P + G vs G alone for 1L Tx of MPC. This post hoc analysis examined 2L Tx use in pts in MPACT. Methods: OS was estimated by the Kaplan-Meier method, using the most updated information from MPACT. Data were summarized by type of 2L Tx. Results: 347 pts received 2L Tx. Baseline characteristics (at start of 1L) of those pts were balanced between arms and representative of the ITT population: median age, 61-62 years; 12% had > 3 metastatic sites, and ≈ 30% had Karnofsky PS 70-80 in each arm. 26% and 14% of pts in the nab-P + G and G arms, respectively, discontinued 1L Tx for adverse events. OS in the 347 pts was significantly longer for nab-P + G vs G (Table). The median time from the end of 1L Tx to death for pts receiving no 2L Tx was 2.5 and 1.6 mo in the nab-P + G and G arms, respectively (HR, 0.67; P < 0.001), less than half for those who received any 2L Tx (5.3 and 4.5 mo). 78% and 76% of pts received a 5FU/capecitabine (cape)–containing regimen as 2L Tx after nab-P + G and G and achieved 13.5 and 9.5 mo of median OS, respectively. Conclusions: 2L Tx after nab-P + G or G alone in MPC is feasible and may potentially improve pt outcomes. Clinical trial information: NCT00844649. [Table: see text]

TPS474 Background: In pts with APC, the distal common bile duct is frequently obstructed, which can lead to elevated bilirubin levels. Normalization of bilirubin by stenting can take weeks, so treatment options that could be initiated in pts with elevated bilirubin are desirable. In a phase III trial of pts with metastatic PC, nab-P + Gem demonstrated superior efficacy vs Gem alone for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio, 0.72; P < 0.001). This study will be the first to analyze safety and PK profiles of nab-P + Gem in pts with APC and CH secondary to bile duct obstruction. Methods: Treatment-naive pts (≈ 12 to 40) with APC, Karnofsky performance status ≥ 70, and CH due to bile duct obstruction are eligible. Pts with a biliary stent must have 2 stable (within 20% of each other) bilirubin readings within 48 to 72 hours of each other taken between 5 and 21 days after stenting. Exclusion criteria consist of brain metastases, any other active malignancy, infection requiring systemic therapy, a history of myocardial infarction, or current use of medications known to be strong inducers of CYP3A4 and CYP2C8. Pts will enter 1 of 2 cohorts based on bilirubin level: cohort 1, > 1.5 to 3 × upper limit of normal (ULN), or cohort 2, > 3 to 5 × ULN. Cohort 2 will proceed only after review of safety and PK data from cohort 1 by a safety monitoring committee (SMC) and a decision has been made to proceed. The starting doses are nab-P 100 mg/m2 and Gem 800 mg/m2 for cohort 1 and nab-P 75 mg/m2 and Gem 600 mg/m2 for cohort 2. Treatment will be administered on days 1, 8, and 15 of each 28-day cycle. Doses in each cohort will be modified according to tolerability as determined by the SMC. The primary endpoints are determination of maximum tolerated dose for each cohort and PK profile. Secondary endpoints include investigator-assessed objective response rate, progression-free survival, OS, PK profile of Gem, and safety. The exploratory endpoint is change in serum CA19-9 level from baseline. Enrollment is ongoing. ClinicalTrials.gov: NCT02267707. Clinical trial information: NCT02267707.

The transportation of hazardous materials is a growing problem world6 wide due to the increasing volumes being transported. In fact, as a consequence of industrial development, huge quantities of hazardous materials are yearly produced, and obviously the production of them goes together with their transportation. Historical evidence has shown that accidents due to hazardous releases during transportation can lead to consequences as serious as those created by fixed plants, and therefore quantified risk analysis also has to be carried out for transportation networks. In this paper a flexible decision support system is proposed to quantify risk due to different transportation of dangerous substances – by road, rail, pipe14 line and inland waterways. First, a brief discussion is given on methodology adopted for evaluating risk. Then, the steps of the algorithm that has been implemented are sketched out in some detail.

Coronary artery disease consists of obstruction (stenosis) of the coronary arteries by the deposition of atherosclerotic plaques, resulting in an insufficient supply of oxygen to the heart muscle. Treatment options include the insertion of a stent - a metal mesh tube - into the obstructed vessel to keep the artery open, thus preventing acute occlusion and restenosis. The occlusion of vessels resulting from subacute stent thrombosis and late in-stent restenosis are potential complications after successful revascularization. However, the rate of stent thrombosis has been reduced dramatically by means of adequate antiplatelet therapy, and in-stent restenosis has been addressed successfully with drug-eluting stents. These drug-eluting stents are engineered to release bioactive agents into the affected blood vessels, plaques or tissues adjacent to the stent. Various antimitotic, anti-inflammatory, and anticoagulant immunosuppressive agents have been attached to stents, including sirolimus and tacrolimus. Future opportunities include the use of gene therapies released from gene-eluting stents. These advances highlight some of the opportunities for optimizing stent-based treatment for coronary artery disease.

1. BRL-3A cells posses a specific LDL receptor with an apparent mol. wt of 160,000 that binds, with saturation, both human and rat I-125-LDL. 2. Like human fibroblasts, BRL-3A cells also bind, internalize and degrade I-125-hLDL but to a lesser extent. 3. BRL-3A cells also bind the monoclonal antibody against rat liver LDL receptor P1B3. Moreover the LDL receptor activity increases when cells are preincubated with medium containing 5% of LPDS. 4. As with human (h) fibroblasts, treatment of BRL-3A cells with 10(-7) M insulin enhances binding (30%), internalization (18%) and degradation (20%) of I-125-hLDL.

Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up.Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided.The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P.001). Long-term (three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P.001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR5).These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.

439 Background: Weekly nab-P + Gem is a new option for first-line treatment (Tx) of mPC. In the MPACT trial, nab-P/Gem demonstrated superior overall survival (OS; primary endpoint) vs Gem alone as first-line Tx of mPC (Table). Here we report a subgroup analyses evaluating the efficacy and safety outcomes with nab-P + Gem vs Gem alone from the Canadian cohort of the MPACT trial. Methods: Previously untreated pts (N = 861) with mPC were randomized 1:1 (stratified by Karnofsky Performance Status [KPS], region, and the presence of liver metastases) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: 63 pts from Canada enrolled in the MPACT trial. Baseline pt characteristics were well balanced. Median age was 61 years and KPS was similar for both groups and comparable to the intent-to-treat (ITT) populations. Primary lesion in the pancreatic head was more common among pts in the nab-P + Gem vs Gem arm (55% vs 30%); use of biliary stent was similar (33% nab-P + Gem; 27% Gem). Median OS and progression-free survival (PFS) were longer with nab-P + Gem vs Gem (Table). Median Tx duration was 4.2 mo with nab-P + Gem vs 3.2 mo with Gem. Use of subsequent therapy was 30% in the nab-P + Gem arm vs 43% in the Gem arm. The median relative dose intensity for Gem was similar in each arm (81% nab-P + Gem vs 85% Gem). The most common grade ≥ 3 AEs for nab-P + Gem vs Gem were neutropenia (22% vs 10%), fatigue (34% vs 33%), and neuropathy (25% vs 0%). Conclusions: Canadian pts participating in MPACT were similar to the ITT population and nab-P + Gem was well tolerated and showed improved median OS, PFS, and ORR vs Gem alone, although not statistically significant (likely due to the small number of pts). Clinical trial information: NCT00844649. [Table: see text]

This paper presents the authors’ work and results in a time frame of about two years for the design of a Safety and Health Management System to be applied to hospitals and health care facilities and for the elaboration of specific guidelines for the management and safety staff of these structures.

Recent project engeneering have permitted to find technical solutions wich using in an original way consolidated building technologies and introducing others more innovative, have pointed out solutions to several problems. That solutions aim at solving a wide and expandable range of problems connected with bunkering existing buildings and newly constructed buildings. The parameters wich can be determined through the risk analysis are sufficient to define the requisites of resistant capacity wich the construction is to sustain and therefore to plan the necessary adjustment interventions. The article illustrates some project solutions which have been adopted and which in that case had to make the building resistant to an overpressure wave of 0, 1 bar and to a 180minute fire. Project solutions refer to: the system of fixed glass windows, the system used for blind or grid doors, both fire-proof and explosion-proof; how to determine the size and the characteristics of a 16cm thick concrete wall and the criteria used for steel reinforcement.

Aim: nab-P + Gem demonstrated superior efficacy over Gem alone in the MPACT trial of patients with metastatic PC. An updated analysis confirmed the superior OS (primary endpoint) of nab-P + Gem vs Gem alone (8.7 vs 6.6 mo; HR 0.72; P Methods: Previously untreated pts with metastatic PC were randomized 1:1—stratified by performance status, region (Australia [AU], Eastern Europe [EE], Western Europe [WE], or North America [NA]), and the presence of liver metastases—to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then d 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: The analysis included 861 pts. An updated OS analysis (data cutoff 9 May 2013) revealed that OS was longer for nab-P + Gem vs Gem alone in each region, although the difference was not statistically significant in all cases (table). Similar trends were observed for PFS and ORR. White blood cell growth factors were used at the following rates (nab-P + Gem vs Gem): NA, 28% vs 16%; EE, 16% vs 13%; AU, 16% vs 12%; WE, 37% vs 11%. The safety profile of each treatment arm was similar across the regions. Differences in the proportion of pts receiving post-progression therapies were noted for some regions (nab-P + Gem vs Gem): NA, 40% vs 42%; EE, 20% vs 31%; AU, 39% vs 41%; WE, 45% vs 55%. The rates of use were different across regions for 5-FU/capecitabine-based therapies (NA, 26% vs 31%; EE, 17% vs 26%; AU, 26% vs 22%; WE, 42% vs 47%) and FOLFIRINOX (NA, 6% vs 7%; EE, 0 vs 2%; AU, 2% vs 2%; WE, 3% vs 8%). nab-P + Gem Gem HR (95% CI) P Value n Median OS, mo n Median OS, mo North America 268 8.8 271 6.6 0.69 (0.57-0.82) Eastern Europe 64 7.7 62 5.9 0.84 (0.58-1.23) 0.372 Australia 61 9.4 59 6.7 0.59 (0.40-0.88) 0.010 Western Europe 38 10.7 38 6.9 0.82 (0.48-1.40) 0.471 Conclusions: nab-P + Gem was associated with improved survival compared with Gem alone in pts with metastatic PC, regardless of region. Variations in postprogression therapy use were noted across regions. Disclosure: R.K. Ramanathan: a consultant/advisor to Celgene, receives honoraria and research funding from them as well; D. Goldstein: is a consultant/advisor for Celgene and receives research funding from them; A. Romano: is a Celgene employee and owns stock; D. Penenberg: is a an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisor for Celgene and receives honoraria from them. He also receives research funding from TG Clinical Research. All other authors have declared no conflicts of interest.

Aim: Metastatic PC is associated with one of the worst prognoses among all the types of solid tumors. The presence of LMs and multiple sites of metastasis are factors associated with poorer prognosis. In the MPACT trial, nab-P + Gem demonstrated superior overall survival (OS, primary endpoint) vs Gem alone as first-line treatment for metastatic PC (Table). We report the efficacy and safety of nab-P + Gem vs Gem alone based on the presence of LMs and the number of metastatic sites. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 (stratified by performance status, region, and the presence of LMs) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem alone 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: Treatment arms were well balanced with respect to LMs and the number of metastatic sites: 84% of pts had LMs and 79% had 2 or 3 metastatic sites. In pts with LMs, median OS was significantly longer with nab-P + Gem vs Gem alone (Table). Similar trends were seen for PFS (5.4 vs 3.6 mo; HR 0.65; P Patient Population n Median OS, mo nab-P + Gem Gem nab-P + Gem Gem HR P Value ITT 431 430 8.5 6.7 0.72 Subgroups With LMs 365 360 8.3 5.9 0.69 No. of metastatic sites 1 33 21 13.5 9.0 0.41 0.021 2 202 206 8.3 7.1 0.75 0.015 3 136 140 8.0 5.9 0.79 0.093 > 3 60 63 8.6 5.0 0.50 0.001 Conclusions: In the MPACT trial, nab-P + Gem demonstrated longer OS vs Gem alone in the ITT population. The results for pts with LMs and in subgroups defined by the number of metastatic sites were consistent with the ITT findings. No new safety signals were observed. Disclosure: C. Weekes: has received honoraria for advisory board participation in the past 3 years from Celgene F. Parnis: servied on the advisory board for Specialised Therapeutics; A. Santoro: is a consultant/advisor to Celgene; A. Romano, D. McGovern and D. Penenberg: is an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisory for Celgene and receives honoraria from them. He also receives research funding from TGen Clinical Research Service. All other authors have declared no conflicts of interest.

4027^ Background: In the phase III MPACT trial, nab-P + Gem demonstrated superior OS vs Gem (primary endpoint; median 8.5 vs 6.7 months; HR 0.72; P< 0.001) with manageable toxicity in pts with meta...

178^ Background: In the phase III MPACT trial, nab-paclitaxel (nab-P) + gemcitabine (G) was tolerable and demonstrated superiority to G alone for all efficacy endpoints in pts with metastatic pancreatic cancer (MPC). nab-P + G vs G alone met the study’s primary endpoint by demonstrating a significant improvement in overall survival (OS; median 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.617 - 0.835; P < 0.001) and the secondary endpoints of progression-free survival (PFS; median 5.5 vs 3.7 months; HR 0.69; 95% CI, 0.581 - 0.821; P < 0.001) and overall response rate (ORR; 23% vs 7%; P < 0.001). The 1-year survival rates for nab-P + G vs G alone were 35% vs 22%. The OS data reported above were based on a database cutoff of September 17, 2012, at which time 80% of pts had died. Here, we report an updated OS analysis (post hoc) from MPACT. Methods: 861 pts with MPC and a Karnofsky performance status (KPS) ≥ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of a 28-day cycle (cycle ≥ 2). The data for this survival analysis were collected through April 1, 2013. Results: As of the updated data cutoff, 380/431 (88%) pts in the nab-P + G arm and 394/430 (92%) pts in the G alone arm had died. OS was superior for nab-P + G vs G alone in the intent-to-treat population, and the longer follow-up allowed an estimate of the 3-year survival rates (Table). The treatment effect was consistent across all pt subgroups examined. Conclusions: This updated survival analysis revealed a sustained difference in OS over time between the 2 arms. MPACT is the first phase III study in MPC to report 3-year survival rates. These data confirm and extend the previous report of the primary endpoint and support the superior efficacy of nab-P + G over G alone. These results may encourage efforts to build upon this well tolerated backbone to further extend survival. Clinical trial information: NCT00844649. [Table: see text]

The incorporation of [14C]acetate into cholesterol shows that FRTL-5 cells possess an active cholesterol biosynthetic pathway. When these cells were made quiescent, and synchronized by thyrotropin (TSH) starvation, in the presence of low serum (0.2%), addition of this hormone increased acetate conversion into cholesterol up to a maximum of 8-fold. Feedback inhibition of sterol synthesis by exogenous cholesterol occurs in FRTL-5 cells since, in the presence of higher serum concentration (5%), acetate conversion into cholesterol was significantly depressed. Even in high serum TSH increased sterol synthesis, albeit to a lesser extent. The time course of the TSH effect on cholesterol synthesis, strongly suggests that this process is necessary for quiescent FRTL-5 cells to enter the cell cycle. Thus, the rate of cholesterol synthesis was maximal 12-16 h after TSH challenge and declined thereafter, returning to levels slightly above the basal at 48 h. Thymidine incorporation into DNA, measured under identical conditions of TSH starvation/challenge, increased after 20 h, was maximal at 36 h, and returned to pre-TSH level at 70 h. The effect of TSH on cholesterol synthesis is not a general feature of lipid synthesis in FRTL-5 since [14C]acetate incorporation into triglycerides after TSH treatment has a different magnitude and time course. TSH increases cholesterol synthesis through the induction of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. This is due to an increase in the level of 3-hydroxy-3-methylglutaryl-CoA reductase messenger RNA up to 8-fold caused by a proportional increase in the rate of gene transcription, as assessed by nuclear "run on" experiments. The effect of TSH on cholesterol synthesis and reductase gene expression is likely to be mediated by cAMP since 8-bromo-cAMP mimicked the effect of the hormone. The data presented suggest that an active cholesterol biosynthetic pathway is required for DNA synthesis to occur.

The Saccharomyces cerevisiae Rad53 protein kinase is required for the execution of checkpoint arrest at multiple stages of the cell cycle. We found that Rad53 autophosphorylation activity depends on in trans phosphorylation mediated by Mec1 and does not require physical association with other proteins. Uncoupling in trans phosphorylation from autophosphorylation using a rad53 kinase‐defective mutant results in a dominant‐negative checkpoint defect. Activation of Rad53 in response to DNA damage in G 1 requires the Rad9, Mec3, Ddc1, Rad17 and Rad24 checkpoint factors, while this dependence is greatly reduced in S phase cells. Furthermore, during recovery from checkpoint activation, Rad53 activity decreases through a process that does not require protein synthesis. We also found that Rad53 modulates the lagging strand replication apparatus by controlling phosphorylation of the DNA polymerase α‐primase complex in response to intra‐S DNA damage.

This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA+ naïve T cells 3-fold while increasing the percentage HLA-DR+ activated T helper cells and percentage total CD45RO+ CD8+ memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p