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The hybrid algorithm was designed to assist with initial and subsequent crossing strategy selection in chronic total occlusion (CTO) percutaneous coronary interventions (PCIs). However, the success of the initially selected strategy has received limited study.We examined the impact of adherence to the hybrid algorithm recommendation for initial CTO crossing technique selection in 4178 CTO PCIs from a large multicenter registry.The initial crossing strategy was concordant with the hybrid algorithm recommendation in 1833 interventions (44%). Patients in the concordant group had a similar age to those in the discordant group but a lower mean J-CTO score (2.0 ± 1.4 vs 2.8 ± 1.1; P .01). The concordant group showed higher technical success with the first crossing strategy (68% vs 48%; P .01) and higher overall technical success (88% vs 83%; P .01) with no difference in the incidence of in-hospital major adverse events (1.8% vs 2.3%; P = .26). In multivariable analysis, after adjustment for age, prior myocardial infarction, prior PCI, prior coronary artery bypass grafting, J-CTO score, and scheduled CTO PCI, nonadherence to the hybrid algorithm was independently associated with lower technical success of the initial crossing strategy (odds ratio, 0.55; 95% confidence interval, 0.48-0.64; P .01).Adherence to the hybrid algorithm for initial crossing strategy selection is associated with higher CTO PCI success but similar in-hospital major adverse cardiac events.

Resumen Introduccion y objetivos El algoritmo hibrido se diseno para ayudar en la seleccion de las estrategias de cruce inicial y siguientes en la intervencion coronaria percutanea (ICP) para la oclusion cronica total (OTC); sin embargo, el exito de la estrategia de inicio seleccionada se ha estudiado poco hasta ahora. Metodos Se estudio el impacto de la adherencia a la recomendacion del algoritmo hibrido para la seleccion de la tecnica de cruce inicial en 4.178 ICP de OTC en un registro multicentrico de gran tamano. Resultados La estrategia de cruce inicial coincidio con la recomendacion del algoritmo hibrido en 1.833 casos (44%). Los pacientes en el grupo concordante tuvieron una edad similar, pero un indice J-OTC menor (2,0 ± 1,4 frente a 2,8 ± 1,1; p Conclusiones La adherencia al algoritmo hibrido para la seleccion de la estrategia inicial de cruce se asocio con mayor exito de la ICP para la OTC y similar tasa de eventos cardiovasculares hospitalarios graves.

Paxlovid, a drug combining nirmatrelvir and ritonavir, was designed for the treatment of COVID-19 and its rapid development has led to emergency use approval by the FDA to reduce the impact of COVID-19 infection on patients.In order to overcome potentially suboptimal therapeutic exposures, nirmatrelvir is dosed in combination with ritonavir to boost the pharmacokinetics of the active product.Here we consider examples of drugs co-administered with pharmacoenhancers.Pharmacoenhancers have been adopted for multiple purposes such as ensuring therapeutic exposure of the active product, reducing formation of toxic metabolites, changing the route of administration, and increasing the cost-effectiveness of a therapy.We weigh the benefits and risks of this approach, examining the impact of technology developments on drug design and how enhanced integration between cross-discipline teams can improve the outcome of drug discovery.

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I–II clinical trial in patients with advanced solid tumors (NCT03520075).

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed no difference in outcomes between medical therapy vs coronary revascularization in the management of patients with stable coronary artery disease. We aimed to determine the percentage of patients with at least moderate ischemia that would have been eligible for enrollment and evaluate the outcomes of those who would not. Consecutive patients who underwent cardiac single-photon emission computed tomography (SPECT) between April 2016 and September 2019 were identified and all-cause mortality was determined. There were a total of 1508 patients (mean age 67 ± 11.6 years, 69.5% males) with any perfusion defect on SPECT. Patients had a high prevalence of cardiac risk factors (73.4% with hypertension and 54.4% with diabetes mellitus.) Nearly half (709, 47%) had moderate-to-severe ischemia but over two-thirds (479/709, 66.3%) had at least one ISCHEMIA trial exclusion criteria. Patients meeting ISCHEMIA enrollment criteria had a significantly lower all-cause mortality than those who would have been excluded (3.91% vs. 11.3%, respectively, P

The articles in our Points to Remember column highlight important "need to know" facts about conditions that cardiovascular healthcare professionals may encounter. These may come from any medical specialty, such as nephrology or neurology. The article in this issue is provided by Swaminathan Perinkulam Sathyanarayanan, MD, Department of Internal Medicine, University of South Dakota, and Smitha Narayana Gowda, MD, and Alpesh Shah, MD, Houston Methodist DeBakey HeartVascular Center, Houston Methodist.

Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)–based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8–dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8–proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.

The prognostic impact of high-sensitivity C-reactive protein (CRP) levels in patients with left main coronary artery disease (LMCAD) treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) is unknown. We sought to determine the effect of elevated baseline CRP levels on the 3-year outcomes after LMCAD revascularization and to examine whether CRP influenced the relative outcomes of PCI versus CABG.In the EXCEL trial, patients with LMCAD and Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) scores ≤32 were randomized to PCI versus CABG. The primary composite outcome of death, myocardial infarction (MI), or stroke was analyzed according to baseline CRP levels.Among 999 patients with available CRP levels, median CRP was 3.10 mg/L (interquartile range 1.12-6.40 mg/L). The rate of the primary composite end point of death, MI, or stroke at 3 years steadily increased with greater baseline CRP levels. The adjusted relationship between the 3-year composite rate of death, MI, or stroke and baseline CRP modeled as a continuous log-transformed variable demonstrated steadily increasing event rates with greater CRP levels (adjusted hazard ratio, 1.26, 95% CI 1.10-1.44, P = .0008). Similarly, patients with CRP ≥10 mg/L had a 3-fold higher risk of the 3-year primary end point compared to patients with lower CRP levels (adjusted hazard ratio 2.92, 95% CI 1.88-4.54, P.0001). The association between an elevated CRP level and the adjusted 3-year risk of the primary composite end point did not differ according to revascularization strategy (PIn patients with LMCAD undergoing revascularization, elevated baseline CRP levels were strongly associated with subsequent death, MI, and stroke at 3 years, irrespective of the mode of revascularization. Further studies are warranted to determine whether anti-inflammatory therapies may improve the prognosis of high-risk patients with LMCAD following revascularization.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed no difference in outcomes between medical therapy vs coronary revascularization in the management of patients with stable coronary artery disease. We aimed to determine the percentage of patients with at least moderate ischemia that would have been eligible for enrollment and evaluate the outcomes of those who would not.Consecutive patients who underwent cardiac single-photon emission computed tomography (SPECT) between April 2016 and September 2019 were identified and all-cause mortality was determined.There were a total of 1508 patients (mean age 67 ± 11.6 years, 69.5% males) with any perfusion defect on SPECT. Patients had a high prevalence of cardiac risk factors (73.4% with hypertension and 54.4% with diabetes mellitus.) Nearly half (709, 47%) had moderate-to-severe ischemia but over two-thirds (479/709, 66.3%) had at least one ISCHEMIA trial exclusion criteria. Patients meeting ISCHEMIA enrollment criteria had a significantly lower all-cause mortality than those who would have been excluded (3.91% vs. 11.3%, respectively, P .001).Our results show that ISCHEMIA selected a relatively small subset of lower risk patients among the larger higher risk group of patients with moderate-to-severe ischemia typical to most cardiology centers.

Cancer cells frequently express elevated levels of Inhibitor of Apoptosis Proteins (IAPs): cIAPI, cIAP2 and XIAP. Elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in microsatellite stable (MSS) stage-III colorectal cancer (CRC) patients treated with adjuvant chemotherapy, suggesting their involvement in promoting resistance. Preclinical analysis of the IAP inhibitor tolinapant in CRC cell lines demonstrated robust on-target effects and caspase-8-dependent apoptosis that was inhibited by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinipant-induced apoptosis was augmented by standard-of-care chemotherapy (FOLFOX) in CRC disease models, due (at least in part) to FOLFOX-induced downregulation of Class-I histone deacetylases, leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, this effect could be phenocopied using a Class-I HDAC inhibitor. Further analyses revealed that caspase-8-knockout RIPK3-positive CRC models were sensitive to tolinostat-induced necroptosis, an effect that could be exploited with the FDA-approved caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX chemotherapy in poor prognosis MSS CRC with elevated cIAP1/2 expression.

Introduction: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has been advancing due to improvement of equipment, operator experience, and techniques. Methods: We examined contemporary outcomes of CTO PCI by analyzing the clinical, angiographic, and procedural characteristics of 7,031 CTO interventions performed in 6,984 patients at 35 participating centers between 2012 and 2020. Results: Mean age was 64.5 ± 10 years and 82% of the patients were men. The patients had high prevalence of comorbidities, such as diabetes (42%), prior coronary artery bypass graft surgery (29%), prior myocardial infarction (45%), and prior heart failure (29%). The most common CTO target vessel was the right coronary artery (53%), followed by the left anterior descending artery (26%), and left circumflex artery (20%). The mean J-CTO and PROGRESS scores were 2.41 ± 1.28 and 1.09 ± 1.01, respectively. The overall technical and procedural success rates were 85.9% and 83.8% and the rate of in-hospital major cardiac adverse events (MACE) was 2.06%. Technical success and procedural success rates were lower for higher values of J-CTO and PROGRESS scores, and MACE rate was higher ( Figure 1 ). The final successful crossing strategy was antegrade wire escalation in 53.7%, retrograde in 19.9%, and antegrade dissection reentry in 14.6%. The overall median air kerma radiation dose, contrast volume, procedure and fluoroscopy time were 2.30 (1.30, 3.90) Gray, 225 (160, 305) ml, 115 (75, 170) and 43 (26, 70) minutes, respectively. Conclusions: Using a combination of crossing strategies, high success and acceptable complication rates can be achieved in CTO PCI among various centers and patient populations.

Remote robotic-assisted endovascular interventions require real-time control of the robotic system to conduct precise device navigation. The delay (latency) between the input command and the catheter response can be affected by factors such as network speed and distance. This study evaluated the effect of network latency on robotic-assisted endovascular navigation in three vascular beds using in-vivo experimental model. Three operators performed femoral, carotid, and coronary endovascular robotic navigation blinded from the hybrid room with the prototype remote-enabled CorPath GRX system in a porcine model. Navigation was performed to different targets with randomly assigned network latencies from 0 to 1000 ms. Outcome measurements included navigation success, navigation time, perceived lag (1 = imperceptible, 5 = too long), and procedural impact scored by the operators (1 = no impact, 5 = unacceptable). Robotic-assisted remote endovascular navigation was successful in all 65 cases (9 femoral, 38 external carotid, 18 coronary). Guidewire times were not significantly different across the simulated network latency times. Compared to 0 ms added latency, both the procedural impact and perceived lag scores were significantly higher when the added latency was 400 ms or greater (

A significant application has been found in making the task of automation easier. Computer vision is a very powerful method for understanding the contents from the images. Weighing sheep for the analysis of their health and growth is a very arduous task, and traditional methods of weighing using a balance are very time-consuming. Estimating sheep weights using computer vision algorithms has already been tried, but these methods are not efficient enough. They also require some extra instruments set-up. We tried to utilize this powerful technology to make the difficult task of estimating sheep weights quick and accurate. We bring a novel approach to image segmentation in order to calculate the area of the sheep directly. The various other features are fed to a neural network-based regression model for achieving better results for the task of estimating sheep’s weight. The proposed approach has enabled us to minimize the complexities of carrying heavy equipment and errors through human involvement in measuring the weight of the sheep.

Long-term outcomes of patients with prior coronary artery bypass graft (CABG) surgery undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have received limited study.We compared the clinical and angiographic characteristics and procedural and follow-up outcomes of patients with and without prior CABG in a multicenter international registry.Of the 1572 patients included in this analysis, a total of 498 (32%) had prior CABG. Prior CABG patients had higher J-CTO scores (2.9 ± 1.1 vs 2.2 ± 1.3; P.001) and were less likely to undergo PCI of the left anterior descending artery (16.7% vs 29.6%; P.001). The retrograde technique was used more often (47.4% vs 28.2%; P.001) and was successful more often (27.4% vs 17.1%; P.001) in the prior CABG group vs the non-prior CABG group. Technical success was lower in prior CABG patients (82.6% vs 87.9%; P.01) with similar incidence of in-hospital major adverse cardiovascular events (3.4% vs 3%; P=.65), although in-hospital mortality was higher in the prior CABG group (2.4% vs 1.0%; P=.04). At 1-year follow-up, the composite endpoint of death, myocardial infarction, and revascularization was higher in prior CABG patients (21.79% vs 12.73%; hazard ratio, 1.76; 95% confidence interval, 1.27-2.45; P.001).Compared with non-prior CABG patients, prior CABG patients undergoing CTO-PCI had lower technical success and higher incidence of acute and follow-up adverse cardiovascular events.

The inhibition of aberrant MAPK pathway activity is a clinically validated approach which has resulted in the approval of agents targeting tumors driven by activating mutations in BRAF and KRAS. Although the overall response rate to MAPK-targeting agents is high, duration of response is often limited by the emergence of acquired resistance. In contrast, immune checkpoint inhibitors (ICI) such as the anti-PD1 therapy, pembrolizumab, have a lower response rate but induce more durable responses. It has been demonstrated that inhibition of aberrant MAPK pathway activity enhances immune activation. For example, preclinical studies show that treatment with the BRAFV600E inhibitor dabrafenib or the KRASG12C inhibitor sotorasib induces a pro-inflammatory tumor microenvironment (TME), which is associated with increased anti-tumor immunity. Further, studies using syngeneic, MAPK-activated in vivo models have demonstrated that the combination of MAPK-targeting agents and ICI results in synergistic inhibition of tumor growth. ASTX029 is a dual-mechanism ERK1/2 (ERK) inhibitor, inhibiting both the catalytic activity and phosphorylation of ERK, which is currently undergoing clinical development as part of a Phase 1/2 trial in advanced solid tumors (NCT03520075). ASTX029 has good oral bioavailability and shows potent inhibition of tumor growth in preclinical models bearing activating mutations in the MAPK pathway. We have previously investigated the immunomodulatory effects of ASTX029 using an in vivo syngeneic tumor model and observed that treatment with ASTX029 resulted in a pro-inflammatory TME, with increased interferon signaling consistent with published data describing the effects of treatment with dual-mechanism ERK inhibitors (Kidger et al., Mol Cancer Ther, 2020). We also observed an increased expression of antigen presentation genes. Using digital spatial profiling, we evaluated the expression of 31 proteins in immune infiltrates and observed a significant decrease in CD14 and a significant increase in MHC class II in ASTX029-treated tumors compared to untreated tumors. We therefore investigated the immunomodulatory effects of ASTX029 using primary human monocytes under conditions that induce macrophage differentiation and polarisation. Treatment with ASTX029 induced a decrease in CD14 and an increase in MHC class II cell surface expression, consistent with our previous in vivo mouse model data. In addition, we observed changes in cell surface expression of phenotypic markers, such as CD206, following treatment with ASTX029. These data support our previous observations and demonstrate that ERK inhibition by ASTX029 leads to phenotypic changes during monocyte to macrophage differentiation. Our data provide a strong rationale for the combination of ASTX029 with agents which aim to modulate the myeloid compartment or response to myeloid signaling. Citation Format: Christopher Hindley, Andrea Biondo, Kim-Hien Dao, Lynsey Fazal, Alpesh Shah, Martin Sims, Nicola Wilsher, Harold Keer, John Lyons. Treatment with the dual-mechanism ERK inhibitor, ASTX029, alters myeloid cell differentiation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P112.

Objectives The aim of this study was to assess the safety and effectiveness of the COBRA Polyzene-F NanoCoated Coronary Stent System (CeloNova Biosciences, San Antonio, Texas) for the treatment of de novo coronary artery lesions. Background Polyzene-F–coated coronary stents have shown reduced thrombogenicity and inflammation in preclinical studies. Methods Patients with de novo coronary artery lesions meeting eligibility criteria were enrolled in a nonrandomized, prospective clinical trial. The primary endpoint was target vessel failure (TVF) (defined as a composite of cardiac death, myocardial infarction, or clinically driven target vessel revascularization) at 9 months. A pre-specified subset was planned for routine repeat angiographic follow-up at 9 months. The powered secondary endpoint was mean late lumen loss (LL). The comparator was a performance goal derived from meta-analysis of historical bare-metal stent trials of 19.62% for TVF and 1.1 mm for LL. Other secondary endpoints were clinically driven target lesion revascularization and definite or probable stent thrombosis. Results Of 296 enrolled patients, 287 (97%) completed primary endpoint analysis; 130 were planned for angiographic follow-up and 115 (88%) completed. At 9 months, TVF had occurred in 33 patients (11.5%; upper 95% confidence boundary: 15.07%), including 1 (0.3%) cardiac death, 20 (7.0%) myocardial infarctions (17 periprocedural), and 17 (5.9%) target vessel revascularizations. LL was 0.84 ± 0.48 mm (upper 95% confidence boundary: 0.92). Target lesion revascularization occurred in 13 patients (4.6%). There were no stent thrombosis events. Conclusions The COBRA Polyzene-F stent met performance goals for TVF and LL at 9 months. There was an excellent safety profile, with infrequent late myocardial infarction and no stent thrombosis.

Oncogenic mutations in genes such as the RAS family (KRAS, NRAS or HRAS) or receptor tyrosine kinases (RTKs) drive tumor growth through aberrant activation of the mitogen activated protein kinase (MAPK) signaling pathway. Acute myeloid leukemia (AML) patients frequently exhibit activating mutations in MAPK pathway members, such as NRAS and KRAS, suggesting that these malignancies may be driven by aberrant activation of the MAPK pathway. Targeting of the MAPK pathway has been clinically validated in solid tumors, with agents targeting BRAF and MEK approved for the treatment of BRAF-mutant melanoma. However, there is currently no approved therapy directly targeting activated RAS family members and resistance to MAPK pathway inhibitors is frequently associated with reactivation of MAPK signaling. ERK1/2 (ERK) is a downstream node in the MAPK pathway and therefore represents an attractive therapeutic target for inhibition of MAPK signaling in these settings. We have recently described in vivo anti-tumor activity in MAPK-activated solid tumor models following treatment with ASTX029, a highly potent ERK inhibitor developed using fragment-based drug design. ASTX029 has a distinctive ERK binding mode which confers dual mechanism inhibition of ERK, inhibiting both the catalytic activity of ERK and its phosphorylation by MEK. Here, we demonstrate that ASTX029 is also active in AML models and potently inhibits in vitro and in vivo MAPK signaling and growth in these models. Using a panel of 15 AML cell lines, we investigated sensitivity to ASTX029 in vitro. We observed that 8 cell lines bearing mutations leading to increased MAPK pathway signaling were sensitive to treatment with ASTX029 with an average IC50 value of 47 nM, in contrast to an average IC50 value of 1800 nM for cell lines without activating mutations. The phosphorylation of RSK, a direct substrate of ERK, was suppressed for up to 24 h following treatment with ASTX029 in vitro. We have previously demonstrated good oral bioavailability for ASTX029 and once daily dosing resulted in significant tumor growth inhibition in AML cell line xenograft models. To confirm target engagement in vivo, we examined MAPK signaling in xenograft tissue and observed inhibition of the phosphorylation of RSK and of ERK itself, consistent with the dual mechanism of action proposed for ASTX029. In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations. Disclosures Hindley: Astex Pharmaceuticals: Current Employment. Fazal:Astex Pharmaceuticals: Current Employment. Munck:Astex Pharmaceuticals: Current Employment. Martins:Astex Pharmaceuticals: Current Employment. Shah:Astex Pharmaceuticals: Current Employment. Wilsher:Astex Pharmaceuticals: Current Employment. Wallis:Astex Pharmaceuticals: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Lyons:Astex Pharmaceuticals: Current Employment.

Objectives We sought to describe contemporary guidewire and microcatheter utilization for antegrade wire escalation (AWE) during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Background Equipment utilization for AWE has been variable and evolving over time. Methods We examined device utilization during 694 AWE attempts in 679 patients performed at 15 experienced US centers between May 2012 and April 2015. Results Mean age was 65.6 ± 9.7 years, and 85% of the patients were men. Successful wiring occurred in 436 AWE attempts (63%). Final technical and procedural success was 91% and 89%, respectively. The mean number of guidewire types used for AWE was 2.2 ± 1.4. The most frequently used guidewire types were the Pilot 200 (Abbott Vascular, 56% of AWE procedures), Fielder XT (Asahi Intecc, 45%), and the Confianza Pro 12 (Asahi Intecc, 28%). The same guidewires were the ones that most commonly crossed the occlusion: Pilot 200 (36% of successful AWE crossings), Fielder XT (20%), and Confianza Pro 12 (11%). A microcatheter or over-the-wire balloon was used for 81% of AWE attempts; the Corsair microcatheter (Asahi Intecc) was the most commonly used (44%). No significant association was found between guidewire type and incidence of major adverse cardiac events (MACE). Conclusions Our contemporary, multicenter CTO PCI registry demonstrates that the most commonly used wires for AWE are polymer-jacketed guidewires. "Stiff" and polymer-jacketed guidewires appear to provide high crossing rates without an increase in MACE or perforation, and may thus be considered for upfront use. © 2016 Wiley Periodicals, Inc.

The hybrid algorithm was designed to assist with crossing strategy selection in chronic total occlusion (CTO) percutaneous coronary interventions (PCI) (Figure), however the success of the initially selected strategy has received limited study. We examined the impact of hybrid algorithm

Primary care providers are often the first line of defense against disease. Given the increasing incidence and prevalence of cardiovascular disease (CVD), it is essential that non-cardiologists be aware of updates in clinical guidelines for early identification, management and treatment of CVD.

Percutaneous coronary intervention (PCI) of chronic coronary total occlusion is the latest frontier in percutaneous intervention. There are vast improvements in the initial success and safety of the procedure as well as a better understanding of appropriateness and benefits. Advances in technology and skill allow for increased utilization of PCI in cases of chronic coronary total occlusion, with benefits regarding symptoms and quality of life. Percutaneous coronary intervention for chronic coronary total occlusion can correct ischemia and achieve complete revascularization while avoiding traditional coronary bypass grafting, although survival benefits remain unclear.

Revascularization of coronary chronic total occlusion (CTO) are challenging as often the vessel course is unclear. Coronary computed tomography angiography (CTA) may overcome this shortcoming. A 70 year old man with a RCA CTO (~100mm) (figure 1(a)) and an occluded bypass graft to the RCA presented

Non-small cell lung cancer (NSCLC) molecular profiling is a key factor in treatment selection. Although, patients with NSCLC tumors harboring EGFR or ALK mutations can benefit from personalized therapies, there are currently no approved targeted therapies for KRAS mutant tumors which occur in 25% to 30% of patients with NSCLC. The constitutive activation of the MAPK pathway in these tumors provides a rationale for targeting effectors such as MEK1/2 (MEK) or ERK1/2 (ERK). Inhibitor of MEK kinase have been tested clinically in KRAS-mutant NSCLC but results have been disappointing, possibly because compensatory signaling such as the reactivation of ERK is triggered following the inhibition of MEK, leading to cancer cell survival. Therefore, targeting ERK directly represents an attractive therapeutic approach. As previously described, we have developed a novel, potent and selective ERK inhibitor identified by fragment-based drug discovery which has potent activity in vitro and in vivo. Here, we demonstrate the activity of this lead compound in KRAS-mutant NSCLC models. Our novel ERK inhibitor was tested in a panel of 440 human cancer cell lines of which the KRAS NSCLC population was identified as particularly sensitive. 62% of the KRAS-mutant NSCLC cell lines tested, exhibited antiproliferative IC50s ranging from 1 nM to 500 nM. This lead compound also inhibited ERK downstream signaling in KRAS NSCLC models both in vitro and in vivo. Indeed, the phosphorylation level of the ERK substrate, RSK, was strongly decreased in HCC-44 and Calu-6 xenograft tumors 2h after oral administration of the lead compound at 50 mg/kg. Levels of pRSK remained below those of untreated tumors for up to 16h in HCC-44 tumors and 24h in Calu-6 tumors. We also confirmed that, the ERK inhibitor conferred a decrease in phosphorylation of ERK itself in both models. The inhibition of ERK signaling corresponded to significant anti-tumor activity in these models with a daily oral administration of 50 mg/kg compound leading to significant tumor regression in subcutaneous models of HCC-44 (18.3% T/C) and Calu-6 (8.9% T/C) xenograft tumors. This work demonstrates the in vitro and in vivo activity of a novel, highly potent, selective ERK inhibitor in models of KRAS-mutant NSCLC. These data support the further optimisation of this series of compounds for clinical development. Citation Format: Aurelie Courtin, Luke Bevan, Tom Heightman, Birikiti Kidane, Justyna Kucia-Tran, John Lyons, Sandra Muench, Alpesh Shah, Lukas Stanczuk, Neil Thompson, Nicola Wallis, Nicola Wilsher, Joanne Munck. A novel ERK1/2 inhibitor has potent activity in KRAS-mutant non-small cell lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5781.

Primary care providers are often the first line of defense against disease. Given the increasing incidence and prevalence of cardiovascular diseases (CVD), it is essential that this cadre of non-cardiologists be aware of changes in clinical guidelines for early identification, management and

Severe peripheral arterial disease can limit options for coronary revascularization when surgical bypass is not an option and medical therapy fails to control angina. A 58-year-old woman with history of severe peripheral arterial disease (PAD), coronary artery disease with unstable angina and

The MAPK pathway is commonly hyper-activated in human cancers due to the occurrence of oncogenic mutations in RAF, RAS and the upregulation of RTKs. The therapeutic potential of MAPK pathway inhibition has been demonstrated by the clinical efficacy of RAF and MEK1/2 (MEK) inhibitors in the treatment of BRAF-mutant melanoma. However, response to such agents is short-lived due to the onset of resistance mechanisms, which in the majority of cases result in the reactivation of ERK1/2 (ERK) signalling. Therefore, the direct targeting of ERK is an attractive therapeutic approach to overcoming the limitations of RAF or MEK inhibitors. Here, we describe a novel, potent, and selective ERK inhibitor, which inhibits both ERK catalytic activity and also the phosphorylation of ERK by MEK. Using fragment-based drug discovery we have developed a selective ERK inhibitor, which inhibits in vitro ERK catalytic activity with a low nM IC50 value. This lead compound has strong antiproliferative effects in a wide range of MAPK-activated cell lines, including the BRAF-mutant cell lines A375 (melanoma) and Colo205 (colorectal), the KRAS-mutant cell lines HCT116 (colorectal), Calu6 (lung) and Panc05.04 (pancreatic), and the NRAS-mutant cell line Ma-mel-27 (melanoma). The lead compound potently inhibits ERK cell signalling. The potent (nM) inhibition of RSK phosphorylation (a direct ERK substrate) was confirmed in A375 (BRAF-mutant melanoma) cells, using MSD analysis. In addition to inhibiting downstream ERK signalling, we demonstrated by ELISA and Western blotting that the lead compound confers a decrease in phospho-ERK levels in both BRAF-mutant and KRAS-mutant cell lines. We investigated the biochemical mechanism of the modulation of ERK phosphorylation in vitro and demonstrated that the compound prevents the phosphorylation of ERK by MEK (at key ERK activation loop residues, T202/Y204), without directly inhibiting MEK activity. The compound was profiled in a range of subcutaneous xenograft models including A375 (BRAF-mutant melanoma) and Calu-6 (KRAS-mutant lung). Once-daily oral dosing of the lead compound conferred significant antitumor activity in a range of in vivo efficacy studies. The compound potently inhibited the phosphorylation of downstream ERK substrates (including RSK) in tumor xenograft tissue. There was a clear relationship between in vivo compound concentrations and the modulation of ERK substrate phosphorylation. Furthermore, as was demonstrated in vitro, we confirmed that in addition to inhibiting ERK catalytic activity the compound potently inhibited the phosphorylation of ERK itself, in both KRAS and BRAF-mutant tumor xenografts. Here, we characterize a novel, highly potent, selective ERK inhibitor, which inhibits both ERK catalytic activity and also the upstream phosphorylation of ERK by MEK. These data support the further optimization of this series of compounds for clinical development. Citation Format: Joanne M. Munck, Valerio Berdini, Luke D. Bevan, Hannah Braithwaite, Ildiko M. Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E. Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M. Griffiths-Jones, Tom D. Heightman, Chris J. Hindley, Birikiti Kidane, Justyna Kucia-Tran, John F. Lyons, Vanessa Martins, Sandra Muench, Chris W. Murray, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Mike Reader, David C. Rees, Sharna J. Rich, Caroline J. Richardson, Harpreet K. Saini, Alpesh Shah, Lukas Stanczuk, Neil T. Thompson, Hugh Walton, Nicola E. Wilsher, Alison J. Woolford, Nicola G. Wallis. Characterization of a novel ERK1/2 inhibitor, which modulates the phosphorylation and catalytic activity of ERK1/2 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B154.

We sought to describe contemporary guidewire and microcatheter utilization for antegrade wire escalation (AWE) during chronic total occlusion (CTO) percutaneous coronary intervention (PCI).Equipment utilization for AWE has been variable and evolving over time.We examined device utilization during 694 AWE attempts in 679 patients performed at 15 experienced US centers between May 2012 and April 2015.Mean age was 65.6 ± 9.7 years, and 85% of the patients were men. Successful wiring occurred in 436 AWE attempts (63%). Final technical and procedural success was 91% and 89%, respectively. The mean number of guidewire types used for AWE was 2.2 ± 1.4. The most frequently used guidewire types were the Pilot 200 (Abbott Vascular, 56% of AWE procedures), Fielder XT (Asahi Intecc, 45%), and the Confianza Pro 12 (Asahi Intecc, 28%). The same guidewires were the ones that most commonly crossed the occlusion: Pilot 200 (36% of successful AWE crossings), Fielder XT (20%), and Confianza Pro 12 (11%). A microcatheter or over-the-wire balloon was used for 81% of AWE attempts; the Corsair microcatheter (Asahi Intecc) was the most commonly used (44%). No significant association was found between guidewire type and incidence of major adverse cardiac events (MACE).Our contemporary, multicenter CTO PCI registry demonstrates that the most commonly used wires for AWE are polymer-jacketed guidewires. "Stiff" and polymer-jacketed guidewires appear to provide high crossing rates without an increase in MACE or perforation, and may thus be considered for upfront use. © 2016 Wiley Periodicals, Inc.

We sought to describe contemporary guidewire utilization for antegrade wire escalation during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We examined guidewire and microcatheter utilization during antegrade wire escalation attempts among 1097 CTO PCIs performed at 13

Although the hemodynamic response to blunt spinal cord injury has been well described, much less is known about the responses to penetrating spinal cord injuries. In order to elucidate any differences, we reviewed the last 75 patients treated over the past 12 years with penetrating spinal cord injuries. There were 67 men and eight women; the mean age was 26.2 years (range, 15-59 years); 73 patients suffered 120 gunshot wounds; one patient was injured with an ice pick; one was stabbed twice. The offending missile causing spinal cord injury entered the neck in 24%, the thorax in 56%, and the abdomen in 20%. Nine patients (12%) were complete quadriplegics and 49 patients (65%) were complete paraplegics; 69 patients (92%) had no rectal tone; 17 patients (22%) had incomplete injuries. Despite the high proportion of complete spinal injury (78%), only 18 patients (24%) were hypotensive in the field. Five additional patients became hypotensive in the ED. Of the 23 patients with hypotension, 18 (74%) had significant blood loss to explain their low blood pressure. The mean HR was 100 beats/minute in the field (range, 50-130 beats/minute) and 90 beats/minute in the ED. Only five patients (7%) demonstrated the classic presentation of neurogenic shock (hypotension and bradycardia). This classic presentation of neurogenic shock is rare following penetrating spinal cord injury. Despite evidence of a complete spinal cord injury on initial physical examination, hypotension is usually secondary to blood loss in these patients. A careful search for sources of blood loss is mandatory before ascribing hypotension to spinal injury.