Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma.

PURPOSE: Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan­RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. METHODS: This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. RESULTS: Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg. CONCLUSIONS: The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. GOV IDENTIFIER: NCT01425008.

Respiratory Mechanics in a Cohort of Critically Ill Subjects With COVID-19 Infection.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) often develop acute hypoxemic respiratory failure and receive invasive mechanical ventilation. Much remains unknown about their respiratory mechanics, including the trajectories of pulmonary compliance and [Formula: see text]/[Formula: see text], the prognostic value of these parameters, and the effects of prone positioning. We described respiratory mechanics among subjects with COVID-19 who were intubated during the first month of hospitalization. METHODS: We included patients with COVID-19 who were mechanically ventilated between February and May 2020. Daily values of pulmonary compliance, [Formula: see text], [Formula: see text], and the use of prone positioning were abstracted from electronic medical records. The trends were analyzed separately over days 1-10 and days 1-35 of intubation, stratified by prone positioning use, survival, and initial [Formula: see text]/[Formula: see text]. RESULTS: Among 49 subjects on mechanical ventilation day 1, the mean compliance was 41 mL/cm H2O, decreasing to 25 mL/cm H2O by day 14, the median duration of mechanical ventilation. In contrast, the [Formula: see text]/[Formula: see text] on day 1 was similar to day 14. The overall mean compliance was greater among the non-survivors versus the survivors (27 mL/cm H2O vs 24 mL/cm H2O; P = .005), whereas [Formula: see text]/[Formula: see text] was higher among the survivors versus the non-survivors over days 1-10 (159 mm Hg vs 138 mm Hg; P = .002) and days 1-35 (175 mm Hg vs 153 mm Hg; P < .001). The subjects who underwent early prone positioning had lower compliance during days 1-10 (27 mL/cm H2O vs 33 mL/cm H2O; P < .001) and lower [Formula: see text]/[Formula: see text] values over days 1-10 (139.9 mm Hg vs 167.4 mm Hg; P < .001) versus those who did not undergo prone positioning. After day 21 of hospitalization, the average compliance of the subjects who had early prone positioning surpassed that of the subjects who did not have prone positioning. CONCLUSIONS: Respiratory mechanics of the subjects with COVID-19 who were on mechanical ventilation were characterized by persistently low respiratory system compliance and [Formula: see text]/[Formula: see text], similar to ARDS due to other etiologies. The [Formula: see text]/[Formula: see text] was more tightly associated with mortality than with compliance.

Emergency department characteristics and associations with intensive care admission among patients with coronavirus disease 2019.

OBJECTIVE: There have been few descriptions in the literature to date specifically examining initial coronavirus disease 2019 (COVID-19) patient presentation to the emergency department (ED) and the trajectory of patients who develop critical illness. Here we describe the ED presentation and outcomes of patients with COVID-19 presenting during our initial local surge. METHODS: This is a multicenter, retrospective cohort study using data extracted from the electronic health records at 3 hospitals within a single health system from March 1, 2020 to June 1, 2020. Patients were included in the study if they presented to an ED and had laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the study period. Data elements were extracted from the electronic health record electronically and by trained data abstractors and entered into a secure database. We used multivariable regression analysis to examine ED factors associated with the development of critical illness and mortality, with a primary outcome of ICU admission. RESULTS: A total of 330 patients with laboratory-confirmed SARS-CoV-2 infection were admitted during the study period. Of these, 112 (34%) were admitted to the ICU. Among these patients, 20% were female, 50% were White, the median age was 61 (interquartile range [IQR], 52-72), and the median body mass index (BMI) was 28.1 (IQR, 24.3-35.1). On univariable analysis, a doubling of lactate dehydrogenase (LDH) (odds ratio [OR], 3.87; 95% confidence interval [CI], 2.40-6.27) or high-sensitivity C-reactive protein (hsCRP; OR, 1.32; 95% CI, 1.11-1.57) above the reference range or elevated troponin (OR, 12.1; 95% CI, 1.20-121.8) were associated with ICU admission. After adjusting for age, sex, and BMI, LDH was the best predictor of ICU admission (OR, 3.54; 95% CI, 2.12-5.90). Of the patients, 15% required invasive mechanical ventilation during their hospital course, and in-hospital mortality was 19%. CONCLUSIONS: Nearly one-third of ED patients who required hospitalization for COVID-19 were admitted to the ICU, 15% received invasive mechanical ventilation, and 19% died. Most patients who were admitted from the ED were tachypneic with elevated inflammatory markers, and the following factors were associated with ICU admission: elevated hsCRP, LDH, and troponin as well as lower oxygen saturation and increased respiratory rate.

24-carat gold, 14-carat gold, or platinum standards in the treatment of critical limb ischemia: bypass surgery or endovascular intervention?

Critical limb ischemia (CLI) remains a poorly understood, rarely reported, and inconsistently treated major global healthcare epidemic. The incidence in the US is estimated at 1% of the population aged 50 years and older and at approximately double that rate in the over-70 age group. These frequencies are expected to increase significantly with the aging population and the expected increase in diabetes. Within 1 year of being diagnosed with CLI, 40% to 50% of the now 20 million US diabetics will experience an amputation, and 20% to 25% will die. The estimate for treating CLI in the US alone is $10 to $20 billion per year, but just a 25% reduction in amputations could save $2.9 to $3.0 billion annually. Infrainguinal bypass surgery (IBS) utilizing autogenous saphenous vein has been considered the "24-carat gold standard" treatment for CLI, but over the last decade, endovascular therapy has emerged to seriously challenge IBS, which has created considerable controversy. Despite an overall lack of "hard" level I data, many interventionists are questioning the role of IBS as a first-line CLI therapy or are at least now considering IBS a "tainted" gold standard ("14-carat"). This review will examine the available evidence, but there should be no doubt regarding the huge global clinical and economic impact of CLI and amputations.

A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome.

BACKGROUND: The combination of glycoprotein (GP) IIb-IIIa inhibition and direct thrombin inhibition (DTI) with bivalirudin (Angiomax, The Medicines Company, Cambridge, Massachusetts) have shown ischemic and hemorrhagic outcomes benefit in coronary interventions and may have similar benefits in percutaneous peripheral interventions (PPI). The high incidence of diabetes, chronic renal disease, platelet dysfunction, hypercoagulability, inflammation and a thrombus-rich environment make a GP IIb-IIIa and DTI combination with tirofiban (Aggrastat Merck and Company, Inc., Whitehouse Station, New Jersey) an attractive anticoagulation strategy in the PPI treatment of critical limb ischemia (CLI). METHODS: Between May 1, 2001 and January 31, 2003, a CLI treatment group of 149 patients received PPI with bivalirudin (0.75 mg per kg bolus with 1.75 mg per kg per hour periprocedural infusion) and tirofiban (10 mcg per kg per minute bolus with 12-hour 0.1 mcg per kg per minute infusion) as an anticoagulation and antiplatelet strategy, and were compared to a matched unfractionated heparin (UFH) control group without GP IIb-IIIa inhibitors. Clinical and hemostasis outcomes were analyzed, including distal embolization (DE). RESULTS: Procedural success was 95.9% and 97.3% in the UFH control group and DTI-GP IIb-IIIa group, respectively. Significant differences were observed in the sheath removal time < 2 hours (60.5% UFH group versus 19.4% DTI-GP IIb-IIIa group; p = < 0.0001). Vascular closure devices were used equally in both groups. No statistical significance was observed in major and minor complications, femoral access complications, acute (< 48 hours) or subacute (30 days) vessel thrombosis, and 6-month duplex ultrasound restenosis rate between the DTI-GP IIb-IIIa versus the UFH group. A trend towards statistical significance was observed in the 6-month secondary re-intervention and limb salvage rates (10.7% versus 18.8%; p = 0.0501 and 93.9% versus 88.5%; p = 0.053) in the DTI-GP IIb-IIIa versus the UFH group, respectively. Angiographically relevant DE occurred in 4 of 149 (1.3%) and 8 of 149 (5.4%) of the bivalirudin-tirofiban and UFH groups, respectively. CONCLUSION: The combination of DTI with bivalirudin and GP IIb-IIIa inhibition with tirofiban is a safe and feasible alternative anticoagulation and antiplatelet strategy in PPI, and may offer improved clinical and hemostasis outcomes in treating CLI. A larger, prospective randomized trial is warranted.

Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions.

BACKGROUND: Many heparin (UFH) limitations are overcome by bivalirudin (Angiomax ). The pharmacokinetic profile of bivalirudin appears well suited for percutaneous peripheral intervention (PPI), yet few data exist regarding its safety and feasibility in this setting. METHODS: One hundred and eighty renal and 75 iliac PPIs performed between May 2001 and June 2002 with bivalirudin as anticoagulation were compared to a historical UFH control. Variables evaluated included thrombotic events, intracranial bleeding, major surgical complications, sheath removal time, vascular access complication, time to ambulate and length of stay (LOS). Follow-up included 6-month renal and iliac duplex ultrasound and ankle-brachial index. RESULTS: Procedural success was achieved in 100% of patients treated with bivalirudin, with no thrombotic events, intracranial bleeding or major surgical complications observed. Procedural success was achieved in 179/180 (99%) renal and 74/75 (98.6%) iliac patients treated with UFH. Significant differences were observed for sheath removal time < 60 minutes (84% versus 59%; p < 0.0001), time to ambulation < 6 hours (75.5% versus 58%; p < 0.0005) and LOS < 24 hours (85.5% versus 72%; p = 0.002) in bivalirudin-treated renal PPI patients versus UFH-treated patients, respectively. Significant differences were also observed in favor of bivalirudin for the iliac PPIs for sheath removal time < 60 minutes (p = 0.012) and time to ambulation < 6 hours (p = 0.039). Following 6-month renal and iliac duplex ultrasound, repeat PPI was required in 7/180 (3.9%) and 9/180 (5%) of renal, and 3/75 (4%) and 4/75 (5.3%) of iliac patients treated with bivalirudin or UFH, respectively. CONCLUSION: Bivalirudin is a safe and feasible alternative anticoagulant in renal and iliac PPI and may offer decreased sheath removal time, time to ambulation and LOS. A larger prospective randomized multicenter trial is warranted.

Clinical insights into the use of embolic protection devices during lower extremity peripheral vascular interventions.

The use of embolic protection devices (EPD) during lower extremity peripheral vascular interventions (PVI) remains controversial. We examine the current data and present our Louisiana experience with discussions regarding the unresolved issues surrounding the use of EPD during lower extremity PVI.

A review of the early experience with Targeted Renal Therapy for renal function preservation during endovascular and surgical treatments for cardiovascular disease.

Multiple reports describe the high clinical morbidity and mortality associated with contrast-induced nephropathy (CIN). Similarly, reports have described the glomerular filtration rate (GFR) and worsening renal function as predictors of adverse short and long-term outcomes in several large cardiovascular patient populations including acute myocardial infarction, congestive heart failure, coronary artery bypass surgery (CABG), and endovascular aneurysm repair (EVAR). Targeted renal therapy (TRT) is a novel emerging treatment where high-dose fenoldopam (FEN), a selective renal dopamine-1 receptor agonist and renal arteriolar vasodilator, is infused into both renal arteries via the US FDA-approved 5 Fr bifurcated Benephit PV Catheter Infusion System. TRT has been shown to significantly increase the GFR by 25% vs. placebo and IV-FEN (p < 0.001), which may have important clinical implications in CIN prophylaxis and during surgical procedures including CABG. The aim of this report is to review the early clinical experience and pilot trials with TRT in several clinical scenarios at high-risk for CIN or worsening renal function including percutaneous peripheral vascular interventions (PPI), percutaneous coronary interventions (PCI), CABG and EVAR.

Targeted renal therapy and contrast-induced nephropathy during endovascular abdominal aortic aneurysm repair: results of a feasibility pilot trial.

PURPOSE: To evaluate the feasibility of targeted renal therapy (TRT) to decrease the rate of contrast-induced nephropathy (CIN) during endovascular aortic aneurysm repair (EVAR) in patients at risk for CIN. METHODS: A prospective nonrandomized analysis of TRT was performed in 10 high-risk patients (8 men; median age 66.5 years, range 56-80) with pre-existing renal insufficiency. TRT involved high-dose intrarenal artery infusions of fenoldopam (FEN), a short acting selective dopamine-1 agonist and renal arteriolar vasodilator, delivered percutaneously via a left brachial access using the 5-F Benephit PV Infusion System during EVAR. RESULTS: There were no device-related complications. TRT infusion duration ranged from 3.5 to 6.0 hours (median 4.5). Median contrast dosage was 120 mL (range 50-200). At 24 and 72 hours after EVAR, creatinine clearance (CrCl) had improved in 7 (70%) patients, remained unchanged in 2 (20%), and declined >25% in 1 (10%); the latter returned to baseline on day 5. At 30 days, 7 (70%) patients had improved CrCl and 3 (30%) remained unchanged. CONCLUSION: TRT is feasible during EVAR in high-risk patients. Further investigation is warranted to determine the safety and efficacy of TRT in preserving renal function during EVAR.

Critical limb ischemia: a global epidemic.A critical analysis of current treatment unmasks the clinical and economic costs of CLI.

BACKGROUND: Multiple reports document the higher costs of primary amputation (PA) compared to infrainguinal bypass surgery (IBS). Recent reports document 40-50% cost-effectiveness for percutaneous transluminal angioplasty (PTA) compared to IBS. The literature suggests appropriate initial treatment for critical limb ischemia (CLI) to be IBS = 38%, PTA = 28%, and PA = 16%. The encouraging 6-month Laser Angioplasty for Critical Limb Ischemia (LACI) 93% limb salvage rate prompted an independent CLI and LACI clinical and economic analysis. METHODS: Between 1999-2001 a reference amputation population (RAP) of 417 patients with at least one infrainguinal amputation were identified from a 2.5 million patients Medicare/insurance dataset. Clinical data and all medical cost claims for 18 continuous months, 12-month prior and 6-month post-amputation, were analyzed for PTA, IBS, and PA treatment pathways. Based on multiple assumptions and the LACI phase II results, economic outcomes were used for a LACI pathway analysis compared to PTA, IBS and PA pathways by substituting the LACI trial pathway as the initial treatment in lieu of the RAP actual treatment. RESULTS: Initial treatments for CLI RAP were PA = 67%, IBS = 23%, PTA = 10%; A majority of wound complications (80%) and myocardial infarction 7/9 (77.7%), stroke 13/16 (81.2%), and death 2/2 (100%) occurred in the PA RAP. Only 35% of the RAP had an ankle brachial index (ABI) and only 16% angiography before PA. 227/417 (56%) of the RAP had multiple procedures. Average total costs / patient = $31,638 without LACI and $25,373 with LACI. Average savings/patient with LACI = $6,265. CONCLUSION: The most common current treatments in the US for CLI are still characterized by high rates of primary amputations, multiple procedures, and high rates of procedure-related complications. Despite the limitations and assumptions of this analysis, the utilization of a LACI pathway first revascularization treatment strategy may provide clinical and economic cost savings in treating patients with CLI.

Novel treatment strategy for leg and sternal wound complications after coronary artery bypass graft surgery: bioengineered Apligraf.

PURPOSE: To demonstrate that bioengineered Apligraf improves time to wound healing in sternal and leg wound complications after coronary artery bypass surgery. DESCRIPTION: Between 1998 and 2001, 1,550 patients underwent coronary artery bypass surgery utilizing saphenous vein. In 45 (2.9%) of 1,550 patients, leg wound complications developed (group A); and in 15 (0.9%) of 1,550 patients, sternal wound complications developed (group B). Apligraf was utilized as the primary treatment for 30 (66%) of 45 leg wounds and for 9 (60%) of 15 sternal wounds. Traditional wound care included debridement and daily wet-to-dry dressings. EVALUATION: Time to wound healing ranged from 26 to 72 days (mean, 46) for Apligraf group A and from 34 to 120 days (mean, 84) for traditional wound care group A. The time to wound healing ranged from 21 to 80 days (mean, 39) for Apligraf group B, and from 36 to 110 days (mean, 62) for traditional care group B. Apligraf treatment was simpler, with less time and resource utilization than traditional wound care. CONCLUSIONS: Apligraf significantly improves time to wound healing in patients with leg and sternal wound complications and offers an attractive new treatment alternative to traditional wound care.

Novel simultaneous combination chemical thrombolysis/rheolytic thrombectomy therapy for acute critical limb ischemia: the power-pulse spray technique.

The novel power-pulse spray (P-PS) technique maximizes and combines the advantages and minimizes the disadvantages of both chemical thrombolysis (CT) and rheolytic thrombectomy (RT). Forty-nine consecutive patients with iliofemoral thrombotic occlusion were treated via P-PS technique. Using a 6 Fr RT catheter, saline prime was exchanged for thrombolytic solution [group 1, 10-20 mg tenecteplase (TNK)/50 cc saline, n = 25; group 2, 1,000,000 urokinase (UK)/50 cc saline, n = 24]. The outflow port was closed, then the catheter was advanced at 1 mm increments while pulsing lytic agent. After 30-min lysis time, RT and definitive treatment of the underlying stenosis were performed. Procedure success was 23/25 (92%) and 22/24 (91.6%) for group 1 and 2, respectively. The mean total procedure time was 72 and 75 min in group 1 and 2, respectively. Thirty-day limb salvage was 91% in both groups. There were no major surgical complications. The P-PS technique is safe and effective using either UK or TNK, offering several potential advantages over monotherapy, including more rapid revascularization, decreases systemic lytic exposure and bleeding complications while facilitating both CT and RT capacity and efficacy.

Intraoperative innominate and common carotid intervention combined with carotid endarterectomy: a "true" endovascular surgical approach.

PURPOSE: To report the technique of carotid endarterectomy (CEA) combined with retrograde balloon angioplasty and stenting of proximal "tandem" lesions in the supra-aortic trunk. TECHNIQUE: Intraoperative techniques in 34 patients with 23 left common carotid artery (CCA) and 11 innominate artery lesions included general anesthesia, low-dose dextran, prosthetic patching, selective shunting, 8-F sheath entry into the native CCA before the CEA, manual CCA sizing, and balloon-expandable stent placement after predilation. The technique has a high procedural success rate (97%) and appears durable. Over a mean 34-month follow-up, 2 >70% ostial CCA restenoses were found at 24 months. CONCLUSIONS: Intraoperative innominate or left CCA balloon angioplasty/stenting combined with carotid endarterectomy is safe, effective, and durable.

Continuous tenecteplase infusion combined with peri/postprocedural platelet glycoprotein IIb/IIIa inhibition in peripheral arterial thrombolysis: initial safety and feasibility experience.

PURPOSE: To evaluate a continuous-infusion protocol for peripheral arterial thrombolysis using tenecteplase (TNK), with regard to the technique, dosing, infusion times, and clinical outcomes. METHODS: Between November 1999 and July 2002, 48 patients (30 men; mean age 68.5+/-11.9 years) presented with acute limb ischemia (ALI) owing to iliofemoral arterial thrombosis, which was treated with continuous TNK infusion (either 0.50 mg/h [n=22, group A] or 0.25 mg/h [n=26, group B]). All patients received periprocedural heparin (500 U/h) and peri and postprocedural tirofiban for 6 to 12 hours. Follow-up included ankle-brachial index and duplex ultrasound at baseline, 1 month, and 6 months. The variables retrospectively analyzed included total infusion time, total TNK dose, fibrinogen analysis, clinical and thrombolysis outcomes, and complications. RESULTS: The overall clinical procedural success was 95.8%. Complete (>95%) lysis was observed in 35 (73%) patients; overall mean infusion time was 7.5 hours, and overall mean TNK dose was 4.8 mg. No deaths, intracranial bleeding, or embolic events occurred in either group. Of the 8 (16.7%) complications, 5 (10.4%) were major: 1 femoral repair (group A), 2 >5-cm nonsurgical hematomas (1 in each group), and 2 gastrointestinal hemorrhages (1 in each group). The 3 (6.3%) minor complications were minor hematomas (2 in group A and 1 in group B). The 30-day and 14-month mean limb salvage rates were 95.8% (46/ 48) and 89.6% (43/48), respectively. CONCLUSIONS: Continuous TNK infusion (0.25-0.50 mg/h) is a safe and feasible treatment for continuous pharmacological thrombolysis in ALI, potentially offering decreased infusion times and bleeding complications, as well as improved outcomes.