Multi-proteomic Biomarker Risk Scores for Predicting Risk and Guiding Therapy in Patients with Coronary Artery Disease.

PURPOSE OF REVIEW: Patients with established coronary artery disease (CAD) are at high residual risk for adverse events, despite guideline-based treatments. Herein, we aimed to determine whether risk scores based on multiple circulating biomarkers that represent activation of various pathophysiologically important pathways involved in atherosclerosis and myocardial dysfunction help identify those at greatest residual risk. RECENT FINDINGS: Numerous circulating proteins, representing dysregulation of the pathways involved in the development and stability of coronary and myocardial diseases, have been identified. When aggregated together, biomarker risk scores (BRS) more accurately stratify patients with established CAD that may help target interventions in those individuals who are at elevated risk. Moreover, intensification of guideline-based therapies has been associated with parallel improvements in both BRS and outcomes, indicating that these risk scores may be employed clinically to target therapy. Multi-protein BRS are predictive of risk, independent of, and in addition to traditional risk factor assessments in patients with CAD. Those with elevated risk may benefit from optimization of therapies, and improvements in the BRS will identify those with improved outcomes.

Does Preoperative Platelet Function Predict Bleeding in Patients Undergoing Off Pump Coronary Artery Bypass Surgery?

OBJECTIVE: We sought to examine the relationship between preoperative platelet function and perioperative bleeding in patients undergoing CABG. BACKGROUND: There are many ways to measure platelet aggregability. Little is known about their correlations with one another, or with bleeding. METHODS: We prospectively studied 50 patients undergoing a first isolated off-pump CABG. Thirty-four were exposed to a thienopyridine prior to surgery; 16 were not. Preoperative platelet function was measured by VerifyNow®, TEG®, AggreGuide™, Plateletworks®, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and light transmission aggregometry. Bleeding was assessed 2 ways: drop from pre- to nadir postoperative hematocrit, and chest tube drainage. Correlation coefficients were calculated using Spearman's rank-order correlation. RESULTS: Mean age was 62 years. Patient characteristics and surgical details were similar between the thienopyridine-exposed and non-exposed patients. The correlation coefficients between the 4 point-of-care platelet function measurements and hematocrit change ranged from -0.2274 to 0.2882. Only Plateletworks® correlated with drop in hematocrit (r = 0.2882, P = 0.0470). The correlation coefficients between each of the 4 point-of-care platelet function tests and the chest tube drainage were also poor, ranging from -0.3073 to 0.2272. Both AggreGuide™ (r = -0.3073, P = 0.0317) and VASP (r = -0.3187, P = 0.0272) were weakly but significantly correlated with chest tube drainage. The correlation among the 4 point-of-care platelet function measurements was poor, with coefficients ranging from -0.2504 to 0.1968. CONCLUSIONS: We observed little correlation among 4 platelet function tests, and between those assays and perioperative bleeding defined 2 different ways. Whether any of these assays should be used to guide decision making in individual patients is unclear.

Single-session primary high-intensity focused ultrasonography treatment for localized prostate cancer: biochemical outcomes using third generation-based technology.

UNLABELLED: What's known on the subject? and What does the study add? The experience with HIFU as a minimally invasive treatment for localized prostate cancer is relatively new and most reports are from European centres. Our study is unique in five regards: 1. Data was collected prospectively. 2. All patients were treated with contemporary technology. 3. Outcomes are reported after a single HIFU session using two definitions of biochemical failure that have the ability to predict longer-term clinical failure after primary ablative therapies for prostate cancer (Stuttgart definition for HIFU and Horwitz definition for radiation). 4. All patients were treated in a single centre. 5. No patients underwent peri-HIFU TURP. The present study represents the largest North American prospective cohort of primary HIFU for prostate cancer with mid-term oncological outcome data. OBJECTIVE: To assess 4-year biochemical failure (BCF) rates in patients after high-intensity focused ultrasonography (HIFU) treatment using the Horwitz and Stuttgart definitions. PATIENTS AND METHODS: A total of 447 consecutive patients were treated with a single session of HIFU between May 2005 and December 2010. Follow-up included prostate-specific antigen (PSA) measurement every 3 months during the first year and every 6 months thereafter. Patients who had previously received radiation, androgen deprivation or HIFU therapy, and patients with <2 consecutive PSA measurements were excluded. BCF was reported using the Stuttgart (PSA nadir + 1.2 ng/mL rising) and the Horwitz (two consecutive increases of at least 0.5 ng/mL) definitions. RESULTS: In all, 402 patients met the inclusion criteria and the median (range) follow-up was 24 (6-48) months. Of these patients, 183 (45.5%) had low and 219 (54.5%) had intermediate D'Amico's risk stratification disease. Mean and median absolute PSA nadir levels were 0.36 ± 0.69 and 0.1 ng/mL (Q(1):0, Q(3):0.37), respectively and these were achieved in median time of 3 months. Overall 4-year mean (range) BCF-free rates were 68 (61-75)% and 72 (68-77)% according to the Stuttgart and Horwitz definitions at 4 years, respectively. Mean (range) BCF-free rates were significantly higher for a PSA nadir ≤0.5 ng/mL and prostate volume ≤30 mL for both definitions at 4-year follow-up [Stuttgart: 79 (72-86)% vs. 25 (13-38)%; Horwitz: 82 (77-87)% vs. 33 (21-44)%] and [Stuttgart: 72 (64-79)% vs. 56 (42-69)%; Horwitz: 75 (69-80)% vs. 63 (53-74)%], respectively. Pre-treatment PSA and PSA nadir of >0.5 ng/mL were the predictors of BCF using both definitions. CONCLUSIONS: Primary HIFU appears to result in promising 4-year BCF-free rates in individuals with low- and intermediate-risk prostate cancer who achieve PSA nadir <0.5 ng/mL. A prostate volume <30 mL is associated with PSA nadir levels of <0.5 ng/mL suggesting a potential role for pretreatment volume reduction (medically or surgically) in larger prostates.

Changing Landscape of Systemic Therapy in Biliary Tract Cancer.

Biliary tract cancers (BTC) are often diagnosed at advanced stages and have a grave outcome due to limited systemic options. Gemcitabine and cisplatin combination (GC) has been the first-line standard for more than a decade. Second-line chemotherapy (CT) options are limited. Targeted therapy or TT (fibroblast growth factor 2 inhibitors or FGFR2, isocitrate dehydrogenase 1 or IDH-1, and neurotrophic tyrosine receptor kinase or NTRK gene fusions inhibitors) have had reasonable success, but <5% of total BTC patients are eligible for them. The use of immune checkpoint inhibitors (ICI) such as pembrolizumab is restricted to microsatellite instability high (MSI-H) patients in the first line. The success of the TOPAZ-1 trial (GC plus durvalumab) is promising, with numerous trials underway that might soon bring targeted therapy (pemigatinib and infrigatinib) and ICI combinations (with CT or TT in microsatellite stable cancers) in the first line. Newer targets and newer agents for established targets are being investigated, and this may change the BTC management landscape in the coming years from traditional CT to individualized therapy (TT) or ICI-centered combinations. The latter group may occupy major space in BTC management due to the paucity of targetable mutations and a greater toxicity profile.

An update on EUS-guided ablative techniques for pancreatic cystic lesions.

Pancreatic cystic lesions (PCLs) are increasingly being recognized due to improvements and widespread use of cross-sectional imaging. With an estimated prevalence of 15% in general population, incidentally discovered PCLs represent a dilemma in management. While pancreatectomies offer a chance of cure, the morbidity is considerable in patients with high surgical risks. More recently, EUS-guided approaches for cyst ablation are being offered in clinical trials for the management of PCLs. EUS-chemoablation studies have progressed from first investigating safety and efficacy of EUS-guided alcohol lavage to single-agent paclitaxel ablation. Recent studies have shown that alcohol lavage may not be required, and long-term resolution can be achieved by chemoablation alone. EUS-guided lauromacrogol ablation and EUS-guided radiofrequency ablation (RFA) are new techniques that have shown promising results in a few small studies. Overall, the current literature suggests that EUS-guided paclitaxel ablation has better cyst resolution rates compared to other existing minimally invasive techniques including ethanol injection, lauromacrogol ablation, or RFA. This article will review EUS-guided PCL ablation approaches and future directions the field is headed into.

Biliary Tract Cancers: Treatment Updates and Future Directions in the Era of Precision Medicine and Immuno-Oncology.

The effective management of biliary tract cancers (BTCs) has been hampered by limited options for systemic therapy. In recent years, the focus on precision medicine has made technologies such as next-generation sequencing (NGS) accessible to clinicians to identify targetable mutations in BTCs in tumor tissue (primarily) as well as blood, and to treat them with targeted therapies when possible. It has also expanded our understanding of functional pathways associated with genetic alterations and opened doors for identifying novel targets for treatment. Recent advances in the precision medicine approach allowed us to identify new molecular markers in BTCs, such as epigenetic changes (methylation and histone modification) and non-DNA markers such as messenger RNA, microRNA, and long non-coding RNA. It also made detecting these markers from non-traditional sources such as blood, urine, bile, and cytology (from fine-needle aspiration and biliary brushings) possible. As these tests become more accessible, we can see the integration of different molecular markers from all available sources to aid physicians in diagnosing, assessing prognosis, predicting tumor response, and screening BTCs. Currently, there are a handful of approved targeted therapies and only one class of immunotherapy agents (immune checkpoint inhibitors or ICIs) to treat BTCs. Early success with new targets, vascular endothelial growth factor receptor (VEGFR), HER2, protein kinase receptor, and Dickkopf-1 (DKK1); new drugs for known targets, fibroblast growth factor receptors (FGFRs) such as futabatinib, derazantinib, and erdafitinib; and ICIs such as durvalumab and tremelimumab is encouraging. Novel immunotherapy agents such as bispecific antibodies (bintrafusp alfa), arginase inhibitors, vaccines, and cellular therapy (chimeric antigen receptor-T cell or CAR-T, natural killer cells, tumor-infiltrating lymphocytes) have the potential to improve outcomes of BTCs in the coming years.

Autologous platelet gel: fad or savoir? Do we really know?

Autologous platelet-gel (APG) is the process of harvesting ones own cells (platelets), concentrating them most often through centrifugation, exposing them to an agonist which induces activation which releases intrinsic substances, and applying them to a target area to accelerate wound healing. APG is attractive because it concentrates a large number of biologically active substances, which are primarily proteins that participate in complex series of mechanisms involved in inflammation and wound healing. It has been used in numerous applications including sports medicine, dermatology, and surgery. However, there are few prospective randomized trials that have compared it in a rigorous manner to other techniques or to placebo. The following report is a review of APG, which includes a description of its perceived benefit, identification of the various modalities where it has been used, and criticisms concerning its use.

Characteristics of uncontrolled hemorrhage in cardiac surgery.

Patients with uncontrolled hemorrhage require massive transfusion therapy and consume a large fraction of blood bank resources. Institutional guidelines have been established for treatment, but early identification and prevention in susceptible patients remains challenging. Uncontrolled hemorrhage was defined as meeting institutional guidelines for recombinant FVIIa administration. Patients who received rFVIIa were compared with patients who did not require the therapy but who were operated on during the same time period. After institutional review board approval, demographic, operative, and transfusion data were analyzed from a prospective database. Patients receiving rFVIIa were more likely to undergo multiple procedures (2.6 +/- 0.8 vs. 1.8 +/- 0.8; p < .001); aortic surgery (59% vs. 11%; p < .005); have a higher Cleveland Clinic Clinical Severity score (7.8 +/- 2.7 vs. 5.5 +/- 4.0; p < .005); require longer bypass (265 +/- 92 min vs. 159 +/- 63 min; p < .001), cross-clamp (182 +/- 68 min vs. 112 +/- 56 min; p < .001), and circulatory arrest (15 +/- 24 min vs. 2 +/- 7 min; p < .05) times; and require more autotransfusion (2580 +/- 1847 mL vs. 690 +/- 380 mL; p < .05). Uncontrolled hemorrhage is associated with more complex surgery requiring longer bypass times and more autotransfusion.

Use of platelet gel and its effects on infection in cardiac surgery.

The use of plasmapheresis in cardiac surgery has failed to show an unequivocal benefit. However, the further processing of plasmapheresed blood to obtain a platelet-rich concentrate, termed platelet gel, may reduce patient susceptibility to infection through poorly understood mechanisms related to a combination of platelets, white blood cell content, and expedited wound healing. The purpose of the study was to retrospectively evaluate the incidence wound infections in patients undergoing cardiac surgery. Platelet gel (PG) patients (n = 382) received topical administration of a mixture of platelet concentrated plasma, 10% calcium chloride (5 mL), and bovine thrombin (5000 units). A control group (NoPG, n = 948) operated on concurrently with the treatment group did not receive PG, but otherwise received similar wound care. A historical control (HC, n = 929) included patients operated on before the availability of PG. After Institutional Review Board approval, 20 factors reported in the literature to predispose individuals for increased infection were recorded along with infections classified either as superficial or deep sternal according to the Society of Thoracic Surgeon criteria. All data were obtained from our institutional contribution to the Society of Thoracic Surgeon database. All adult (>19 years of age) patients undergoing cardiac surgery at our institution between October 2002 and June 2005 were included in this study (n = 2259). The incidence of superficial infection was significantly lower in the PG group (0.3%) compared both with the NoPG (1.8%) and HC (1.5%) groups (p < .05). There was a similar relationship found when comparing deep sternal wound infections (PG, 0.0% vs. NoPG, 1.5%; p < .029 and PG vs. HC, 1.7%;p < .01). In conclusion, the application of PG in patients undergoing cardiac surgery seems to confer a level of protection against infection, although the mechanisms of action remain to be elucidated.

Improved outcomes during cardiac surgery: a multifactorial enhancement of cardiopulmonary bypass techniques.

Patients presenting for cardiac surgery with cardiopulmonary bypass (CPB) are more likely to have pre-existing comorbidities, which has resulted in a steady increase in the risk associated with CPB. The resulting challenge has mandated the optimization of perfusion care. The purpose of this study was to retrospectively evaluate the impact of a number of simultaneous, evidence based perfusion care changes on patient outcome. After Institutional Review Board approval, two groups of patients were compared. The control group (n = 317) included all patients undergoing CPB in a 12-month period preceding a multifaceted change in perfusion techniques. The treatment group (n = 259) included all patients undergoing CPB in the 12-month period after the changes, which included the incorporation of updated continuous blood gas monitoring, biocompatible circuitry, updated centrifugal blood propulsion, continuous autotransfusion technology, new generation myocardial protection instrumentation, plasmapheresis, topical platelet gel application, excluding hetastarch while increasing the use of albumin, viscoelastographic coagulation monitoring, and implementing a quantitative quality improvement program. After univariate analysis, propensity scoring and multiple conditional logistical regression were used to control for demographic, preoperative, operative, and postoperative parameters. Results of the primary endpoints revealed a lower mortality rate in the treatment group (4% vs. 9% [95% confidence interval 1.33, 7.72], p = 0.009), lower transfusion rate (51% vs. 59% [1.00, 2.11], p = 0.048), and lower complication rate (55% vs. 65% [1.06,2.19], p = 0.025) despite having similar predicted mortality (11 [2,22] vs. 11[3,22], p = NS) and other preoperative and operative parameters. The lower mortality rate was concurrent with a trend towards a lower incidence of complications, consistent with the differences in primary outcomes. In conclusion, the patients treated after the implementation of a multifactorial improvement plan using evidence based changes in CPB care had decreased complication and mortality rates.

Photoselective vaporization for the treatment of benign prostatic hyperplasia.

BACKGROUND: As an alternative to transurethral resection of the prostate (TURP), photoselective vaporization of the prostate (PVP) provides a bloodless, relatively painless relief of lower urinary tract symptoms for men with benign prostatic hyperplasia. Following a review of the evidence in 2006, the Ontario Health Technology Advisory Committee recommended that a study be conducted to evaluate PVP in Ontario. OBJECTIVES: To compare the clinical effectiveness, safety, cost-effectiveness, and budget impact of PVP compared to conventional TURP for the treatment of benign prostatic hyperplasia in Ontario. METHODS: A prospective, nonrandomized trial was conducted in 3 Ontario centres. Consenting subjects were assessed at baseline and 1, 3, and 6 months following surgery. Outcome measures included International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), post-void residual (PVR) volume, prostate-specific antigen (PSA), health-related quality of life (HRQOL) using the EuroQol 5 Domain questionnaire, and the Sexual Health Inventory for Men (SHIM) score. Adverse events, resource utilization, and productivity losses were also assessed. Cost-effectiveness and budget impact analyses were completed using data from the study. RESULTS: Between February 2008 and August 2010, 164 subjects were enrolled in the study (n = 140 for PVP and n = 24 for TURP). Treatment outcomes were similar between the 2 groups at 6 months, with the IPSS decreasing similarly over time (P = 0.718). For other treatment outcomes (Qmax, PSA, HRQOL, SHIM) both treatments provided similar benefit over time; only changes in PVR volume favoured PVP (P = 0.018). The majority of PVP patients were managed on an outpatient basis, with only 7.1% requiring admission (all TURP subjects were inpatients). At 6 months, PVP was less costly than TURP ($3,891 versus $4,863; P = 0.001), with similar quality-adjusted life-years (0.448 versus 0.441; P = 0.658). PVP remained the most cost-effective treatment across all decision-making thresholds, with the technology costing less and providing similar clinical outcomes. Extrapolating the results to a provincial level indicated (based on an estimated case volume of 12,335 TURPs) that there is an opportunity to reallocate just over $14 million (Cdn), primarily related to the reduced need for hospital admission. LIMITATIONS: This study was nonrandomized, and the results should be interpreted with some caution, despite generally similar baseline characteristics between the 2 groups. Recruiting individuals to the TURP arm was a challenge, resulting in a size imbalance between treatment arms. CONCLUSIONS: Based on this analysis, PVP appears to be a cost-effective alternative to TURP, providing similar clinical benefit at a lower cost to the health system.

A prospective trial of GreenLight PVP (HPS120) versus transurethral resection of the prostate in the treatment of lower urinary tract symptoms in Ontario, Canada.

BACKGROUND: Photoselective vaporization of the prostate (PVP) is a bloodless, relatively painless alternative to transurethral resection of the prostate (TURP) for relief of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). OBJECTIVE: We compare the effectiveness, safety and cost-effectiveness of Greenlight Laser PVP (HPS-120) and TURP. METHODS: We conducted a prospective, non-randomized trial in 3 Ontario centres from March 2008 to February 2011. Assessments were completed at baseline, 1 and 6 months following surgery at the physicians' offices and at 12 and 24 months by phone. The primary outcome was the change in International Prostate Symptoms Score (IPSS) score at 6 months versus baseline. Secondary outcomes were changes in flow rate, postvoid residual (PVR), prostate-specific antigen (PSA) and sexual health inventory for men (SHIM) scores. Adverse events, health-related quality of life (HRQoL), resource utilization and productivity losses were collected. RESULTS: Although the IPSS decreased in both arms (n = 140 for PVP and n = 24 for TURP) between baseline and 6 months, the difference in change over time between the groups was not statistically significant (p = 0.718). Other outcomes improved equally from baseline and 6 months (Qmax, SHIM, PSA and HRQoL), with only changes in PVR favouring PVP (p = 0.018). There were no statistical differences in serious adverse events. In total, 130 of 140 PVP patients were outpatients, all TURP subjects were inpatients. PVP was less costly than TURP ($3891 vs. $4863; p < 0.001) with similar quality-adjusted life years (0.448 vs. 0.441; p = 0.658). CONCLUSION: Greenlight Laser PVP (HPS-120) is a safe and cost-effective alternative to TURP for outpatient treatment of LUTS and can be completed as an outpatient with minimal blood loss.

Coagulation management of a patient with factor V Leiden mutation, lupus anticoagulant, and activated protein C resistance: a case report.

Although patients undergoing cardiac surgery often present with diverse comorbidities, those with coagulation derangements are especially challenging. The present report describes the management of a patient who presented with a Factor V Leiden mutation, lupus anticoagulant, and acquired activated protein C resistance. A 42-year-old female presented with acute shortness of breath and chest pain. She was otherwise healthy 1 month prior to admission when she presented with dysfunctional uterine bleeding, resulting in the transfusion of three units of packed red blood cells. Coagulation evaluation revealed that the patient had lupus anticoagulant, factor V Leiden mutation and an activated protein C resistance. The patient presented with an acute myocardial infarction and was found to have 90% stenosis of her left main coronary artery, moderate mitral and tricuspid regurgitation, and a left ventricular ejection fraction of 25%. An emergent off-pump coronary artery bypass procedure with placement of a vein graft to the left anterior descending artery was completed. Intraoperative thrombophilia was encountered as evidenced by both an elevated thromboelastograph coagulation index (+3.6) and an acquired antithrombin-III deficiency. Postoperatively, the patient was placed on low molecular weight heparin, but developed heparin-induced thrombocytopenia and was switched to a direct thrombin inhibitor, argatroban. The following case report describes the coagulation management of this patient from the time of admission to discharge 43 days later, and the unique challenges this combination of hemostatic defects present to the clinicians.