Front-line Approach Research Articles

A β-1,3/1,6-glucan enhances anti-tumor effects of PD1 antibody by reprogramming tumor microenvironment

Checkpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a β-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhanced the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decrease in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.

Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis.

Urate-lowering therapy (ULT) is widely recognized as the primary treatment for hyperuricemia and gout. Xanthine oxidase inhibitors (XOI), particularly febuxostat, have gained popularity as a frontline approach. However, the divergent efficacy and safety between febuxostat and the traditional ULT drug, benzbromarone, remain poorly understood. This knowledge gap necessitates a comprehensive analysis and evidence update to guide drug selection for physicians and patients. We conducted a systematic analysis by extracting relevant clinical studies from four medical literature databases. Forest plots, funnel plots, sensitivity analysis, Egger's test, and subgroup analysis were utilized to compare relevant indicators. The advantages and disadvantages of the two drugs were evaluated based on various indicators such as serum uric acid (SUA), triglyceride (TG), urinary uric acid (UUA), white blood cell count (WBC), total cholesterol (TC), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine (SC). Benzbromarone demonstrated better efficacy in rapidly reducing SUA levels and inhibiting inflammation for hyperuricemia and gout patients. Febuxostat was slightly less effective in lowering SUA, but there was no significant difference in its impact on liver and kidney function after long-term use. This study highlights the superiority of benzbromarone in rapidly reducing SUA and inhibiting inflammation. Febuxostat shows comparable effects on liver and kidney function after long-term use. These findings provide valuable insights for clinicians and patients in drug selection. Key Points • Benzbromarone stands out as a highly effective treatment for hyperuricemia and gout, offering rapid reduction of serum uric acid levels and potent anti-inflammatory effects. • When it comes to long-term use, febuxostat demonstrates comparable effects on liver and kidney function. This provides reassurance for patients who require extended treatment duration. • Moreover, our study goes beyond previous research by presenting a more comprehensive and detailed analysis.

Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling.

Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.

First Line Therapy Evaluation Using Propensity Score Approach in Newly Diagnosed Advanced Classical Hodgkin Lymphoma Patients from Prospective Real-World Realysa Cohort and Phase 3 AHL2011 Trial

Background: AHL2011, a randomized phase III trial demonstrated that PET-CT after two cycles of BEACOPP escalated chemotherapy safely guided treatment of patients aged 16-60 years with newly diagnosed advanced classical Hodgkin lymphoma (cHL) and allowed the use of ABVD in early responders with reduced toxicities and no impaired disease control. REALYSA study, a real-life multicentric cohort set up in France since 2018, included 6000 newly diagnosed lymphoma patients with over 1000 cHL patients. In the present study, we investigated whether real-world data could reproduce results issued from a randomized phase III clinical trial using the propensity score approach. Methods: After stringent propensity score matching (PSM) on 10 baseline parameters (gender, age, Ann Arbor stage, ECOG Performance Status, number of extranodal sites involved, B symptoms, albumin, hemoglobin, white blood cell count and lymphocytes), we performed a PSM testing ratios 1:1 (one patient from AHL2011 trial and one patient from REALYSA cohort). All patients from AHL2011 and REALYSA included in this study had PET-CT monitoring after two cycles of BEACOPP escalated. This approach allowed us to build well-balanced pairs as demonstrated by the absolute values of the standardize mean differences (SMDs) below 0.1 for all matching covariates except for ECOG (SMD=0.15). We also used the Inverse Probability of Treatment Weighting (IPTW, IPTW stabilized) to compare the experimental arm of the AHL2011 trial with a synthetic control arm established with real-world data from REALYSA cHL patients who respected the main inclusion criteria of AHL2011 trial and were treated following this PET-guided approach. The median follow-up was censored in the AHL2011 data in order to be comparable to the median follow-up observed in the REALYSA cohort. Results: Among the 823 patients of AHL2011 and 942 patients of REALYSA with newly diagnosed cHL, 390 and 100 patients respectively were eligible for propensity score calculation, corresponding to AHL2011 TEP-guided therapy, aged between 16 and 60 years, no missing data for the covariates included in the PSM and at least 12 months of follow-up in the REALYSA study. After 1:1 PSM (n=98 AHL2011 and n=98 REALYSA), the overall response rate at the end of induction was 91.8% vs 89.8% (p=0.81) for patients included in AHL2011 and REALYSA, respectively. The proportion of patients with positive PET-CT after 2 cycles was similar in AHL2011 (13%) and REALYSA (14%). After a median follow-up of 13 months, the 1-year progression free survival rates were 93.8% and 87.8% (HR=0.87; 95%CI 0.4-2.0; P=0.74) in AHL2011 and REALYSA, respectively (Figure 1A). Using IPTW model including covariates from the PSM, similar PFS were obtained between experimental arm of AHL2011 and patients included in REALYSA (Figure 1B). IPTW stabilized and other IPTW models also showed similar results for PFS. Conclusions: In this study, we demonstrated using a propensity score approach that patients with newly diagnosed advanced cHL treated according to the AHL2011 PET-guided frontline approach in routine care and included in REALYSA cohort reached similar outcomes as patients included in prospective phase III clinical trial. Beyond the relevant validation of the AHL2011 trial results in real-life, which will need longer follow up, these data could be used to design composite control arm for future clinical trials.

First-line systemic treatment for hepatocellular carcinoma: A systematic review and network meta-analysis

The rapid development of novel therapeutic options for advanced hepatocellular carcinoma (aHCC) has generated some uncertainty about the rational choice of the systemic upfront treatment. So far, a variety of therapeutic strategies have been investigated, including the combination of immunecheckpoint inhibitors and anti-VEGF. To identify the treatment that should be preferred as front-line approach, we compared the efficacy and toxicity of a variety of therapeutic strategies. With this aim, we performed a systematic review and a meta-analysis of randomized clinical trials. OS, PFS, ORR and tolerability outcomes were considered, and for each outcome the treatment ranking was evaluated by the surface under the cumulative rankings (SUCRAs). Combination of Camrelizumab + Rivoceranib scored the best in OS, followed by Sintilimab + Bevacizumab, whereas Lenvatinib + Pembrolizumab showed higher probability to be the best treatment in PFS and Sintilimab + Bevacizumab performed best in ORR. Finally, Durvalumab is the most tolerated treatment.

Radiotherapy toxicity prediction using knowledge-constrained generalized linear model

Radiation therapy (RT) is a frontline approach to treating cancer. While the target of radiation dose delivery is the tumor, there is an inevitable spill of dose to nearby normal organs causing complications. This phenomenon is known as radiotherapy toxicity. To predict the outcome of the toxicity, statistical models can be built based on dosimetric variables received by the normal organ at risk (OAR), known as Normal Tissue Complication Probability (NTCP) models. To tackle the challenge of the high dimensionality of dosimetric variables and limited clinical sample sizes, statistical models with variable selection techniques are viable choices. However, existing variable selection techniques are data-driven and do not integrate medical domain knowledge into the model formulation. We propose a knowledge-constrained generalized linear model (KC-GLM). KC-GLM includes a new mathematical formulation to translate three pieces of domain knowledge into non-negativity, monotonicity, and adjacent similarity constraints on the model coefficients. We further propose an equivalent transformation of the KC-GLM formulation, which makes it possible to solve the model coefficients using existing optimization solvers. Furthermore, we compare KC-GLM and several well-known variable selection techniques via a simulation study and on two real datasets of prostate cancer and lung cancer, respectively. These experiments show that KC-GLM selects variables with better interpretability, avoids producing counter-intuitive and misleading results, and has better prediction accuracy.

HOCl Rapidly Kills Corona, Flu, and Herpes to Prevent Aerosol Spread

The COVID-19 pandemic has escalated the risk of SARS-CoV-2 transmission in the dental practice, especially as droplet-aerosol particles are generated by high-speed instruments. This has heightened awareness of other orally transmitted viruses, including influenza and herpes simplex virus 1 (HSV1), which are capable of threatening life and impairing health. While current disinfection procedures commonly use surface wipe-downs to reduce viral transmission, they are not fully effective. Consequently, this provides the opportunity for a spectrum of emitted viruses to reside airborne for hours and upon surfaces for days. The objective of this study was to develop an experimental platform to identify a safe and effective virucide with the ability to rapidly destroy oral viruses transported within droplets and aerosols. Our test method employed mixing viruses and virucides in a fine-mist bottle atomizer to mimic the generation of oral droplet-aerosols. The results revealed that human betacoronavirus OC43 (related to SARS-CoV-2), human influenza virus (H1N1), and HSV1 from atomizer-produced droplet-aerosols were each fully destroyed by only 100 ppm of hypochlorous acid (HOCl) within 30 s, which was the shortest time point of exposure to the virucide. Importantly, 100 ppm HOCl introduced into the oral cavity is known to be safe for humans. In conclusion, this frontline approach establishes the potential of using 100 ppm HOCl in waterlines to continuously irrigate the oral cavity during dental procedures to expeditiously destroy harmful viruses transmitted within aerosols and droplets to protect practitioners, staff, and other patients.

Management strategies for chronic idiopathic constipation: an Italian real-life survey

BACKGROUND: Constipation is a common medical condition as affects about 33% of adults older than 60 years.1 Constipation is characterized by infrequent bowel movements, typically fewer than three per week. METHODS: The present nationwide survey involved 67 Italian gastroenterologists. As chronic constipation is a common medical condition, the aim of this survey was to describe the gastroenterologists’ and patients’ characteristics, the workup, and management approaches in clinical practice. The participants completed a questionnaire that was specifically prepared. RESULTS: The results confirmed a high prevalence of chronic constipation in elderly people and females. The workup was different in patients with primary chronic constipation and refractory one. Patients with refractory constipation require more complex approach. Polyethylene glycol is the most popular remedy as frontline approach, but serotoninergic prokinetics are the most common medication prescribed as second line. CONCLUSIONS: The survey also outlined that gastroenterologists need to perform a more adequate approach addressing patient’s characteristics, mainly concerning a more thorough history, use of validated scales for symptoms, and assess quality of life.

Abstract Number ‐ 164: Clot Density as a Predictor for Successful Mechanical Thrombectomy

Introduction Switching mechanical thrombectomy techniques (ADAPT, SR or combination) mid procedure has the potential to prolong time to recanalization as well as increase associated healthcare costs. The basis of selecting the frontline technique still relies heavily on the operators’ preference. Conflicting results indicating the varying performance of techniques relative to clot composition have been reported. Clot composition can be estimated based on clot density calculated in Hounsfield Units (HU) on pre‐intervention CT. Identifying how various clot composites behave can aid in the decision making for selecting a frontline technique.Our objective is to determine if clot density as measured by Hounsfield units can predict successful recanalization with ADAPT and the need for rescue stentriever when using ADAPT as the first line technique. Methods Retrospective review of all patients undergoing mechanical thrombectomy with first pass ADAPT at a single urban tertiary care academic stroke center. Clot HU values were calculated on pre‐intervention scans. We evaluated the number of passes, the use of rescue SR, the post intervention TICI grade and mRS on final follow up. Results There were 167 patients that underwent MT with ADAPT as the frontline approach. 122 were excluded for inability to calculate HU on pre‐ intervention scans, most often due to contamination with contrast media. 45 patients were included in the final analysis. 18/45 (40%) required SR rescue due to incomplete recanalization with first pass ADAPT. HU were dichotomized around the mean to “high” and “low”. Higher HU value was associated higher likelihood of SR use and higher final mRS scores, these however did not reach statistical significance. There was no difference in the total number of passes or the final TICI grade. AUC and ROC did not show a correlation between HU value and the use of SR or a higher number of passes need to achieve TICI ≥ 2b recanalization. Conclusions In our patient cohort, HU value was not able to predetermine the success rate of MT using ADAPT. There was no correlation between HU value and functional outcomes of patients. Reliability of clot HU value in determining MT success with ADAPT could not be established. Other factors should be considered when selecting frontline technique in mechanical thrombectomy.

Abstract WMP96: A Prospective Trial Of The Rapidpulse Tm Aspiration System As Frontline Approach For Stroke Thrombectomy (RapidPulseFS)

Introduction: First-pass effect (FPE) is associated with improved clinical outcomes and reduced mortality in mechanical thrombectomy (MT) for large vessel occlusion strokes (LVOS). However, FPE is achieved in only 30-40% of patients with the current devices. The RapidPulse TM Cyclic Aspiration System (RP) is a novel technology consisting of a valve box that precisely cycles pressure from full to no vacuum multiple times per second adding kinetic energy to the suction forces. Initial clinical evaluation suggests that the system can achieve FPE rates in the 70% range. We aim to evaluate the RP as a frontline approach in LVOS. Methods: Prospective, multicenter, open-label, core lab adjudicated, two-arm study comparing the safety and efficacy of the RP System with non-randomized retrospective controls who were consecutively treated at the study sites based on similar eligibility criteria. Patients with LVOS involving the anterior or posterior circulations in whom the target lesion could be treated with the Medtronic React 71 aspiration catheter up to 24 hours from stroke onset were included in the RP arm. Controls consisted of comparable patients treated with 070-072 ID catheters. The primary outcome was the rate of FPE (complete/near reperfusion [mTICI ≥2c] after a single pass). Secondary outcomes include frontline technical success (defined as mTICI ≥2b after final device pass with no rescue therapy), final mTICI after all passes, symptomatic ICH, device-related complications, the proportion of patients achieving a modified Rankin Scale score of 0-2 at 90 days, and all-cause 90-day mortality. The study will enroll a maximum of 100 participants in the RP and 200 in the control arm at 5 centers in Spain, Turkey, Denmark, Latvia, and Brazil. Results: Final results will be presented at the conference. Conclusion: RapidPulseFS is the first prospective clinical trial aiming to compare cyclic versus standard aspiration technologies. This novel device may allow clinicians to achieve faster and better reperfusion while significantly reducing the disposable device costs associated with treating LVOS (ClinicalTrials.gov Identifier: NCT05122637).

A Front-line Preventive Approach to COVID-19

A Front-line Preventive Approach to COVID-19

Global Treatment Standard in Multiple Myeloma Remains Elusive: Updated Results from the INSIGHT MM Global, Prospective, Observational Study

Introduction INSIGHT MM (NCT02761187) is the largest global, prospective, observational multiple myeloma (MM) study to date, with 4188 newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) patients (pts) included in this cross-sectional analysis. The study aims to describe contemporary, real-world patterns of pt & disease characteristics, treatment patterns, & outcomes. An interim analysis of the first 1000 pts enrolled to INSIGHT MM suggested considerable regional variation in treatment patterns (Boccadoro et al, EHA 2018). The aim of the current analysis is to characterize treatment patterns by world regions & line of therapy (LOT) in the overall INSIGHT MM study population. Methods Pts were enrolled at academic & community treatment facilities in 15 countries between July 2016 & July 2021. Data on prior & current treatments were collected at baseline & every 3 months. Full study methods have been reported previously (Costello 2019). We report a cross-sectional analysis of treatment regimens used in NDMM & RRMM pts at a data cut-off of Sept 30, 2021. A subset of pts with no protocol deviations (pts meeting all inclusion criteria who started index regimen <90 days before enrollment & enrolled at centers where data quality checks could be conducted) were included in an analysis of treatment shift patterns from first to second & subsequent LOTs. Results Among the 4188 pts, there were 2338 (55.8%) NDMM & 1850 (44.2%) RRMM cases at enrollment. This includes 2046 pts from Europe (EUR; Belgium, France, Germany, Greece, Italy, Spain, Turkey, United Kingdom; also includes Israel); 1317 pts from the United States (US); 470 pts from Latin America (LA; Brazil, Columbia, Mexico); & 355 pts from Asia (China, Taiwan). Median follow-up was 27.9 months. In NDMM pts, triplet therapy was the most common frontline approach across all regions (71.1% of pts overall); only 12.0% of pts received frontline doublet therapy. Triplet therapy typically included a proteasome inhibitor (PI) & dexamethasone (d; 62.5%). The most commonly used regimen was bortezomib (V), lenalidomide (R), & d (VRd; 23.5%); V-based triplet therapy with d & an IMiD was prescribed to 34.7% of NDMM pts overall. V-based triplets were the most widely used regimens across all regions. The US was the only region where carfilzomib (K) was included in one of the three most frequently used regimens (KRd in 8.3% of pts). Choice of IMiD varied regionally: R was most commonly used in the US, & thalidomide in EUR, LA, & Asia. In EUR & LA, cyclophosphamide (alkylating agent) was more commonly used than IMiDs. Vd (4.1%) & Rd (4.0%) doublets were the fourth & fifth most common regimens overall. Among RRMM pts, 49.6% received triplets & 33.7% received doublets. Triplet therapy was the most common approach across all LOTs & all regions except Asia; in Asia, doublets were more widely used than triplets (48.9% vs 42.4%). Rd was the most common regimen overall (15.4% across all regions & LOTs), & ixazomib-Rd (IRd) was the most common triplet (7.9% in all regions & LOTs; KRd was the second most common triplet overall [5.2%]). Unlike NDMM pts, RRMM pts were more likely to receive alternative PIs to V in ≥2nd LOT (IRd 6.8%; KRd 6.7%; VRd 2.7%), & daratumumab (D) was used instead of or alongside PIs in some triplets (DRd 4.9%; VDd 4.5%). Overall, 20.8% of pts received D as part of single-agent, doublet, triplet, or >triplet therapy. D was more widely used in the US (33.5%) than other regions (14.4-16.2%). Treatment shift patterns were examined in 3263 pts for whom robust data were available (1236 who underwent stem cell transplantation [SCT] in first line of therapy & 2027 who did not [NSCT]). A shift from predominantly PI- or PI/IMiD-based frontline therapy in both SCT & NSCT pts to more varied second-line regimens, including monoclonal antibody (mAb) therapy, was observed (Figure). Treatment shift patterns in later LOTs & across regions will be presented. Conclusions V-based triplets were the most common frontline treatment in NDMM pts in all regions. Regimens used in later LOTs in RRMM pts were more varied across regions, & generally included greater use of doublets, PIs other than V, & mAbs such as D. Acknowledging that treatment use is dependent on approval status & availability, this analysis shows that, while global frontline standard of care (SOC) is broadly established, there remains no consistent SOC in later LOTs; adoption of newer therapies, such as mAbs, varies across regions worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thrombolytic efficacy of histotripsy combined with thrombolytic-loaded echogenic liposomes

Deep vein thrombosis (DVT) is a substantial burden to the American public. Thrombolytics drugs are the front-line approach to treat the most egregious forms of DVT. Histotripsy is a bubble-based focused ultrasound therapy that enhances thrombolytic activity while simultaneously breaking down erythrocytes within the thrombus mechanically. Loading thrombolytics inside echogenic liposomes may accentuate the action of histotripsy via site-specific thrombolytic release and prompt bubble nuclei. The objective of this study was to assess clot degradation under the action of histotripsy and echogenic liposomes in an in vitro venous flow model. Histotripsy pulses were applied along the length of the clot at pulse peak negative pressures of 0 (control) or 42 MPa. Echogenic liposomes were diluted into the perfusate such that the thrombolytic concentration was 0 or 2.68 μg/ml. The combination of histotripsy and echogenic liposomes displayed increased clot mass loss, thrombolytic activity, hemolysis, and intact erythrocytes in the perfusate relative to echogenic liposomes alone (ANOVA p &amp;lt; 0.05, n = 6–8/group). Expect for hemolysis, markers of clot degradation were increased for histotripsy and echogenic liposome arms relative to histotripsy exposure alone. Together, these data indicate histotripsy combined with thrombolytics is a promising approach for the treatment of DVT.

Coincident Regulation of PLCβ Signaling by Gq-Coupled and μ-Opioid Receptors Opposes Opioid-Mediated Antinociception.

Pain management is an important problem worldwide. The current frontline approach for pain management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3) or selective inhibition of Gβγ regulation of PLCβ3 enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid-sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in human embryonic kidney 293 cells and found that MOR alone could not stimulate PLC but rather required a coincident signal from a Gq-coupled receptor. Knockout of PLCβ3 or pharmacological inhibition of its upstream regulators, Gβγ or Gq, ex vivo in periaqueductal gray slices increased the potency of the selective MOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate salt in inhibiting presynaptic GABA release. Finally, inhibition of Gq- G protein-coupled receptor coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβγ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately, this could lead to identification of new non-MOR targets that would allow for lower-dose utilization of opioid analgesics. SIGNIFICANCE STATEMENT: Previous work demonstrated that deletion of phospholipase Cβ3 (PLCβ3) in mice potentiates μ-opioid receptor (MOR)-dependent antinociception. How PLCβ3 is regulated downstream of MOR had not been clearly defined. We show that PLC-dependent diacylglycerol generation is cooperatively regulated by MOR-Gβγ and Gq-coupled receptor signaling through PLCβ3 and that blockade of either Gq-signaling or Gβγ signaling enhances the potency of opioids in ex vivo brain slices and in vivo. These results reveal potential novel strategies for improving opioid analgesic potency and safety.

Effect of Thrombin and Incubation Time on Porcine Whole Blood Clot Elasticity and Recombinant Tissue Plasminogen Activator Susceptibility.

Deep vein thrombosis is a major source of morbidity and mortality worldwide. Catheter-directed thrombolytics are the frontline approach for vessel recanalization, though fibrinolytic efficacy is limited for stiff, chronic thrombi. Although thrombin has been used in preclinical models to induce thrombosis, the effect on lytic susceptibility and clot stiffness is unknown. The goal of this study was to explore the effect of bovine thrombin concentration and incubation time on lytic susceptibility and stiffness of porcine whole blood clots in vitro. Porcine whole blood was allowed to coagulate at 37°C in glass pipets primed with 2.5 or 15 U/mL thrombin for 15 to 120 min. Lytic susceptibility to recombinant tissue plasminogen activator (rt-PA, alteplase) over a range of concentrations (3.15-107.00 µg/mL) was evaluated using percentage clot mass loss. The Young's moduli and degrees of retraction of the clots were estimated using ultrasound-based single-track-location shear wave elasticity and B-mode imaging, respectively. Percentage mass loss decreased and clot stiffness increased with the incubation period. Clots formed with 15 U/mL and incubated for 2 h exhibited properties similar to those of highly retracted clots: Young's modulus of 2.39 ± 0.36 kPa and percentage mass loss of 8.69 ± 2.72% when exposed to 3.15 µg/mL rt-PA. The histological differences between thrombin-induced porcine whole blood clots in vitro and thrombi in vivo are described.

Hypothesizing in the Face of the Opioid Crisis Coupling Genetic Addiction Risk Severity (GARS) Testing with Electrotherapeutic Nonopioid Modalities Such as H-Wave Could Attenuate Both Pain and Hedonic Addictive Behaviors.

In the United States, amid the opioid overdose epidemic, nonaddicting/nonpharmacological proven strategies are available to treat pain and manage chronic pain effectively without opioids. Evidence supporting the long-term use of opioids for pain is lacking, as is the will to alter the drug-embracing culture in American chronic pain management. Some pain clinicians seem to prefer classical analgesic agents that promote unwanted tolerance to analgesics and subsequent biological induction of the “addictive brain”. Reward genes play a vital part in modulation of nociception and adaptations in the dopaminergic circuitry. They may affect various sensory and affective components of the chronic pain syndromes. The Genetic Addiction Risk Severity (GARS) test coupled with the H-Wave at entry in pain clinics could attenuate pain and help prevent addiction. The GARS test results identify high-risk for both drug and alcohol, and H-Wave can be initiated to treat pain instead of opioids. The utilization of H-Wave to aid in pain reduction and mitigation of hedonic addictive behaviors is recommended, notwithstanding required randomized control studies. This frontline approach would reduce the possibility of long-term neurobiological deficits and fatalities associated with potent opioid analgesics.

Endovascular Treatment of Acute Ischemic Stroke With the Penumbra System in Routine Practice: COMPLETE Registry Results

The purpose of the COMPLETE (International Acute Ischemic Stroke Registry With the Penumbra System Aspiration Including the 3D Revascularization Device) registry was to evaluate the generalizability of the safety and efficacy of the Penumbra System (Penumbra, Inc, Alameda) in a real-world setting. COMPLETE was a global, prospective, postmarket, multicenter registry. Patients with large vessel occlusion-acute ischemic stroke who underwent mechanical thrombectomy using the Penumbra System with or without the 3D Revascularization Device as frontline approach were enrolled at 42 centers (29 United States, 13 Europe) from July 2018 to October 2019. Primary efficacy end points were successful postprocedure angiographic revascularization (modified Thrombolysis in Cerebral Infarction ≥2b) and 90-day functional outcome (modified Rankin Scale score 0-2). The primary safety end point was 90-day all-cause mortality. An imaging core lab determined modified Thrombolysis in Cerebral Infarction scores, Alberta Stroke Program Early CT Scores, clot location, and occurrence of intracranial hemorrhage at 24 hours. Independent medical reviewers adjudicated safety end points. Six hundred fifty patients were enrolled (median age 70 years, 54.0% female, 49.2% given intravenous recombinant tissue-type plasminogen activator before thrombectomy). Rate of modified Thrombolysis in Cerebral Infarction 2b to 3 postprocedure was 87.8% (95% CI, 85.3%-90.4%). First pass and postprocedure rates of modified Thrombolysis in Cerebral Infarction 2c to 3 were 41.5% and 66.2%, respectively. At 90 days, 55.8% (95% CI, 51.9%-59.7%) had modified Rankin Scale score 0 to 2, and all-cause mortality was 15.5% (95% CI, 12.8%-18.3%). Using Penumbra System for frontline mechanical thrombectomy treatment of patients with large vessel occlusion-acute ischemic stroke in a real-world setting was associated with angiographic, clinical, and safety outcomes that were comparable to prior randomized clinical trials with stringent site and operator selection criteria. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03464565.

Atezolizumab plus vemurafenib and cobimetinib for the treatment of BRAF V600-mutant advanced melanoma: from an hypothetic triplet to an approved regimen

ABSTRACT Introduction Breakthrough changes in melanoma management induced by the introduction of BRAF/MEK inhibitors and immune checkpoint inhibitors (ICPIs) have motivated subsequent research to combine these strategies in the frontline approach of BRAFV600-mutant advanced melanoma. Initial preclinical data have shown that targeted agents may have a favorable immune impact on the tumor microenvironment and next, numerous trials tried to identify the optimal combination and sequence of immunotherapy and targeted therapy. Up until last year, when the first immune/targeted regimen including atezolizumab, vemurafenib and cobimetinib, was approved by the FDA. Areas covered Focusing on this first-in-class immune/targeted regimen, we describe here the entire process for its approval, from the bench of preclinical studies to the clinical evaluation of its efficacy and its toxicity profile on treated patients with advanced BRAF-mutant melanoma. All raised concerns about the use of atezolizumab/vemurafenib/cobimetinib triplet are thoroughly discussed. Expert opinion The atezolizumab/vemurafenib/cobimetinib triplet is an effective frontline option for advanced BRAF-mutant melanoma but its generalized implementation remains limited due to toxicity and cost. Results of ongoing trials are expected to identify more clearly the best candidates for such combinations and to update the role of immune/targeted triplets in melanoma treatment.

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

BackgroundHereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient’s personal and/or family history of cancer.MethodsA 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).ResultsA 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.ConclusionThis study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.