Cancer Nano-Immunotherapy: The Novel and Promising Weapon to Fight Cancer.

Cancer is a complex disease that, despite advances in treatment and the greater understanding of the tumor biology until today, continues to be a prevalent and lethal disease. Chemotherapy, radiotherapy, and surgery are the conventional treatments, which have increased the survival for cancer patients. However, the complexity of this disease together with the persistent problems due to tumor progression and recurrence, drug resistance, or side effects of therapy make it necessary to explore new strategies that address the challenges to obtain a positive response. One important point is that tumor cells can interact with the microenvironment, promoting proliferation, dissemination, and immune evasion. Therefore, immunotherapy has emerged as a novel therapy based on the modulation of the immune system for combating cancer, as reflected in the promising results both in preclinical studies and clinical trials obtained. In order to enhance the immune response, the combination of immunotherapy with nanoparticles has been conducted, improving the access of immune cells to the tumor, antigen presentation, as well as the induction of persistent immune responses. Therefore, nanomedicine holds an enormous potential to enhance the efficacy of cancer immunotherapy. Here, we review the most recent advances in specific molecular and cellular immunotherapy and in nano-immunotherapy against cancer in the light of the latest published preclinical studies and clinical trials.

Integrin alpha9 emerges as a key therapeutic target to reduce metastasis in rhabdomyosarcoma and neuroblastoma.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.

Contemporary risk factors for a longer hospital stay following bidirectional cavopulmonary anastomosis.

BACKGROUND: Despite high survival after bidirectional cavopulmonary anastomosis, a considerable number of patients suffer significant post-operative morbidities related to prolonged length of stay. METHODS: A single-center retrospective cohort study of all consecutive patients undergoing a first-time bidirectional cavopulmonary anastomosis from 2006 to 2019. RESULTS: Prolonged length of stay was defined as hospital stay greater than the 75th percentile for our cohort. Of 195 patients who met inclusion criteria, the median post-operative length of stay was 8 days (interquartile range, 4-15 days). Prolonged length of stay was defined as greater than 15 days. In multivariate analysis, greater than mild systemic atrioventricular valve regurgitation (odds ratio 3.7, 95% CI 1.05-13.068, p = 0.04), longer length of stay after the initial palliative procedure (odds ratio 1.028, 95% CI 1.004-1.05, p = 0.02), and pre-operative higher superior vena cava oxygen saturation (odds ratio 0.922, 95% CI 0.85-0.99, p = 0.04) maintained statistical significance as independent risk and protective factors for prolonged length of stay. A one-level increase in the severity of pre-operative systemic atrioventricular valve regurgitation was associated with a multiplicative change in the odds ratio of prolonged length of stay of 5.45 (p = 0.005) independent of the severity of systemic ventricular dysfunction. CONCLUSION: Pre-operative characteristics with greater than mild systemic atrioventricular valve regurgitation, longer length of stay after the initial palliative procedure, and lower superior vena cava oxygen saturation were associated with prolonged length of stay after a first-time bidirectional cavopulmonary anastomosis.

Defining the Emergence of New Immunotherapy Approaches in Breast Cancer: Role of Myeloid-Derived Suppressor Cells.

Breast cancer (BC) continues to be the most diagnosed tumor in women and a very heterogeneous disease both inter- and intratumoral, mainly given by the variety of molecular profiles with different biological and clinical characteristics. Despite the advancements in early detection and therapeutic strategies, the survival rate is low in patients who develop metastatic disease. Therefore, it is mandatory to explore new approaches to achieve better responses. In this regard, immunotherapy arose as a promising alternative to conventional treatments due to its ability to modulate the immune system, which may play a dual role in this disease since the relationship between the immune system and BC cells depends on several factors: the tumor histology and size, as well as the involvement of lymph nodes, immune cells, and molecules that are part of the tumor microenvironment. Particularly, myeloid-derived suppressor cell (MDSC) expansion is one of the major immunosuppressive mechanisms used by breast tumors since it has been associated with worse clinical stage, metastatic burden, and poor efficacy of immunotherapies. This review focuses on the new immunotherapies in BC in the last five years. Additionally, the role of MDSC as a therapeutic target in breast cancer will be described.

Gore Cardioform ASD device thrombus weeks after COVID-19 infection.

Device-related thrombosis and device-related endocarditis after atrial septal defect (ASD) transcatheter closure are extremely rare. It is known that COVID-19 infection could lead to a thrombotic microangiopathy-like phenomenon. We present the case of a 14-year-old female who developed fever and was found to have a thrombus on the right atrial side of the ASD closure device weeks after an asymptomatic COVID-19 infection and negative COVID-19 test 2 days before transcatheter ASD closure. Although there is no certainty that the thrombus was related to the prior COVID-19 infection, the possibility of an ongoing COVID-19-related hypercoagulable state should be entertained.

The incidence of recurrent laryngeal nerve injury resulting in vocal cord paralysis following interventional congenital catheterisation procedures.

BACKGROUND: Recurrent laryngeal nerve injury leading to vocal cord paralysis is a known complication of cardiothoracic surgery. Its occurrence during interventional catheterisation procedures has been documented in case reports, but there have been no studies to determine an incidence. OBJECTIVE: To establish the incidence of left recurrent laryngeal nerve injury leading to vocal cord paralysis after left pulmonary artery stenting, patent ductus arteriosus device closure and the combination of the procedures either consecutively or simultaneously. METHODS: Members of the Congenital Cardiovascular Interventional Study Consortium were asked to perform a retrospective analysis to identify cases of recurrent laryngeal nerve injury after the aforementioned procedures. Twelve institutions participated in the analysis. They also contributed the total number of each procedure performed at their respective institutions for statistical purposes. RESULTS: Of the 1337 patients who underwent left pulmonary artery stent placement, six patients (0.45%) had confirmed vocal cord paralysis. 4001 patients underwent patent ductus arteriosus device closure, and two patients (0.05%) developed left vocal cord paralysis. Patients who underwent both left pulmonary artery stent placement and patent ductus arteriosus device closure had the highest incidence of vocal cord paralysis which occurred in 4 of the 26 patients (15.4%). Overall, 92% of affected patients in our study population had resolution of symptoms. CONCLUSION: Recurrent laryngeal nerve injury is a rare complication of left pulmonary artery stent placement or patent ductus arteriosus device closure. However, the incidence is highest in patients undergoing both procedures either consecutively or simultaneously. Additional research is necessary to determine contributing factors that might reduce the risk of recurrent laryngeal nerve injury.

Obesity and Risk for Lymphoma: Possible Role of Leptin.

Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.

Long-term outcome of percutaneous intervention for pulmonary vein stenosis after pulmonary vein isolation procedure.

OBJECTIVES: Report long-term outcomes of percutaneous intervention in patients with pulmonary vein stenosis (PVS) after pulmonary vein isolation (PVI) from a single center over 16 years. BACKGROUND: Outcome reports of percutaneous intervention for PVS resulting from PVI are limited. METHODS: Retrospective review of all patients with PVS after PVI who underwent percutaneous intervention at the Cleveland Clinic Foundation between January 2000 and December 2016. RESULTS: A total of 205 patients underwent cardiac catheterization for PVS during the study period. Completely occluded veins which could not be recanalized occurred in six patients. Of the remaining 199 patients, 27 (14%) were lost to follow-up, leaving 172 patients with 276 veins for analysis. Balloon angioplasty was performed in 62 veins and stent implantation in 250 (primary in 214, to treat postdilation restenosis in 36). Re-intervention occurred in 45/62 (73%) balloon-dilated veins and 45/250 (18%) stented veins. Freedom from re-intervention at 1 and 5 years was 90 and 73% following stenting versus 40 and 23% following balloon dilation (p < .001, Hazard ratio (HR) = 5.7). Veins with stent diameter ≥7 mm (n = 231) had greater freedom from re-intervention (95% at 1 year, 79% at 5 years) than veins with stents <7 mm (43% at 1 year, 9% at 5 years), p < .001. There was clear symptomatic improvement after intervention and no procedural mortality. CONCLUSIONS: Stent implantation at ≥7 mm for PVS after PVI is associated with low rates of re-intervention, in contrast to balloon dilation and stenting with small conventional stents.

Treatment of Congenital and Acquired Pulmonary Vein Stenosis.

PURPOSE OF REVIEW: Pulmonary vein stenosis (PVS) is a rare entity that until the last 2 decades was seen primarily in infants and children. Percutaneous and surgical interventions have limited success due to relentless restenosis, and mortality remains high. In adults, acquired PVS following ablation for atrial fibrillation has emerged as a new syndrome. This work will review these two entities with emphasis on current treatment. RECENT FINDINGS: Greater emphasis on understanding and addressing the mechanism of restenosis for congenital PVS has led to the use of drug-eluting stents (DES) and systemic drug therapy to target neo-intimal growth. Frequent reinterventions are positively affecting outcomes. Longer-term outcomes of percutaneous treatment for acquired PVS are emerging. Treatment of congenital PVS continues to be plagued by restenosis. DES show promise, but frequent reinterventions are required. Larger upstream vein diameter predicts success for congenital and acquired PVS interventions. Efforts to induce/maintain vessel growth are important for future treatment strategies.

PiSCES: Pi(scine) stream community estimation system.

The Piscine Stream Community Estimation System (PiSCES) provides users with a hypothesized fish community for any stream reach in the conterminous United States using information obtained from Nature Serve, the US Geological Survey (USGS), StreamCat, and the Peterson Field Guide to Freshwater Fishes of North America for over 1000 native and non-native freshwater fish species. PiSCES can filter HUC8-based fish assemblages based on species-specific occurrence models; create a community abundance/biomass distribution by relating relative abundance to mean body weight of each species; and allow users to query its database to see ancillary characteristics of each species (e.g., habitat preferences and maximum size). Future efforts will aim to improve the accuracy of the species distribution database and refine/augment increase the occurrence models. The PiSCES tool is accessible at the EPA's Quantitative Environmental Domain (QED) website at https://qed.epacdx.net/pisces/.

Multicenter Assessment of Radiation Exposure during Pediatric Cardiac Catheterizations Using a Novel Imaging System.

OBJECTIVES: To quantify radiation exposure during pediatric cardiac catheterizations performed by multiple operators on a new imaging platform, the Artis Q.zen (Siemens Healthcare, Forchheim, Germany), and to compare these data to contemporary benchmark values. BACKGROUND: The Artis Q.zen has been shown to achieve significant radiation reduction during select types of pediatric cardiac catheterizations in small single-center studies. No large multicenter study exists quantifying patient dose exposure for a broad spectrum of procedures. METHODS: Retrospective collection of Air Kerma (AK) and dose area product (DAP) for all pediatric cardiac catheterizations performed on this new imaging platform at four institutions over a two-year time period. RESULTS: A total of 1,127 pediatric cardiac catheterizations were analyzed. Compared to dose data from earlier generation Artis Zee imaging systems, this study demonstrates 70-80% dose reduction (AK and DAP) for similar patient and procedure types. Compared to contemporary benchmark data for common interventional procedures, this study demonstrates an average percent reduction in AK and DAP from the lowest dose saving per intervention of 39% for AK and 27% for DAP for transcatheter pulmonary valve implantation up to 77% reduction in AK and 70% reduction in DAP for atrial septal defect closure. CONCLUSION: Use of next-generation imaging platforms for pediatric cardiac catheterizations can substantially decrease patient radiation exposure. This multicenter study defines new low-dose radiation measures achievable on a novel imaging system.

EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma.

Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling. Now we wanted to explore EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897 ), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p-EphA2S897 . Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non-phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.

Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes.

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.

Capturing Microbial Sources Distributed in a Mixed-use Watershed within an Integrated Environmental Modeling Workflow.

Many watershed models simulate overland and instream microbial fate and transport, but few provide loading rates on land surfaces and point sources to the waterbody network. This paper describes the underlying equations for microbial loading rates associated with 1) land-applied manure on undeveloped areas from domestic animals; 2) direct shedding (excretion) on undeveloped lands by domestic animals and wildlife; 3) urban or engineered areas; and 4) point sources that directly discharge to streams from septic systems and shedding by domestic animals. A microbial source module, which houses these formulations, is part of a workflow containing multiple models and databases that form a loosely configured modeling infrastructure which supports watershed-scale microbial source-to-receptor modeling by focusing on animal- and human-impacted catchments. A hypothetical application - accessing, retrieving, and using real-world data - demonstrates how the infrastructure can automate many of the manual steps associated with a standard watershed assessment, culminating in calibrated flow and microbial densities at the watershed's pour point.

Translational Pharmacology of the Metabotropic Glutamate 2 Receptor-Preferring Agonist LY2812223 in the Animal and Human Brain.

LY2812223 [(1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid] was identified via structure-activity studies arising from the potent metabotropic glutamate mGlu2/3 receptor agonist LY354740 [(+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid] as an mGlu2-preferring agonist. This pharmacology was determined using stably transfected cells containing either the human mGlu2 or mGlu3 receptor. We extended the pharmacological evaluation of LY2812223 to native brain tissues derived from relevant species used for preclinical drug development as well as human postmortem brain tissue. This analysis was conducted to ensure pharmacological translation from animals to human subjects in subsequent clinical studies. A guanosine 5'-O-(3-[35S]thio)triphosphate (GTPγS) functional binding assay, a method for measuring Gi-coupled signaling that is inherent to the group 2 mGlu receptors, was used to evaluate LY2812223 pharmacology of native mGlu receptors in mouse, rat, nonhuman primate, and human cortical brain tissue samples. In native tissue membranes, LY2812223 unexpectedly acted as a partial agonist across all species tested. Activity of LY2812223 was lost in cortical membranes collected from mGlu2 knockout mice, but not those from mGlu3 knockout mice, providing additional support for mGlu2-preferring activity. Other signal transduction assays were used for comparison with the GTP binding assay (cAMP, calcium mobilization, and dynamic mass redistribution). In ectopic cell line-based assays, LY2812223 displayed near maximal agonist responses at the mGlu2 receptor across all assay formats, while it showed no functional agonist activity at the mGlu3 receptor except in the cAMP assay. In native brain slices or membranes that express both mGlu2 and mGlu3 receptors, LY2812223 displayed unexpected partial agonist activity, which may suggest a functional interplay between these receptor subtypes in the brain.

Results of coil closure of patent ductus arteriosus using a tapered tip catheter for enhanced control.

OBJECTIVES: This article describes the efficacy and embolization rates of coil delivery via modified vertebral catheter (MVC) for patent ductus arteriosus (PDA) closure. BACKGROUND: Various techniques have been devised to enhance coil control and prevent embolization during PDA closure. Since 1995, they have delivered coils via tapered vertebral catheters for improved coil control. METHODS: Catheterization reports, angiograms, and echocardiograms were reviewed for patients with PDA occlusion via MVC from 2001 to 2014. Residual shunting was determined by angiography and echocardiogram within 24 hr post-procedure. Procedural success was defined as ≤ trivial angiographic and echocardiographic shunt, and no aortic nor LPA obstruction, after final coil delivery. RESULTS: About 125 coil occlusions were attempted in 103 patients. Minimal PDA diameter was 2 (0.6-6) mm. Four coils were removed with a snare/bioptome due to aortic/LPA obstruction following release. Seven were malpositioned while still held by the MVC of which three embolized while attempting withdrawal. Five embolized after full release from the MVC. The embolization rate was 6.4%. Embolizations were more likely in PDAs ≥ 2.5 mm (P < 0.05). Ultimately, 98/103 PDAs were occluded using the MVC. No patient had greater trivial residual shunt or aortic/LPA obstruction for an overall success rate of 95%. For PDAs < 2.5 mm the success rate was 97%. CONCLUSIONS: Coil delivery via MVC was safe and effective for small PDAs. While fully controlled release and retrieval devices are now available for PDA closure with lower embolization rates, coil occlusion by MVC should still be considered for small PDAs, especially in resource limited regions. © 2016 Wiley Periodicals, Inc.

Percutaneous removal of unraveled HELEX® septal occluder 4 months post deployment.

The GORE® HELEX® Septal Occluder (HSO: W.L. Gore & Associates; Flagstaff, AZ) is preferentially used at our institution for percutaneous closure of the patent foramen ovale (PFO). Adequate deployment of the device requires capture of three sequential eyelets by the locking loop. At times, the right atrial eyelet is not caught, particularly when a long tunnel PFO causes too much separation between the discs. Although rarely, unlocked devices have been left in the atrial septum with no untoward events provided they appear stable in the catheterization laboratory and the shunt has been eliminated. We report a patient in whom an unlocked, but otherwise well positioned, HSO subsequently unraveled with the right atrial disc migrating through the tricuspid valve while the left atrial disc remained well apposed to the left side of the atrial septum. The PFO was closed prior to liver transplantation to prevent an embolic event during the transplant. The patient required placement of several internal jugular central lines prior to transplant, and this instrumentation in the right atrium may have caused unraveling of the device. The HSO was removed percutaneously 15 weeks after implantation despite a well-seated and likely partially endothelialized left atrial disc.

Transcatheter structural cardiac intervention: a radiology perspective.

OBJECTIVE: Valvular heart disease continues to remain a significant cardiovascular problem worldwide. Imaging techniques, such as echocardiography, CT, and MRI have enabled development of newer transcatheter approaches for cardiovascular diseases. CONCLUSION: In this article, we discuss the commonly seen valvular diseases and various transcatheter valvular intervention techniques. We highlight the roles of CT and MRI in planning these procedures and discuss critical reporting information that needs to be conveyed to the interventionalists.

Complications related to transhepatic venous access in the catheterization laboratory--a single center 12-year experience of 124 procedures.

OBJECTIVES: To identify complications and measures that can be undertaken to prevent complications from transhepatic central venous access. BACKGROUND: Utility and safety data from a large experience of patients undergoing transhepatic venous access are lacking. METHODS: The records of patients who underwent transhepatic venous access between June 2000 and October 2012 at The Center for Pediatric and Congenital Heart Disease at The Cleveland Clinic were reviewed. RESULTS: One hundred twenty-four transhepatic procedures were performed in 81 patients. The median weight of the patients was 6.3 (2.2-94) kg at a median age of 7 months (2 weeks to 35 years). Diagnostic catheterizations were performed in 75, interventions in 39, and central venous line placement in 91 procedures. The median maximum sheath size inserted was 8 (4-14) French. There were 10 (8%) major adverse events in 8 procedures-bleeding related (n = 6 with 1 death as a result) or complete heart block with instability or requiring intervention (n = 4). Heart block persisted after the catheterization in three patients (2 days, 2 weeks, 1 month). Minor adverse events (transient heart block) occurred in 5 (4 %) procedures. Weight, age, and French size of sheath (P = 0.46, 0.84, and 0.18) were not associated with complications. In addition, time to gain access was not different between non-complicated and complicated cases (median 19.5 versus 15.1 min, P = 0.72). Diagnostic and interventional procedures were not associated with more complications compared with procedures involving central venous line placement alone (P = 0.5). CONCLUSIONS: Transhepatic access is an extremely useful modality of access to the heart and vascular structures in some patients with complex heart disease. Prevention of complications should focus on minimizing bleeding risks and heart block.

Helex device closure of multiple atrial septal defects.

OBJECTIVES: To describe the effectiveness of the Helex Septal Occluder (HSO) to close multiple atrial septal defects (mASDs). Background : Limited information is available describing closure of mASDs with the HSO. METHODS: A total of 28 patients who underwent closure of mASDs with the HSO were identified by retrospective review of our catheterization database between 2001 and 2012. Procedural details and follow up information were collected. RESULTS: Median age was 19.2 years, median weight 48 kg, with 10 (36%) patients weighing <25 kg. Indication for closure was RV enlargement (RVE) in all patients and additionally neurologic events occurred in 3/28 (11%). Median stop-flow diameter for the largest ASD was 14 (4-23) mm. One HSO was implanted in 21/28 (75%), 2 in 6/28 (21%), and 3 in 1/28 (4%). One embolization and one transient arrhythmia occurred with no sequelae. Immediate residual shunt was absent in 5/28 (18%), trivial in 15/28 (54%), small in 6/28 (21%), and moderate in 2/28 (7%). Of the 25 patients with ≥6 months follow-up (median 53 months), residual shunt was absent in 13/25 (52%), trivial in 5/25 (20%), and small in 7/25 (28%). RVE resolved in all but one patient with no other associated lesions and ≥6 months of follow-up. No patient with prior neurological event had recurrence at last follow-up. CONCLUSIONS: We conclude that closure of mASDs with ≥1 HSO is effective with a low complication rate. The ability of HSO devices to overlap or sandwich each other may facilitate safe implantation of multiple devices in smaller patients.