Chest Pain in the Cancer Patient.

Chest pain is one of the most common presenting symptoms in patients seeking care from a physician. Risk assessment tools and scores have facilitated prompt diagnosis and optimal management in these patients; however, it is unclear as to whether a standardised approach can adequately triage chest pain in cancer patients and survivors. This is of concern because cancer patients are often at an increased risk of cardiovascular mortality and morbidity given the shared risk factors between cancer and cardiovascular disease, compounded by the fact that certain anti-cancer therapies are associated with an increased risk of cardiovascular events that can persist for weeks and even years after treatment. This article describes the underlying mechanisms of the most common causes of chest pain in cancer patients with an emphasis on how their management may differ to that of non-cancer patients with chest pain. It will also highlight the role of the cardio-oncology team, who can aid in identifying cancer therapy-related cardiovascular side-effects and provide optimal multidisciplinary care for these patients.

Entrectinib-related myocarditis in a young female patient with metastatic non-small cell lung cancer.

A 51-year-old woman presented with a 2-week history of off balance, left lower limb weakness and neglect and neck pain radiating down the right arm. Investigations revealed a metastatic, ROS1 fusion-positive, non-small cell lung cancer, and treatment with entrectinib, a recently approved multikinase inhibitor, was started. Two weeks after, she was admitted to the emergency department with new-onset pressure-like chest pain and dyspnoea. Laboratory evaluation showed elevated troponin and mild left ventricular systolic dysfunction with reduced global longitudinal strain on transthoracic echocardiogram. Cardiac magnetic resonance revealed mild oedema and non-ischaemic fibrosis. A diagnosis of drug-induced myocarditis was made. Cardioprotective medication with an angiotensin-converting enzyme inhibitor and a beta-blocker was started. Entrectinib was temporarily discontinued and restarted at a reduced dose after a multidisciplinary team meeting involving both the oncology and cardio-oncology teams. This is the second described case of entrectinib-induced myocarditis and the first one without eosinophilia.

Cardiac computed tomography in cardio-oncology: an update on recent clinical applications.

Chemotherapy and radiotherapy have drastically improved cancer survival, but they can result in significant short- and long-term cardiovascular complications, most commonly heart failure from chemotherapy, whilst radiotherapy increases the risk of premature coronary artery disease (CAD), valve, and pericardial diseases. Cardiac computed tomography (CT) with calcium scoring has a role in screening asymptomatic patients for premature CAD, cardiac CT angiography (CTCA) allows the identification of significant CAD, also in the acute settings where concerns exist towards invasive angiography. CTCA integrates the diagnostic work-up and guides surgical/percutaneous management of valvular heart diseases and allows the assessment of pericardial conditions, including detection of effusion and pericardial calcification. It is a widely available and fast imaging modality that allows a one-step evaluation of CAD, myocardial, valvular, and pericardial disease. This review aims to provide an update on its current use and accompanying evidence-base for cardiac CT in the management of cardio-oncology patients.

Cardiovascular Disease Amongst Women Treated for Breast Cancer: Traditional Cytotoxic Chemotherapy, Targeted Therapy, and Radiation Therapy.

PURPOSE OF REVIEW: Cardiotoxicity can occur acutely during breast cancer treatment and impact the potential for the intended cancer treatment regime to be completed, or as a late effect affecting cancer survivorship. Indeed, the most common cause of mortality in females with early breast cancer is cardiovascular disease, especially in those over the age of 65. Optimal cancer care therefore needs to be delivered without jeopardising cardiovascular health. Understanding the different cardiotoxicities associated with breast cancer treatment is vital to this approach, and therefore, this article seeks to provide an overview of this. RECENT FINDINGS: Tyrosine kinase inhibitors targeting human epidermal growth factor receptor (HER)-2, immune checkpoint inhibitors (ICI), and cyclin-dependent kinase (CDK) inhibitors are new targeted breast cancer treatments. In particular, ICI are associated with myocarditis that carries a significant mortality, whilst the CDK inhibitor ribociclib causes QT prolongation that requires cardiac surveillance and appropriate dose adjustment to prevent ventricular arrhythmias. The need has always been for strategies to mitigate the risks of cardiovascular toxicities, and new data is promising for the use of dexrazoxane in anthracyclines, and the role of beta blockers and angiotensin converting enzymes inhibitors in anthracyclines and HER-2 monoclonal antibodies such as trastuzumab. Significant headways in breast cancer treatment have resulted in reductions in disease recurrence and mortality, but cardiovascular complications continue to impact the ability to deliver some of these cancer treatments, and the period of cancer survivorship.

A Multimetric Health Literacy Analysis of Autologous Versus Implant-Based Breast Reconstruction.

BACKGROUND: Over the past decade, the demand for breast reconstruction has mirrored the rising incidence of breast cancer. Common postoncologic surgical options include autologous and implant-based reconstruction. Patient-directed health information for breast reconstruction can play a critical role in the decision-making process. This study comparatively evaluates the top online resources for autologous versus implant-based reconstruction using a multimetric health literacy analysis. METHODS: The top 10 websites for autologous and implant-based reconstruction were identified using a Google search. A total of 20 unique links were appraised by 2 independent raters for understandability and actionability using the Patient Education Materials Assessment Tool and cultural sensitivity using the Cultural Sensitivity Assessment Tool. A Cohen κ for interrater reliability was calculated. Mean reading grade level and word complexity were also determined. RESULTS: Websites for both autologous and implant-based modalities exceeded the recommended sixth- to eighth-grade reading level (12.4 and 12.1, respectively; P = 0.65). Mean understandability scores for each modality were low (60.5 and 62.5, P = 0.65). Autologous-based resources had a lower mean actionability score compared with implant-based materials (19.5 and 24, respectively; P = 0.04). Both reconstructive modalities met the threshold for acceptability for cultural sensitivity (2.79 and 2.58, P = 0.09). CONCLUSIONS: Our study revealed a chasm between the health literacy needs of the average adult and the quality of both implant-based and autologous breast reconstruction resources. Materials for both modalities were often too complex and failed to include tools to facilitate active decision making, particularly for autologous-based reconstruction. Strategies to improve materials should be patient centered and include simplification of reading grade level, incorporation of clear visual aids, and inclusion of procedural risks to promote patient comprehension, participation, and ultimately health outcomes.

CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?

CD19-specific chimeric antigen receptor (CAR) T cell therapies have shown remarkable early success in highly refractory and relapsing hematological malignancies. However, this potent therapy is accompanied by significant toxicity. Cytokine release syndrome and neurotoxicity are the most widely reported, but the true extent and characteristics of cardiovascular toxicity remain poorly understood. Thus far, adverse cardiovascular effects observed include sinus tachycardia and other arrhythmias, left ventricular systolic dysfunction, profound hypotension, and shock requiring inotropic support. The literature regarding cardiovascular toxicities remains sparse; prospective studies are needed to define the cardiac safety of CAR T cell therapies to optimally harness their potential. This review summarizes the current understanding of the potential cardiovascular toxicities of CD19-specific CAR T cell therapies, outlines a proposed cardiac surveillance protocol for patients receiving this new treatment, and provides a roadmap of the future direction of cardio-oncology research in this area.

Anterior Column Realignment in Adult Spinal Deformity: A Case Report and Review of the Literature.

OBJECTIVE: Anterior column realignment (ACR) is a new emerging minimally invasive surgical technique for adult spinal deformity (ASD) that has the potential to provide similar corrective ability to traditional posterior approaches. This article reviews the current literature on the clinical efficacy and safety of ACR and illustrates an additional use of this technique in a case of sagittal imbalance after posterior spinal fusion with segmental instrumentation. METHODS: We performed a literature search of all published ACR reports using PubMed, including only clinical studies describing the ACR technique and reporting radiographic and/or clinical outcomes. RESULTS: Thirteen studies were included. Improvement in lumbar lordosis after ACR ranged from 12.7° to 39°, and increases in focal segmental lordosis at each ACR level ranged from 1° to 34°. Good clinical and functional outcomes have consistently been reported after ACR. The complication rate has been comparable to or lower than traditional posterior-based techniques. We also illustrate the use of ACR in a patient with sagittal imbalance after a prior posterior instrumented spinal fusion. ACR in combination with a posterior osteotomy allowed for the induction of lordosis by cantilevering of rods and compression of pedicle screws. CONCLUSIONS: Radiographic and clinical outcomes after ACR have been promising so far. In addition to primary ASD surgery, ACR can also be effectively used in cases with prior posterior instrumented spinal fusion to correct sagittal imbalance.

Characterization of the incipient smoke point for steam-/air-assisted and nonassisted flares.

Flares are important safety devices for pressure relief; at the same time, flares are a significant point source for soot and highly reactive volatile organic compounds (HRVOCs). Currently, simple guidelines for flare operations to maintain high combustion efficiency (CE) remain elusive. This paper fills the gap by investigating the characteristics of the incipient smoke point (ISP), which is widely recognized as the condition for good combustion. This study characterizes the ISP in terms of 100-% combustion inefficiency (CE), percent opacity, absorbance, air assist, steam assist, air equivalence ratio, steam equivalence ratio, exit velocity, vent gas net heating value, and combustion zone net heating value. Flame lengths were calculated for buoyant and momentum-dominated plumes under calm and windy conditions at stable and neutral atmosphere. Opacity was calculated using the Beer-Lambert law based on soot concentration, flame diameter, and mass-specific extinction cross section of soot. The calculated opacity and absorbance were found to be lognormally distributed. Linear relations were established for soot yield versus absorptivity with R2 > 0.99 and power-law relations for opacity versus soot emission rate with R2 ≥ 0.97 for steam-assisted, air-assisted, and nonassisted flares. The characterized steam/air assists, combustion zone/vent gas heating values, exit velocity, steam, and air equivalence ratios for the incipient smoke point will serve as a useful guideline for efficient flare operations.Implications: A Recent EPA rule requires an evaluation of visible emissions in terms of opacity in compliance with the standards. In this paper, visible emissions such as soot particles are characterized in terms of opacity at ISP. Since ISP is widely recognized as most efficient flare operation for high combustion efficiency (CE)/destruction efficiency (DE) with initial soot particles formed in the flame, this characterization provides a useful guideline for flare operators in the refinery, oil and gas, and chemical industries to sustain smokeless and high combustion efficiency flaring in compliance with recent EPA regulations, in addition to protecting the environment.

Modeling and Preventing Progressive Hearing Loss in Usher Syndrome III.

Usher syndrome type III (USH3) characterized by progressive loss of vision and hearing is caused by mutations in the clarin-1 gene (CLRN1). Clrn1 knockout (KO) mice develop hair cell defects by postnatal day 2 (P2) and are deaf by P21-P25. Early onset profound hearing loss in KO mice and lack of information about the cochlear cell type that requires Clrn1 expression pose challenges to therapeutic investigation. We generated KO mice harboring a transgene, TgAC1, consisting of Clrn1-UTR (Clrn1 cDNA including its 5' and 3' UTR) under the control of regulatory elements (Atoh1 3' enhancer/ß-globin basal promoter) to direct expression of Clrn1 in hair cells during development and down regulate it postnatally. The KO-TgAC1 mice displayed delayed onset progressive hearing loss associated with deterioration of the hair bundle structure, leading to the hypothesis that hair cell expression of Clrn1 is essential for postnatal preservation of hair cell structure and hearing. Consistent with that hypothesis, perinatal transfection of hair cells in KO-TgAC1 mice with a single injection of AAV-Clrn1-UTR vector showed correlative preservation of the hair bundle structure and hearing through adult life. Further, the efficacy of AAV-Clrn1 vector was significantly attenuated, revealing the potential importance of UTR in gene therapy.

Reduced combustion mechanism for C1-C4 hydrocarbons and its application in computational fluid dynamics flare modeling.

Emissions from flares constitute unburned hydrocarbons, carbon monoxide (CO), soot, and other partially burned and altered hydrocarbons along with carbon dioxide (CO2) and water. Soot or visible smoke is of particular concern for flare operators/regulatory agencies. The goal of the study is to develop a computational fluid dynamics (CFD) model capable of predicting flare combustion efficiency (CE) and soot emission. Since detailed combustion mechanisms are too complicated for (CFD) application, a 50-species reduced mechanism, LU 3.0.1, was developed. LU 3.0.1 is capable of handling C4 hydrocarbons and soot precursor species (C2H2, C2H4, C6H6). The new reduced mechanism LU 3.0.1 was first validated against experimental performance indicators: laminar flame speed, adiabatic flame temperature, and ignition delay. Further, CFD simulations using LU 3.0.1 were run to predict soot emission and CE of air-assisted flare tests conducted in 2010 in Tulsa, Oklahoma, using ANSYS Fluent software. Results of non-premixed probability density function (PDF) model and eddy dissipation concept (EDC) model are discussed. It is also noteworthy that when used in conjunction with the EDC turbulence-chemistry model, LU 3.0.1 can reasonably predict volatile organic compound (VOC) emissions as well. IMPLICATIONS: A reduced combustion mechanism containing 50 C1-C4 species and soot precursors has been developed and validated against experimental data. The combustion mechanism is then employed in the computational fluid dynamics (CFD) of modeling of soot emission and combustion efficiency (CE) of controlled flares for which experimental soot and CE data are available. The validated CFD modeling tools are useful for oil, gas, and chemical industries to comply with U.S. Environmental Protection Agency's (EPA) mandate to achieve smokeless flaring with a high CE.

A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.

Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.

Zebrafish Models for the Mechanosensory Hair Cell Dysfunction in Usher Syndrome 3 Reveal That Clarin-1 Is an Essential Hair Bundle Protein.

Usher syndrome type III (USH3) is characterized by progressive loss of hearing and vision, and varying degrees of vestibular dysfunction. It is caused by mutations that affect the human clarin-1 protein (hCLRN1), a member of the tetraspanin protein family. The missense mutation CLRN1(N48K), which affects a conserved N-glycosylation site in hCLRN1, is a common causative USH3 mutation among Ashkenazi Jews. The affected individuals hear at birth but lose that function over time. Here, we developed an animal model system using zebrafish transgenesis and gene targeting to provide an explanation for this phenotype. Immunolabeling demonstrated that Clrn1 localized to the hair cell bundles (hair bundles). The clrn1 mutants generated by zinc finger nucleases displayed aberrant hair bundle morphology with diminished function. Two transgenic zebrafish that express either hCLRN1 or hCLRN1(N48K) in hair cells were produced to examine the subcellular localization patterns of wild-type and mutant human proteins. hCLRN1 localized to the hair bundles similarly to zebrafish Clrn1; in contrast, hCLRN1(N48K) largely mislocalized to the cell body with a small amount reaching the hair bundle. We propose that this small amount of hCLRN1(N48K) in the hair bundle provides clarin-1-mediated function during the early stages of life; however, the presence of hCLRN1(N48K) in the hair bundle diminishes over time because of intracellular degradation of the mutant protein, leading to progressive loss of hair bundle integrity and hair cell function. These findings and genetic tools provide an understanding and path forward to identify therapies to mitigate hearing loss linked to the CLRN1 mutation. SIGNIFICANCE STATEMENT: Mutations in the clarin-1 gene affect eye and ear function in humans. Individuals with the CLRN1(N48K) mutation are born able to hear but lose that function over time. Here, we develop an animal model system using zebrafish transgenesis and gene targeting to provide an explanation for this phenotype. This approach illuminates the role of clarin-1 and the molecular mechanism linked to the CLRN1(N48K) mutation in sensory hair cells of the inner ear. Additionally, the investigation provided an in vivo model to guide future drug discovery to rescue the hCLRN1(N48K) in hair cells.

Cardiologist operated ultrasound guided thrombin injection as a safe and efficacious first line treatment for iatrogenic femoral artery pseudoaneurysms.

OBJECTIVES: To assess the efficacy and safety of ultrasound guided thrombin injection (UGTI) as a first line treatment for post arterial cannulation iatrogenic femoral artery pseudoaneurysms (IFAP). BACKGROUND: IFAPs complicate up to 1% of diagnostic and 8% of interventional cardiac catheterisation procedures. UGTI remains a second line or non-attempted treatment after ultrasound guided manual compression (UGMC) and surgical repair in many centres. METHODS: A retrospective review was undertaken of 121 consecutive patients who received UGTI as a first line treatment for IFAPs following cardiac diagnostic, interventional or catheter ablation procedures between 1999 and 2011 at our centre. The mean patient age was 70.7 years and 63% were male. At the time of injection, 89% were on at least one antiplatelet or anticoagulant. Pseudoaneurysms had a mean maximum dimension of 26.7mm (range 10-122mm) and 25% were multilobed. UGTI was performed by an interventional cardiologist with a mean bovine thrombin dose of 648 IU (range 50-5000 IU). RESULTS: Primary success, defined as immediate IFAP thrombosis with UGTI, was achieved in 111 (92%) patients. Recurrence occurred in seven patients, three of whom required surgical repair. Multilobed IFAPs had significantly lower primary success rates than unilobed IFAPs (80% vs. 96%, p=0.016). Antiplatelet and anticoagulant use and IFAP size did not significantly affect outcomes. UGTI was not associated with any serious complications (such as thromboembolism, aneurysm rupture, venous thrombosis or abscess formation). CONCLUSION: Interventional cardiologist operated UGTI should be considered as a first line therapy for uncomplicated IFAPs following interventional and diagnostic cardiac procedures. Despite high rates of concomitant antiplatelet and antithrombotic therapy, initial thrombosis rates exceeded 90% and we did not experience serious complications.

Computational fluid dynamics modeling of laboratory flames and an industrial flare.

A computational fluid dynamics (CFD) methodology for simulating the combustion process has been validated with experimental results. Three different types of experimental setups were used to validate the CFD model. These setups include an industrial-scale flare setups and two lab-scale flames. The CFD study also involved three different fuels: C3H6/CH/Air/N2, C2H4/O2/Ar and CH4/Air. In the first setup, flare efficiency data from the Texas Commission on Environmental Quality (TCEQ) 2010 field tests were used to validate the CFD model. In the second setup, a McKenna burner with flat flames was simulated. Temperature and mass fractions of important species were compared with the experimental data. Finally, results of an experimental study done at Sandia National Laboratories to generate a lifted jet flame were used for the purpose of validation. The reduced 50 species mechanism, LU 1.1, the realizable k-epsilon turbulence model, and the EDC turbulence-chemistry interaction model were usedfor this work. Flare efficiency, axial profiles of temperature, and mass fractions of various intermediate species obtained in the simulation were compared with experimental data and a good agreement between the profiles was clearly observed. In particular the simulation match with the TCEQ 2010 flare tests has been significantly improved (within 5% of the data) compared to the results reported by Singh et al. in 2012. Validation of the speciated flat flame data supports the view that flares can be a primary source offormaldehyde emission.

Noise exposure immediately activates cochlear mitogen-activated protein kinase signaling.

Noise-induced hearing loss (NIHL) is a major public health issue worldwide. Uncovering the early molecular events associated with NIHL would reveal mechanisms leading to the hearing loss. Our aim is to investigate the immediate molecular responses after different levels of noise exposure and identify the common and distinct pathways that mediate NIHL. Previous work showed mice exposed to 116 decibels sound pressure level (dB SPL) broadband noise for 1 h had greater threshold shifts than the mice exposed to 110 dB SPL broadband noise, hence we used these two noise levels in this study. Groups of 4-8-week-old CBA/CaJ mice were exposed to no noise (control) or to broadband noise for 1 h, followed by transcriptome analysis of total cochlear RNA isolated immediately after noise exposure. Previously identified and novel genes were found in all data sets. Following exposure to noise at 116 dB SPL, the earliest responses included up-regulation of 243 genes and down-regulation of 61 genes, while a similar exposure at 110 dB SPL up-regulated 155 genes and down-regulated 221 genes. Bioinformatics analysis indicated that mitogen-activated protein kinase (MAPK) signaling was the major pathway in both levels of noise exposure. Nevertheless, both qualitative and quantitative differences were noticed in some MAPK signaling genes, after exposure to different noise levels. Cacna1b , Cacna1g , and Pla2g6 , related to calcium signaling were down-regulated after 110 dB SPL exposure, while the fold increase in the expression of Fos was relatively lower than what was observed after 116 dB SPL exposure. These subtle variations provide insight on the factors that may contribute to the differences in NIHL despite the activation of a common pathway.

Conformational problem of alkanes in liquid crystals by NMR spectroscopy: a mini-review.

Recent discoveries of the role of alkane flexibility in determining liquid-crystal behaviour are surveyed. With the impetus for understanding the alkane conformational problem established, recent model dependent (1)H NMR work on the topic will be reviewed where progress is made but the need to circumvent models eventually becomes evident. A closer look at the rigid basic units of alkanes will provide the way forward where it is shown that the orientational ordering and anisotropic potentials of these molecules dissolved in liquid crystals scale with each other. Once this relationship is established, a series of works using anisotropic and isotropic (1)H NMR spectroscopy to study alkane conformational statistics will be covered, wherein the influence of the gas, isotropic condensed and anisotropic condensed phases will be described.

Noddy, a mouse harboring a missense mutation in protocadherin-15, reveals the impact of disrupting a critical interaction site between tip-link cadherins in inner ear hair cells.

In hair cells of the inner ear, sound or head movement increases tension in fine filaments termed tip links, which in turn convey force to mechanosensitive ion channels to open them. Tip links are formed by a tetramer of two cadherin proteins: protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which have 11 and 27 extracellular cadherin (EC) repeats, respectively. Mutations in either protein cause inner ear disorders in mice and humans. We showed recently that these two cadherins bind tip-to-tip in a "handshake" mode that involves the EC1 and EC2 repeats of both proteins. However, a paucity of appropriate animal models has slowed our understanding both of the interaction and of how mutations of residues within the predicted interface compromise tip link integrity. Here, we present noddy, a new mouse model for hereditary deafness. Identified in a forward genetic screen, noddy homozygotes lack inner ear function. Mapping and sequencing showed that noddy mutant mice harbor an isoleucine-to-asparagine (I108N) mutation in the EC1 repeat of PCDH15. Residue I108 interacts with CDH23 EC2 in the handshake and its mutation impairs the interaction in vitro. The noddy mutation allowed us to determine the consequences of blocking the handshake in vivo: tip link formation and bundle morphology are disrupted, and mechanotransduction channels fail to remain open at rest. These results offer new insights into the interaction between PCDH15 and CDH23 and help explain the etiology of human deafness linked to mutations in the tip-link interface.